MX2008005940A - Immunomodulatory properties of multipotent adult progenitor cells and uses thereof - Google Patents

Abstract

Isolated cells are described that are not embryonic stem cells, not embryonic germ cells, and not germ cells. The cells can differentiate into at least one cell type of each of at least two of the endodermal, ectodermal, and mesodermal lineages. The cells do not provoke a harmful immune response. The cells can modulate immune responses. As an example, the cells can suppress an immune response in a host engendered by allogeneic cells, tissues, and organs. Methods are described for using the cells, by themselves or adjunctively, to treat subjects. For instance, the cells can be used adjunctively for immunosuppression in transplant therapy. Methods for obtaining the cells and compositions for using them also are described.

Description

PROPERTIES I MU OMODULATORS OF CELLS PROGENITURAS ADULT MUL IPOTENTES AND ITS USES FIELD OF THE INVENTION The field of the invention is immunomodulation by multipotent adult progenitor cells ("MAPCs" for its acronym in English) and its use for the modulation of immune responses in primary and additive therapies. BACKGROUND OF THE INVENTION The therapeutic use of organ transplants, including bone marrow transplants, has increased gradually since its inception. It has become an important therapeutic option for a number of diseases, including, but not limited to, hematological, immunological, and malignant disorders. Unfortunately, therapeutic uses are often complicated, become inefficient, or are avoided by the adverse immune responses generated by the transplant. Among the most prominent adverse reactions encountered as a result of transplant therapies are: (i) graft-versus-host response ("HVG") (transplant rejection by an immunocompetent host animal), and (ii) ) graft-versus-host disease ("GVHD") (processes that occur primarily in an immunocompromised host animal when it is recognized as not Ref.: 192702 own by the immunecompetent cells of a graft). The rejection of graft in a host animal can be avoided, of course, by the perfect correspondence between the donor and the host animal. Except for autologous tissue, however, only identical twins could be expected to be truly syngeneic. The perfect correspondences between the individual donor and another individual host / recipient animal are virtually non-existent. Thus, the use of autologous tissue is the only other way to make a perfect correspondence. Unfortunately, the tissue of the host animal is typically not suitable or isolated prior to need. Frequently, the need for a transplant therapy, in effect, is to replace the damaged tissue in the host animal. The use of syngeneic tissue, therefore, although it is an effective solution to the problems of the host animal's adverse response to graft tissue, is generally not useful in practical applications. If syngeneic correspondence is not possible, the adverse immune effects that arise in transplant therapies can be mitigated by the correspondence of an allogeneic donor and the host animal as closely as possible. The typing of the blood and / or the tissue is used to match the donors and the host animals to provide more probability elevated therapeutic success. Even closer correspondence of the allogeneic tissue, however, will not prevent serious HGV, and, consequently, transplantation therapies involve the use of immunosuppression and immunosuppressive drugs, as described below. Another method to avoid the complications of HVG in transplant therapies has been to disable the immune system of the receiving host animal. This has been effected by the use of radiation therapy, and / or by immunosuppressive chemotherapy, and / or by antibody therapy. The resulting suppression of the host animal's immune responses often very effectively aids the establishment of the graft (such as bone marrow) in the host animal. However, immunoablation or suppression compromises the immune defenses of the host animal. This leads to the host animal also becoming fully susceptible to infections after even less exposure to infectious agents. The resulting infections are a leading cause of morbidity and mortality among patients with transplants. When the immune system of the host animal is compromised, another serious problem encountered in transplant therapy - graft-versus-host disease ("GVHD") is also engendered or aggravated. GVHD occurs when the donor tissue contains cells immunocompetent proteins that recognize the MHC proteins of the receptor as not own. This activates the T cells, and they secrete cytokines, such as IL-2 (interleukin 2), IFN? (interferon gamma) and TNFa (tumor necrosis factor alpha). These signals trigger an immune attack on the recipient's targets including the skin, the Gl tract, the liver, and the lymphoid organs (Ferrara and Deeg, 1991). GVHD is particularly a problem in bone marrow transplants, where it has been shown that it will be mediated mainly by T lymphocytes (Grebe and Streilein, 1976). In effect, approximately 50% of patients with bone marrow transplantation develop acute GVHD. Many of the patients die (from 15% to 45%). There are also other dysfunctions, disorders, and diseases of the immune system that arise as major pathologies and as side effects of other pathologies and / or treatments thereof. These include neoplasms, bone marrow pathologies, blood pathologies, autoimmune disorders, and some inflammatory disorders, as described further below. The primary and additive therapy for these disorders and diseases, similar to the primary and additive therapies for HVG and GVHD, frequently involve the use of immunosuppressive drugs. All common therapies have disadvantages and side effects.

Immunosuppressive Drugs A good amount of effort has been directed to the development of drugs to treat these dysfunctions of the immune system to improve or eliminate their detrimental effects, without causing additional harmful side effects. There has been some progress toward this goal, and a number of drugs have been developed and are in use to prevent and / or treat these dysfunctions. The introduction of the most effective of these commercialized drugs has been a breakthrough in the medical practice of transplant therapies; but, none has been ideal. Actually, none of the immunosuppressive drugs currently available for clinical use in transplant therapies is completely effective. All of the drugs have serious disadvantages and harmful side effects, as summarized briefly below. For a review see Farag (2004), "Chronic graft-versus-host disease: where do we go from here?" Bone Marrow Transplantation 33: 569-577. Corticosteroids, which are used primarily to treat inflammation and inflammatory diseases, are already known to be immunosuppressive and are considered by many to be the best primary treatment for HVG and GVHD. They inhibit the proliferation of T cells and immune responses dependent on the T cell, at least in part, by the inhibition of expression of certain cytosine genes involved in T cell activation and the T cell-dependent immune response. Cyclosporin is among the most frequently used drugs for immune suppression and the prevention of HVG and GVHD. It is strongly immunosuppressive in general. Although it may be effective in reducing immune reactions in transplant patients, it also weakens the immune system so that many patients are left highly vulnerable to infections. Consequently, patients are much more easily infected by exposure to pathogens, and have a small capacity for mounting an effective immune response to infections. Even pathogens that are not so dangerous can then be life-threatening. Cyclosporine also causes a variety of undesirable side effects. Methotrexate is also widely used in the prophylaxis and treatment of HVG and GVHD, by itself, or in combination with other drugs. Studies have shown that, if it is fully effective, it is also apparently less effective than cyclosporine. As with cyclosporine, methotrexate causes a variety of side effects, some of which can be detrimental to the patient's health. FK-506 is a compound similar to a macrolide. From Similar to cyclosporine, it is derived from fungal sources. The immunosuppressive effects of ciclosporin and FK-506 are similar. They block the initial events of T cell activation by the formation of a heterodimeric complex with its respective cytoplasmic receptor proteins (ie, cyclophilin and agglutination protein to FK). This then inhibits the activity of calcineurin phosphatase, whereby it ultimately inhibits the expression of nuclear regulatory proteins and T cell activation genes. Other drugs that have been used for immunosuppression include antithymocyte globulin, azathioprine, and cyclophosphamide. They have not proven that they will be advantageous. Rapamycin, another macrolide-like compound that interferes with the response of T cells to IL-2, has also been used to block the immune response activated by the T cell. RS-61443, a mycophenolic acid derivative, has been found that inhibits the rejection of the allograft in experimental animals. Mizoribine, an imizadol nucleoside, blocks the purine biosynthetic pathway and inhibits the proliferation of T and B cells stimulated by the mitogen in a manner similar to azathioprine and RS-61443. Deoxypergualin, a synthetic analogue of spergualin, has been found to exert immunosuppressive properties in pre-transplant models. clinical The brequinar sodium of the anti-metabolite is an inhibitor of the dihydro-orotate dehydrogenase and blocks the formation of the nucleotides of uridine and cytidine by inhibiting the synthesis of pyrimidine. Berberine and its pharmacologically tolerable salts have been used as an immunosuppressant for the treatment of autoimmune diseases such as rheumatism, for the treatment of allergies, and to prevent rejection of the graft. It has been reported that berberine inhibits the production of the B cell antibody and generally suppresses the humoral immune response, but does not affect the spread of T cells. See Japanese Patent 07-316051 and US Patent No. 6,245,781. None of these immunosuppressive drugs, whether used alone or in combination with other agents, are fully effective. All of them generally leave patients still susceptible to HVG and GVHD and weaken their ability to defend against infection. This makes them much more susceptible to infection and much less able to fight against infections when they occur. In addition, all of these drugs cause serious side effects, including, for example, gastrointestinal toxicity, nephrotoxicity, hypertension, myelosuppression, hepatotoxicity, hypertension, and hypertrophy of the gums, among others. None of them has proven that it will be a totally acceptable or effective treatment. In summary, given these disadvantages, in the present there is no treatment based on a pharmaceutical substance, totally satisfactory, for dysfunctions and / or adverse responses of the immune system, such as HVG and GVHD. It has long been thought that a more specific type of immune suppression could be developed without these disadvantages. For example, an agent that suppressed or eliminated alloreactive T cells, specifically, could be effective against HVG and GVHD (at least for allogeneic grafts) without harmful side effects that occur with agents that attack globally and compromise the immune system. However, until now, none of such agent (s) has been developed. Use of restricted stem cells in transplantation The use of stem cells instead of or together with immunosuppressive agents has recently attracted interest. There have been some stimulating observations in this area. A variety of stem cells have been isolated and characterized in recent years. They vary from those of a highly restricted differentiation potential and limited capacity to grow in a crop to those with a seemingly unrestricted differentiation potential and an unlimited capacity to grow in the crop. The former have generally been the easiest to derive and can be obtained from a variety of tissues of adults. The latter have had to be derived from germ cells and embryos, and are called embryonic stem cells ("ES"), embryonic germ cells ("EG"), and germ cells. The embryonic stem cell ("ES") has unlimited self-renewal and can be differentiated in all types of tissue. The ES cells are derived from the mass of the inner cell of the blastocyst. Embryonic germ cells ("EG") are derived from the primordial germ cells of a post-implant embryo. Stem cells derived from the tissues of adults have been of limited value because they are immunogenic, have a limited differentiation potential, and have a limited capacity for propagation in culture. The ES, EG and germinal cells do not suffer from these disadvantages, but they have a marked propensity to form teratomas in the allogenic host animals, which arise due to the interest towards their use in medical treatments. For this reason, there is a pessimism about its utility in clinical applications, despite its advantageously broad differentiation potential. Stem cells derived from embryos are also subject to ethical controversies that could prevent their use in the treatment of the disease. Some efforts find an alternative to the ES, EG, and germinal cells that have focused on the cells derived from adult tissue. Although adult stem cells have been identified in most tissues of mammals, their potential for differentiation is restricted and is considerably narrower than that of ES, EG, and germ cells. Actually, many such cells can arise only for one or a small number of differentiated cell types, and many others are restricted to a single embryonic lineage. For example, hematopoietic stem cells can be differentiated only to form cells of the hematopoietic lineage, neural stem cells differentiate into cells of neuroectodermal origin only, and mesenchymal stem cells ("MSCs") are limited to cells of mesenchymal origin. For the reasons mentioned above that refer to the limitations, risks and controversies of, and which refer to ES, EG and germinal cells, a substantial portion of work on the use of stem cells in transplant therapies has been used MSCs. The results of few in recent years seem to show that allografts from MSCs do not generate an immune reaction to HVG, which is a response invariably observed when other tissue is transplanted among allogenic individuals. However, the results suggest that MSCs weaken the immune response of lymphocytes, at least in some circumstances.

Although these results suggest immediately that MSCs could be useful for reducing HVG and / or GVHD that could ordinarily accompany allogeneic transplantation, the observed immunosuppressive effects of MSCs were highly dose-dependent, and relatively high doses were required to observe an effect immunosuppressant. Indeed, the reduced proliferation of the lymphocytes in the mixed lymphocyte assays in vi tro was "marked" only at or above a 1:10 ratio of MSCs to the lymphocytes. In addition, the observed inhibitory effect was reduced and became non-observable when the dose of MSCs was reduced, and at the proportions below 1: 100 the presence of the MSCs actually seemed to stimulate the proliferation of T cells. The same effects of The doses were also observed in proliferation assays of lymphocytes stimulated by mitogens. See, for a review, Ryan et al. (2005) "Mesenchymal stem cells avoid allogeneic rejection," J. Inflammation 2: 8; Le Blanc (2003) "Immunomodulatory effects of fetal and adult mesenchymal stem cells", Cytotherapy 5 (6): 485-489, and Jorgensen et al (2003) "Engineering mesenchymal stem cell for immunotherapy", Gene Therapy 10: 928-931 . The additional results are summarized later. For example, Bartholomew and coworkers found that baboon MSCs do not stimulate allogeneic lymphocytes to proliferate in vi tro and that MSCs reduce the proliferation of lymphocytes stimulated by mitogens by more than 50% in mixed lymphocyte assays in vi tro. They further showed that administration of MSCs in vivo prolonged skin graft survival (relative to controls). Both the in vi tro results and the in vivo results required a high dose of MSCs: in a 1: 1 ratio with the lymphocytes for in vi tro results. The amount of MSCs that could be required to approach such an in vivo ratio in humans may be too high to be achieved, as a practical matter. This may limit the usefulness of the MSCs. See Bartholomew et al. (2002): "Mesenchymal stem cells suppress lymphocyte proliferation in vi tro and prolonged skin graft survival in vivo", Experimental Hematology 30: 42-48. Maitra et al. Examined the effect of human MSCs on the grafting of allogeneic human umbilical cord blood cells after co-infusion in subletically irradiated NOD-SCID mice. They found that human MSCs promoted grafts and did not activate allogeneic T cells in in vitro proliferation assays. They also found that human MSCs suppressed the activation in vitro of human allogeneic T cells by mitogens. The effects were dose dependent and proportions were required relatively high for suppression. (Maitra et al. (2004) Bone Marrow Transplantation 33: 597-604). Recently, Le Blanc and colleagues reported the successful treatment of a patient with an acute grade IV GVHD, which is usually fatal, by the administration of a "haploidentical third party" of MSCs. The patient was a 9-year-old boy with acute lymphoblastic leukemia, who was in his third remission. Initially, the patient was treated with radiation and cyclophosphamide, and then blood cells were provided that were identical to their own cells at the HLA-A, HLA-B, and HLA-DRbetal sites. These have been obtained from an unrelated female donor. Despite aggressive treatment, including dosing with a variety of immunosuppressants, for 70 days after transplantation, the patient developed grade IV acute GVHD. He was frequently afflicted by bacterial, fungal and viral invasive infections. Under these clearly terrible conditions, the alternative of a blood stem cell transplant was attempted. The haploidentical MSCs were isolated from the patient's mother and expanded in vi tro for three weeks. The cells were collected and 2 x 106 cells per kilogram were administered intravenously to the patient. There were no signs of toxicity associated with the MSCs, nor were there substantial side effects. Many symptoms they resolved within a few days after the transplant; but, a residual disease was apparent. After several additional intravenous injections of MSCs using the same methods, the patient's symptoms and GVHD were completely resolved. The patient was still free of the disease one year after discharge. According to the authors, in his experience, this patient is unique in surviving the GVHD of this severity. The results reported by Le Blanc et al., Are both promising and inspiring, and should be a stimulus to develop effective therapies that use stem cells. Le Blanc et al. (2004) "Treatment for severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells", Lancet 363: 1439-41. However, these results, including those of Le Blanc et al. Reveal potential disadvantages of MSCs. The cells need to be administered with traditional immunosuppressive modalities that will then continue to generate damaging immune responses. The dosage requirements for MSCs will apparently need to be very high to be effective, which could incur in increasing cost, in greater administration difficulty, in a greater risk of toxicity and other harmful side effects, and other disadvantages.

In view of these limitations, of the therapies related to the transplantation based on common stem cells, there is clearly a strong need for progenitor cells that can be used for all or at most the majority of recipient host animals without need. a correspondence of the host-recipient haplotype. In addition, there is a need for cells of a larger "specific activity" so that they are therapeutically effective at lower doses and their administration does not raise the problems associated with the dosage regimens required for beneficial results using MSCs. And, there is a need for cells that have an essentially unlimited differentiation potential to form the cells that are present in the organism of interest. Consequently, there has been a need for cells that have the capacity for self-renewal and differentiation of ES, EG, and germ cells, but which are not immunogenic; that they do not form teratomas when they are allografted or xenografted to a host animal; that they do not raise other safety issues associated with ES, EG, and germinal cells; that retain the other advantages of ES, EG, and germ cells; that are easy to isolate from easily available sources, such as the placenta, the umbilical cord, the umbilical cord blood, and the bone marrow; that can be safely stored for long periods; that can be obtained easily and without risk for volunteers, donors or patients, and that others provide consent; and that they do not involve the technical and logistical difficulties involved in obtaining and working with ES, EG, and germ cells. Recently, a cell type, here called multipotent adult progenitor cells ("MAPCs"), have been isolated and characterized (see, for example, US Patent No. 7,015,037, which is incorporated herein by reference in its entirety). ("MAPCs" are also referred to as "MASCs"). These cells provide many of the advantages of ES, EG, and germ cells without many of their disadvantages. For example, MAPCs are capable of indefinite cultivation without losing their differentiation potential. They show a long-term, efficient graft and differentiation, along the lineages of multiple development in the NOD-SCID mice and without showing evidence of teratoma formation (frequently observed with the ES, EG, and germinal) (Reyes, M. and CM Verfaillie (2001) Ann NY Acad Sci 938: 321-5). BRIEF DESCRIPTION OF THE INVENTION In some of its embodiments, therefore, the invention provides cells that: (i) are non-stem cells embryonic, non-embryonic germ cells, and non-germ cells; (ii) can be differentiated into at least one cell type from each of at least two of the endodermal, ectodermal, and mesodermal embryonic lineages; (iii) do not cause a deleterious immune response during introduction to a non-syngeneic subject; and (iv) can modulate an immune response during introduction into a subject. In certain embodiments in this regard, the invention provides cells which, in addition to the foregoing, are immunosuppressive. In addition, various embodiments of the invention provide cells according to the above having immunomodulatory properties that are useful for treatment, such as to prevent, prevent, improve, reduce, mitigate, minimize, eliminate, and / or cure the responses and / or damaging immune processes in a host animal. In some embodiments of the invention the cells are used in this regard alone or together with other therapeutic agents and in modalities such as primary therapeutic modalities. In some embodiments of the invention, the cells are used in an additive therapeutic modality in which they can be used either as the sole therapeutic agent or together with other therapeutic agents. In some embodiments of the invention, the cells are used, alone or with other agents or therapeutic modalities, either in one or more primary therapeutic modalities or in one or more additive therapeutic modalities. The cells according to the invention are described in greater detail here and are generally referred to herein as "multipotent adult progenitor cells" and by the acronyms "MAPC" (singular) and "MAPCs" (plural). It will be appreciated that these cells are not ES cells, nor EG cells, nor germ cells, and that they have the ability to differentiate into cell types from at least two of the three primitive germ layer lineages ( ectoderm, mesoderm, and endoderm), for example, in cells of all three primitive lineages. For example, MAPCs can form the following cells and other cells of the lineages thereof: splanchnic mesodermal cells, muscle cells, bone cells, cartilage cells, endocrine cells, exocrine cells, endothelial cells, forming cells of hair, teeth-forming cells, visceral mesodermal cells, hematopoietic cells, stromal cells, marrow stromal cells, neuronal cells, neuroectodermal cells, epithelial cells, ocular cells, pancreatic cells, and hepatocyte-like cells, among many others . Among the cells formed by the MAPCs are the osteoblasts, chondroblasts, adipocytes, musculoskeletal cells, skeletal myocytes, biliary epithelial cells, acinar cells pancreatic, mesangial cells, smooth muscle cells, cardiac muscle cells, cardiomyocytes, osteocytes, vascular tube-forming cells, oligodendrocytes, neurons, including serotonergic cells, GABAergic, dopaminergic neurons, glial cells, microglial cells, pancreatic epithelial cells, epithelial cells of the intestine, epithelial cells of the liver, epithelial cells of the skin, kidney epithelial cells, renal epithelial cells, pancreatic islet cells, fibroblasts, hepatocytes, and other cells of the same lineages as the previous ones, among many others. MAPCs have the telomerase activity necessary for self-renewal and it is thought that they will be necessary to maintain an undifferentiated study. In general, they also express oct-3/4. Oct-3/4 (oct-3A in humans) in cells otherwise specific for ES, EG, and germ cells. It is considered that it is a marker of undifferentiated cells that have broad differentiation capabilities. Oct-3/4 is also generally thought to have a role in maintaining a cell in the undifferentiated state. Oct-4 (oct-3 in humans) is a transcription factor expressed in the embryos of the pregastrulation, the embryos of the segmentation stage initial, the cells of the internal cell mass of the blastocysts, and the cells of the embryonic carcinoma ("EC") (Nichols, J. et al. (1998) Cell 95: 379-91), and are down-regulated when the cells are induced to differentiate. The oct-4 gene (oct-3 in humans) is transcribed in at least two splice variants in humans, oct-3A and oct-3B. The oct-3B splice variant is found in many differentiated cells while the oct-3A splice variant (also previously designated oct-3/4) was reported to be specific for undifferentiated embryonic stem cells. See Shimozaki et al. (2003) Development 130: 2505-12. The expression of oct-3/4 plays an important role in determining the initial steps in embryogenesis and differentiation. Oct-3/4, in combination with rox-1, causes the transcriptional activation of the Zn-finger rex-1 protein, which is also required to maintain the ES cells in an undifferentiated state (Rosfjord, E. Rizzino, A. (1997) Biochem Biophys Res Commun 203: 1795-802; Ben-Shushan, E. et al. (1998) Mol Cell Biol 18: 1866-78). MAPCs also generally express other markers that are thought to be specific for primitive stem cells. Among these are rex-1, rox-1, and sox-2. Rex-1 is controlled by oct-3/4, which activated the current expression of rex-1. Rox-1 and sox-2 are expressed in the cells different from ES. Various embodiments of the invention provide methods of using MAPCs to prevent, prevent, treat, ameliorate, mitigate, reduce, minimize, eliminate, and / or cure a disease and / or an adverse immune response and / or processes in a subject. Certain embodiments of the invention provide methods of using the cells themselves as a primary therapeutic modality. In some embodiments of the invention the cells are used together with one or more other agents and / or therapeutic modalities as the primary therapeutic modality. In some embodiments of the invention, the cells are used as an additive therapeutic modality, that is, as an additional modality to another, primary therapeutic modality. In some embodiments, the cells are used as the sole active agent of an additive therapeutic modality. In others, the cells are used as an additive therapeutic modality together with one or more other agents or therapeutic modalities. In some embodiments, the cells are used as agents and / or therapeutic modalities both primary and additive. In both aspects, the cells can be used alone in the primary modality and / or in the additive modality. They can also be used together with other agents or therapeutic modalities, in the primary or additive modality or in both.

As described above, a primary treatment, such as a therapeutic agent, therapy, and / or therapeutic modality, has as its objective (ie, is proposed to act on) the primary dysfunction, such as a disease, which is to be treated . An adjunctive treatment, such as a therapy and / or a therapeutic modality, may be administered in combination with a primary treatment, such as an agent, therapy, and / or therapeutic modality, to act on primary dysfunction, such as a disease, and supplement the effect of the primary treatment, whereby the total effectiveness of the treatment regimen is increased. An additive treatment, such as an agent, therapy, and / or therapeutic modality may also be administered to act on the complications and / or side effects of a primary dysfunction, such as a disease, and / or those caused by a treatment, such as a therapeutic agent, therapy and / or therapeutic modality. With respect to any of these uses, one, two, three, or more primary treatments may be used together with one, two, three or more additive treatments. In some embodiments, MAPCs are administered to a subject prior to the onset of a dysfunction, such as a disease, side effect, and / or deleterious immune response. In some modalities, the cells are administered while the dysfunction is developing. In some modalities, the cells are administered after the dysfunction has been established. The cells can be administered at any stage in the development, persistence, and / or spread of the dysfunction and / or after the same has a relapse. As described above, the embodiments of the invention provide cells and methods for primary or additive therapy. In certain embodiments of the invention, the cells are administered to an allogeneic subject. In some modalities, they are autologous with respect to the subject. In some modalities they are syngeneic for the subject. In some embodiments, the cells are xenogeneic for a subject. Whether they are allogenic, autologous, syngeneic, or xenogenic, in various embodiments of the invention, MAPCs are weakly immunogenic or are not immunogenic in the subject. In some embodiments the MAPCs have a sufficiently low immunogenicity or are not immunogenic, and are sufficiently free from detrimental immune responses in general so that when administered to allogenic subjects they can be used as "universal" donor cells without typing and tissue correspondence. According to various embodiments of the invention, MAPCs can also be stored and maintained in cell banks, and therefore can be kept available for use. when necessary. In all of these considerations and others, the embodiments of the invention provide MAPCs of mammals, including in one embodiment humans, and in other non-human primate modalities, rats and mice, and dogs, pigs, goats, sheep, horses. , and cows. The MAPCs prepared from the mammals as described above can be used in all of the methods and other aspects of the invention as described herein. MAPCs according to various embodiments of the invention can be isolated from a variety of compartments and tissues of such mammals, including but not limited to, bone marrow, blood, spleen, liver, muscles, of the brain, and others described later. MAPCs in some modalities are cultivated before use. In some embodiments, MAPCs are genetically engineered, such as to improve their immunomodulatory properties. In some modalities, genetically engineered MAPCs are produced by in vitro cultivation. In some embodiments, genetically engineered MAPCs are produced from a transgenic organism. In various modalities, MAPCs are administered to a subject by any route for the effective delivery of the therapeutic substances of the cell. In some embodiments, the cells are administered by injection, including local and / or systemic injection. In certain embodiments, the cells are administered within and / or in proximity to the site of the dysfunction that they are proposed to treat. In some embodiments, cells are administered by injection at a location that is not in proximity to the site of dysfunction. In some embodiments, the cells are administered by systemic injection, such as by intravenous injection. In some embodiments, the MAPCs are administered once, twice, three times, or more than three times until a desired therapeutic effect is achieved or the administration no longer appears to be likely to provide a benefit to the subject. In some embodiments MAPCs are administered continuously for a period of time, such as by intravenous drip. The administration of MAPCs can be for a short period of time, for days, for weeks, for months, for years, or for a longer period of time. The following numbered paragraphs describe a small number of illustrative embodiments of the invention that exemplify some of their aspects and characteristics. They are not exhaustive in the illustration of the many aspects and modalities, and therefore are not limiting in no way of the invention. Many other aspects, features, and embodiments of the invention are described herein. Many other aspects and modalities will be readily apparent to those skilled in the art during the reading of the application and provide due consideration in full view of prior art and knowledge in the field. The paragraphs numbered later are of self-reference. The phrase "in accordance with any of the above or the following" refers to all of the preceding numbered paragraphs and all of the following numbered paragraphs and their contents. All phrases of the form "according to #" are direct references to this numbered paragraph, for example "according to 46" means according to paragraph 46, in this collection of numbered paragraphs. All cross-references are combinatorial, except for redundancies and inconsistencies in scope. Cross-references are used explicitly to provide a concise description that shows the inclusion of the various combinations of subject materials with each other. A method of treating an immune dysfunction in a subject, characterized in that it comprises: administering to the subject who is likely to suffer, who suffers, or who has suffered from an immune dysfunction, by an effective route and in an effective amount to treat immune dysfunction, cells (MAPCs) that: are not embryonic stem cells, embryonic germ cells, or germ cells; they can be differentiated into at least one cell type from each of at least two of the endodermal, ectodermal, and mesodermal embryonic lineages; and do not elicit a detrimental immune response in the subject; and are effective to treat immune dysfunction. 2. An additive treatment method of a subject, characterized in that it comprises: administering to a subject who is likely to suffer, who suffers, or who has suffered from immune dysfunction by an effective route and in an effective amount to treat immune dysfunction , cells (MAPCs) that: are not embryonic stem cells, embryonic germ cells, or germ cells; they can be differentiated into at least one cell type from each of at least two of the endodermal, ectodermal, and mesodermal embryonic lineages; do not cause a damaging immune response in a subject; and are effective to treat immune dysfunction, wherein the cells are administered additively to one or more other treatments administered to the subject to treat the same thing, to treat something different or both. 3. A method according to any of the above or the following, characterized in that the cells can be differentiated into at least one cell type from each of the endodermal, ectodermal, and embryonic lineages, and mesodermal 4. A method of conformance with any of the above or the following, characterized in that the cells are expressed in telomerase. 5. A method of conformance with any of the above or the following, characterized in that the cells are positive for oct-3/4. 6. A method according to any of the above or the following, characterized in that the cells have suffered at least 10 to 40 duplications of the cells in the culture prior to their administration to the subject. 7. A method according to any of the above or the following, characterized in that the cells are mammalian cells. 8. A method of conformance with any of the foregoing or the following, characterized in that the cells are human, horse, cow, goat, sheep, rat, or mouse cells. 9. A method according to any of the above or the following, characterized in that the cells are human, rat, or mouse cells. 10. A method according to any of the above or the following, characterized in that the cells are human cells. 11. A method of compliance with any of the previous or following, characterized in that the cells are derived from cells isolated from either the placental tissue, umbilical cord tissue, umbilical cord blood, bone marrow, blood, spleen tissue, thymus tissue , the tissue of the spinal cord, adipose tissue, and liver tissue. 12. A method of conformance with any of the foregoing or the following, characterized in that the cells are derived from cells isolated from any of the placental tissue, the umbilical cord tissue, the umbilical cord blood, the bone marrow, the blood, and spleen tissue. 13. A method of conformance with any of the foregoing or the following, characterized in that the cells are derived from cells isolated from either the placental tissue, umbilical cord tissue, umbilical cord blood, bone marrow or bone marrow. blood. A method of conformance with any of the foregoing or the following, characterized in that the cells are derived from cells isolated from any one or more of the bone marrow or blood. 15. A method of conformance with any of the above or the following, characterized in that the cells are allogenic with respect to the subject. 16. A method of compliance with any of the previous or following, characterized in that the cells are xenogeneic for the subject. 17. A method of compliance with any of the above or the following, characterized in that the cells are autologous with respect to the subject. 18. A method of conformance with any of the foregoing or the following, characterized in that the subject is a mammal. 19. A method of conformance with any of the foregoing or the following, characterized in that the subject is a mammalian pet, a mammalian cattle animal, a mammalian research animal, or a non-human primate. 20. A method of conformance with any of the foregoing or the following, characterized in that the subject is a human being. 21. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject in one or more doses comprising 104 to 108 of the cells per kilogram of the mass of the subject. 22. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject in one or more doses comprising 105 to 107 of the cells per kilogram of the mass of the subject. 23. A method of conformance with any of the foregoing or the following, characterized in that the cells they are administered to the subject in one or more doses comprising 5 x 10 6 to 5 x 10 7 of the cells per kilogram of the mass of the subject. 24. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject in one or more doses comprising 2 × 10 7 to 4 × 10 7 of the cells per kilogram of the mass of the subject. 25. A method of conformance with any of the foregoing or the following, characterized in that in addition to the cells, one or more factors are administered to the subject. 26. A method of conformance with any of the foregoing or the following, characterized in that in addition to the cells, one or more growth factors, differentiating factors, and signaling factors, and / or factors that increase self-targeting are administered to the subject. 27. A method of conformance with any of the foregoing or the following, characterized in that in addition to the cells, one or more cytokines are administered to the subject. 28. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to a subject additively with respect to another treatment that is administered before, at the same time, or after the cells are administered. 29. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject additively for administration to the subject of one or more immunosuppressive agents. 30. A method of conformance with any of the foregoing or the following, characterized in that in addition to the treatment with the cells, the subject is going to receive or has received a transplant, wherein the cells are administered additively thereto. 31. A method according to any of the foregoing or the following, characterized in that in addition to the treatment with the cells, the subject is going to receive or has received a kidney, heart, lung, liver, or other organ transplant, where the cells are administered additively to it. 32. A method according to any of the above or the following, characterized in that in addition to the treatment with the cells, the subject is going to receive or has received a transplant of bone marrow, a vein, an artery, a muscle, or another tissue, wherein the cells are administered additively to it. 33. A method according to any of the above or the following, characterized in that in addition to the treatment with the cells, the subject will receive or have received a transplant of blood cells, islet cells, or other regenerative cells of a tissue or organ, wherein the cells are administered additively thereto. 34. A method according to any of the above or the following, characterized in that in addition to the treatment with the cells, the subject is going to receive or has received a transplant of blood cells, wherein the cells are administered additively to the same. 35. A method according to any of the above or the following, characterized in that in addition to the treatment with the cells, the subject is going to receive or has received a bone marrow transplant, where the cells are administered additively to it. 36. A method according to any of the foregoing or the following, characterized in that in addition to the treatment with the cells, the subject has been, will be, or is being treated with one or more immunosuppressive agents, wherein the cells are administered additively to the same. 37. A method according to any of the above or the following, characterized in that in addition to the treatment with the cells, the subject has been, will be, or is being treated with one or more of a corticosteroid, cyclosporin A, a similar immunosuppressive agent to ciclosporin, cyclophosphamide, antithymocyte globulin, azathioprine, rapamycin, FK-506, and an immunosuppressive agent similar to the macrolide other than KF-506, rapamycin, and an immunosuppressive monoclonal antibody agent (i.e., an immunosuppressant which is an immunosuppressive monoclonal antibody or is an agent comprising an antibody monoclonal, as a whole or in one or more parts, such as a chimeric protein comprising a Fe or Ag agglutination site of a monoclonal antibody), wherein the cells are administered additively thereto. 38. A method according to any of the above or the following, characterized in that in addition to the treatment with the cells, the subject has been, will be, or is being treated with one or more of a corticosteroid, cyclosporin A, azathioprine, rapamycin, cyclophosphamide, FK-506, and an immunosuppressive monoclonal antibody agent, wherein the cells are administered additively thereto. 39. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject additively with respect to administration to the subject of one or more antibiotic agents. 40. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject additively with respect to administration to the subject of one or more antifungal agents. 41. A method of compliance with any of the previous or following, characterized in that the cells are administered to the subject additively with respect to the administration of the subject of one or more antiviral agents. 42. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject additively with respect to administration to the subject of any combination of two or more of any immunosuppressive agents and / or antibiotic agents and / or antifungal agents and / or antiviral agents. 43. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject additively with respect to a transplant therapy to treat a host response against the graft in a subject that is altering or which could alter the therapeutic efficacy of the transplant and / or that is or that could lead to a rejection of the transplant. 44. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to a subject having a weakened immune system, such as one or more of a compromised immune system and / or an immune system subjected to ablation . 45. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to a subject additively with respect to radiation therapy or chemotherapy or a combination of radiation and chemotherapy that either has been, is being, or will be administered to the subject. 46. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to a subject additively with respect to a regimen in progress of radiation therapy or chemotherapy or a combination of radiation and chemotherapy. 47. A method of conformance with any of the foregoing or the following, characterized in that the subject's immune system has been weakened, compromised, and / or ablative by radiation therapy, chemotherapy, or a combination of radiation and chemotherapy. 48. A method of conformance with any of the foregoing or the following, characterized in that the subject is the recipient of the transplant of non-syngeneic blood cells or of the bone marrow, the immune system of the subject has been weakened or ablated by therapy of radiation, chemotherapy, or a combination of radiation and chemotherapy, and the subject is at risk of developing or has developed graft-versus-host disease. 49. A method of conformance with any of the foregoing or the following, characterized in that the subject is the recipient of a bone marrow transplant or non-syngeneic blood cells, the subject's immune system has been weakened or ablated by radiation therapy, by chemotherapy, or by a combination of radiation therapy and chemotherapy, and immunosuppressive drugs are being administered to the subject, wherein the subject is also at risk of developing or has developed graft-versus-host disease and the cells are administered to the subject for treating graft-versus-host disease additively with respect to one or more of the other treatments (ie: transplantation, radiation therapy, chemotherapy, and / or immunosuppressant drugs). 50. A method of conformance with any of the foregoing or the following, characterized in that the subject will be or is the recipient of the non-syngeneic transplant and is at risk for or has developed a host versus graft response, wherein the cells are administered for treat the response of the host against graft. 51. A method according to any of the above or the following, characterized in that the subject is at risk of or suffering from a neoplasm and the cells are administered additively to a treatment thereof. 52. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from a neoplasm of the cells of the bone marrow or blood and the cells are administered additively with respect to a treatment thereof. 53. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from a benign neoplasm of the bone marrow cells, a myeloproliferative disorder, a myelodysplastic syndrome, or an acute leukemia and the cells are administered additively to a treatment thereof. 54. A method according to any of the above or the following, characterized in that the subject is at risk or suffering from a benign neoplasm of the cells of the bone marrow and the cells are administered additively to a treatment thereof. 55. A method according to any of the above or the following, characterized in that the subject is at risk of or is suffering from a myeloproliferative disorder and the cells are administered additively to a treatment thereof. 56. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk for or is suffering from one or more chronic myelocytic leukemia ("CML") (for its acronym in English) (also called chronic leukemia ("CGL")), agnogenic myelofibrosis, essential thrombocytopenia, 4 polycythemia vera, or another myeloproliferative disorder and the cells are administered additively to a treatment thereof. 57. A method according to any of the above or the following, characterized in that the subject is at risk of or suffering from a myelodysplastic syndrome and the cells are administered additively to a treatment thereof. 58. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from acute leukemia and the cells are administered additively to a treatment thereof. 59. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of acute myeloma, myeloblastic leukemia, chronic myelocytic leukemia ("CML"), acute promyelocytic leukemia , acute pre-B lymphoblastic leukemia, chronic lymphocytic leukemia ("CLL"), B-cell lymphoma, hair-cell leukemia, myeloma, acute T-cell lymphoblastic leukemia, peripheral T-cell leukemia, other lymphoid leukemias , other lymphomas, or other acute leukemias and the cells are administered additively to a treatment thereof. 60. A method of compliance with any of the above or the following, characterized in that the subject is at risk of or is suffering from an anemia or other disorder of the blood and the cells are administered additively to a treatment thereof. 61. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from hemoglobinopathies, thalassemia, bone marrow failure syndrome, sickle cell anemia, aplastic anemia, Fanconi anemia, or an immune haemolytic anemia and the cells are administered additively to a treatment thereof. 62. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with blasts in excess in transformation, chronic myelomonocytic leukemia, or other myelodysplastic syndrome, and the cells are administered additively to a treatment thereof. 63. A method of conformance with any of the above or the following, characterized in that the subject is at risk of or is suffering from Fanconi anemia and the cells are administered additively to a treatment of the same. 6 A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from an immune dysfunction and the cells are administered additively to a treatment thereof. 65. A method according to any of the above or the following, characterized in that the subject is at risk of or is suffering from a congenital immune deficiency and the cells are administered additively to a treatment thereof. 66. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from an immune dysfunction, disorder, or disease and the cells are administered additively to a treatment thereof. 67. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of the following autoimmune dysfunctions: Crohn's disease, Guillain-Barré syndrome, lupus erythematosus (also called "SLE" and systemic lupus erythematosus), multiple sclerosis, myasthenia gravis, optic neuritis, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's disease, Ord's thyroiditis, diabetes mellitus (type 1), Reiter, autoimmune hepatitis, primary biliary cirrhosis, antiphospholipid antibody syndrome ("APS"), opsoclonia-myoclonus syndrome ("OMS"), temporal arteritis, acute disseminated encephalomyelitis ("ADEM" and "ADE"), Goodpasture syndrome, Wegener's granulomatosis, celiac disease, pemphigus, polyarthritis, and autoimmune hemolytic anemia by hot antibodies and the cells are administered additively to a treatment thereof. 68. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of the following autoimmune dysfunctions: Crohn's disease, lupus erythematosus (also called "SLE" and lupus) systemic erythematosus), multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's disease, diabetes mellitus (type 1), Reiter's syndrome, primary biliary cirrhosis, celiac disease, polyarthritis, and autoimmune hemolytic anemia due to antibodies hot and the cells are administered additively to a treatment of the same. 69. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of the following diseases that are thought to have an autoimmune component: endometriosis, interstitial cystitis, neuromyotonia, scleroderma, progressive systemic scleroderma, vitiligo, vulvodynia, Chagas disease, sarcoidosis, chronic fatigue syndrome, and dysautonomia and the cells are administered additively to a treatment of the same. 65. A method according to any of the above or the following, characterized in that the subject is at risk of or is suffering from a congenital immune deficiency and the cells are administered additively to a treatment thereof. 66. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from an immune dysfunction, disorder, or disease and the cells are administered additively to a treatment thereof. 67. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of the following autoimmune dysfunctions: Crohn's disease, Guillaint-Barré syndrome, lupus erythematosus (also called "SLE" and systemic lupus erythematosus), multiple sclerosis, myasthenia gravis, optic neuritis, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's disease, Ord's thyroiditis, diabetes mellitus (type 1), Reiter's syndrome, autoimmune hepatitis, biliary cirrhosis Primary, antiphospholipid antibody syndrome ("APS"), opsoclonus-myoclonus syndrome ("OMS"), temporal arteritis, acute disseminated encephalitis ("ADEM" and "ADE"), Goodpasture syndrome, Wegener's granulomatosis, celiac disease, pemphigus, polyarthritis, and hot autoimmune hemolytic anemia and the cells are administered additively to a treatment thereof. 68. A method of conformance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of the following autoimmune dysfunctions: Crohn's disease, lupus erythematosus (also called "SLE" and lupus) systemic erythematosus), multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's disease, diabetes mellitus (type 1), Reiter's syndrome, primary biliary cirrhosis, celiac disease, polyarthritis, and hot autoimmune hemolytic anemia and the cells are administered additively to a treatment thereof. 69. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from one or more of the following diseases that are thought to have an autoimmune component: endometriosis, interstitial cystitis, neuromyotonia, scleroderma, progressive systemic scleroderma, vitiligo, vulvodynia, Chagas disease, sarcoidosis, chronic fatigue syndrome, and dysautonomia and the cells are administered additively to a treatment of the same. 70. A method of compliance with any of the foregoing or the following, characterized in that the subject is at risk of or is suffering from an autoimmune disease and the cells are administered additively to a treatment thereof. 71. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered in a formulation comprising one or more other pharmaceutically active agents. 72. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered in a formulation comprising one or more other immunosuppressive agents. 73. A method according to any of the foregoing or the following, characterized in that the cells are administered in a formulation comprising one or more of a corticosteroid, cyclosporin A, an immunosuppressive agent similar to cyclosporin, cyclophosphamide, antithymocyte globulin; azathioprine, rapamycin, FK-506, and an immunosuppressive agent similar to the macrolide, different from FK-506, rapamycin, and an immunosuppressive monoclonal antibody agent. 74. A method according to any of the foregoing or the following, characterized in that the cells are administered in a formulation comprising one or more of a corticosteroid, cyclosporin A, azathioprine, cyclophosphamide, rapamycin, FK-506, and a monoclonal antibody agent immunosuppressant. 75. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered in a formulation comprising one or more antibiotic agents. 76. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered in a formulation comprising one or more antifungal agents. 77. A method of conformance with any of the above or the following, characterized in that the cells are administered in a formulation comprising one or more antiviral agents. 78. A method of conformance with any of the above or the following, characterized in that the cells are administered to the subject by a parenteral route. 79. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject by one or more of the following parenteral routes: intravenous, intraarterial injection, intracardiac, intraspinal, intrathecal, intraosseous, intraarticular, intrasynovial, intracutaneous, intradermal, subcutaneous, and intramuscular. 80. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered by one or more of the following parenteral routes: intravenous, intraarterial, intracutaneous, intradermal, subcutaneous, and intramuscular injection. 81. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered by one or more of the following parenteral routes: intravenous, intraarterial, intracutaneous, subcutaneous, and intramuscular injection. 82. A method according to any of the above or the following, characterized in that the cells are administered to the subject through a hypodermic needle, by means of a syringe. 83. A method of conformance with any of the above or the following, characterized in that the cells are administered to the subject by means of a catheter. 84. A method of conformance with any of the above or the following, characterized in that the cells are administered by surgical implant. 85. A method of conformance with any of the above or the following, characterized in that the cells they are administered to the subject by implant using an arthroscopic procedure. 86. A method of conformance with any of the above or the following, characterized in that the cells are administered to the subject on or on a support. 87. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject in an encapsulated form. 88. A method of conformance with any of the foregoing or the following, characterized in that the cells are suitably formulated, for administration by one or more of the following routes: oral, rectal, epicutaneous, ocular, nasal, and pulmonary. 89. A method of conformance with any of the above or the following, characterized in that the cells are administered to the subject in a dose. 90. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered to the subject in a series of two or more doses in succession. 91. A method of conformance with any of the foregoing or the following, characterized in that the cells are administered in a single dose, in two doses, or in two or more doses, wherein the doses are the same or different, and the cells are administered at equal intervals or with unequal intervals between them. 92. A method of compliance with any of the above or the following, characterized in that the cells are administered for a period of less than one day to one week, one week to one month, one month to one year, one year to two years , or a period longer than two years. 93. A method of treating an immune dysfunction in a subject, characterized in that it comprises administering to the subject suffering from an immune dysfunction, by a route and in an amount effective for the treatment of immune dysfunction in the subject, cells that: are embryonic stem cells, embryonic germ cells, or germ cells; they can be differentiated into at least one cell type from each of at least two of the endodermal, ectodermal, and mesodermal embryonic lineages; they do not provoke a harmful immune response in the subject; and they are effective to treat immune dysfunction in the subject. 94. An additive treatment method of an immune dysfunction in a subject, characterized in that it comprises administering to the subject suffering from an immune dysfunction, by a route and in an amount effective for the treatment of immune dysfunction in the subject, cells which: they are not embryonic stem cells, embryonic germ cells, or germ cells; they can be differentiated into at least one cell type from each of at least two of the embryonic lineages endodermal, ectodermal and mesodermal; they do not provoke a harmful immune response in the subject; and are effective to treat immune dysfunction in the subject, wherein the cells are administered to the subject additively to one or more other treatments that are administered to the subject to treat the same immune dysfunction, to treat one or more other dysfunctions, or both Other aspects of the invention are described in or are obvious from the following description, and are within the scope of the invention. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic representation of the transcriptional profiling studies that were performed to generate (identify) the gene and the surface receptor-based markers that distinguish between the MAPCs of the invention and other stem and progenitor cells which are of more concomitant lineages. The experiments have led to a panel of 75 markers that have a 10-fold different expression between the MSC cultures and the MAPCs. Figure 2 is a set of graphs showing triple lineage differentiation of rat MAPCs labeled with GFP. The results show that MAPCs can differentiate into cells of all three embryonic lineages. As described below, for endothelial differentiation, the MAPCs were cultured on fibronectin-coated plates in the presence of a vascular endothelial growth factor B (VEGF-B) (for its acronym in English). For the differentiation of the hepatocytes, the cells were grown on plates coated with matrigel and treated with the factor 4 of the growth of fibroblasts (FGF-4) (for its acronym in English) and the growth factor of hepatocytes (HGF) (for its acronym in English) . Neuronal differentiation was induced by sequential treatment with basic FGF (bFGF), both with FGF-8 and Sonic Hedgehog (SHH), and with the brain-derived neurotrophic factor (BDNF) (for its acronym in English). After two weeks, the mRNA was extracted from the cells and applied to the qPCR analysis using the specific primers for the detection of several lineage markers. In all trials, cells cultured in the absence of the lineage-inducing cytokines served as controls. The expression levels of the lineage markers were normalized first with respect to the level of expression of an internal control gene (GAPDH) that is not affected during differentiation. The success of the differentiation was then evaluated by calculating the relative expression in the differentiated or control cells, compared to the levels in the original rat line, using an increase of more than 5 times in the relative expression as a cut for successful differentiation. Rat MAPCs differentiated exhibited significant expression of endothelial markers, von Willebrand factor and PECAM-1 (upper panel); albumin of hepatic markers, cytokeratin-18, and HNF-la (intermediate panel); and the neuronal / astrocyte GFAP markers, nestin, and NF-200 (lower panel). Figure 3 is a pair of bar graphs showing low immunogenicity (upper panel) and immunosuppression (lower panel) of MAPCs in mixed lymphocyte reactions (MLR), as described below. additional way. In the upper panel: B + B = donor B + donor B; B + A = donor B + donor A; B + K = donor B + donor K; B + R = donor B + donor R; B + T = donor B + donor T; B + PHA donor; B + BMPC = donor B + MAPC. The same result was achieved with twelve different donors. In the lower panel: donor W + donor W; donor W + donor A; donor W + donor T; donor W + MCS; W + MAPC donor (17); W + PHA donor; donor W + donor A + MSC; donor W + donor A + MAPC (17); donor W + donor T + MSC; donor W + donor T + MAPC (17); donor W + donor P + MSC; donor W + donor P + MAPC (17). PHA is phytohemagglutinin (positive control for T cell activation). Figure 4 is a graph showing that MAPCs can suppress the proliferation of stimulated T cells with ConA as described in example 6. The heading "LN only" designates the results for the control reactions omitting the MAPCs. The numbers for the MAPCs indicate how many cells were used in the trials. Figure 5A is a graph showing the immunosuppressive effects of Lewis MAPCs on the reactions of mixed lymphocytes, as described in example 7. The table in Figure 5A lists the MAPCs in each reaction. In the box, R designates the responder cells and S designates the stimulator cells (irradiated splenocytes from DA rats). Figure 5B is a graph showing the immunosuppressive effects of Sprague-Dawley MAPCs on the reactions of mixed lymphocytes, as described in example 7. The headings and abbreviations are the same as in Figure 5A. Figure 6 is a graph showing that the infusion of MAPCs does not adversely affect the health of the recipients that is determined by their respiratory rate. The graph is further described in Example 8. Figure 7 is a bar graph showing the results of an experiment demonstrating the ability of MAPCs to suppress an immune response in progress. The graph shows that MAPCs are strongly immunosuppressive in MLRs, both when they are added at the same time as with the activator of the T cells (stimulator) (day 0, left side of the graph), and when they are added 3 days after the addition of the activator of the T cell (stimulator) (day 3, right side of the graph). The details of the experiments are further described in Example 10. Figure 8 is a bar graph showing that the inhibition of MAPC from the proliferation of T cells in MLRs are reversible. The results are shown in average CTM +/- SD of the triplicate crop. The graph is further described in example 11. Figure 9 is a graph showing that MAPCs inhibit GVHD as described in example 13. DETAILED DESCRIPTION OF THE INVENTION Definitions When used herein, certain terms have the meanings described below. "A" or "an" means one or more; at least one. "Additive" means jointly, together with, in addition to, in conjunction with, and the like. "Co-administration" may include the simultaneous or consecutive administration of two or more agents. "Cytokines" refers to cellular factors that induce or enhance cell movement, such as auto-targeting of MAPCs or other stem cells, cells progenitors, or differentiated cells. Cytokines can also stimulate such cells to divide. "Harmful" means, as used here, mean that it causes damage. By way of illustration, "detrimental immune response" means, when used herein, a deleterious immune response, such as those that are lacking or are too weak, those that are too strong, and / or those that have an erroneous address. Among the damaging immune responses, are the damaging immune responses that occur in immune diseases. Examples include the lack of immune responses in immunodeficiency diseases, and immune responses exaggerated and / or misdirected in autoimmune diseases. Immune responses that interfere with medical treatment, including the immune response in other normal ways, are also among the immune responses. Examples include the immune responses involved in the rejection of transplants and grafts, and the responses of the immunocompetent cells in the transplants and grafts that cause graft-versus-host disease. "Differentiation factors" refers to cellular factors, such as growth factors, that induce lineage commitment. "Dysfunction" means, when used here, a disorder, illness, or detrimental effect of an otherwise normal process. By way of illustration, an immune dysfunction includes immune diseases, such as autoimmune diseases and immune deficiencies. Also included are immune responses that interfere with medical treatment, including immune responses in other normal ways that interfere with medical treatment. Examples of such dysfunctions include the immune responses involved in the rejection of transplants and grafts, and the response of competent immune cells in the transplants and grafts that cause graft-versus-host disease. "EC cells" refer to embryonic carcinoma cells. "Effective amount" generally means an amount that provides the desired local or systemic effect. For example, an effective amount is an amount sufficient to effect a desired clinical or beneficial result. The effective amounts can be provided all at once in a single administration or in fractional amounts that provide the effective amount in several administrations. For example, an effective amount of MAPCs could be administered in one or more administrations and could include any preselected number of cells. The precise determination of what could be considered as An effective amount may be based on individual factors for each subject, including their size, age, injury, and / or illness or injury that is treated, and the amount of time since the injury occurred or since the illness began. An expert in the art will be able to determine the effective amount for a given subject based on these considerations that are routine in the art. Thus, for example, the expert in this art, such as a physician, based on the known properties of MAPCs as described herein and in the art, together with a consideration of the preceding factors, will be able to determine the effective amount of MAPCs. for a given subject. When used here, "effective dose" means the same as "effective amount". "EG cells" refers to embryonic germ cells. "Injertar" refers to the process of cell contact and the incorporation of an existing tissue of interest in vivo. "Enriched population" means a relative increase in the numbers of MAPCs relative to other cells or constituents in a minimum population, such as an increase in the numbers of MAPCs relative to one or more cell types other than MAPC in the culture, such as the primary culture, or in vivo. "ES cells" refers to embryonic stem cells.

"Expansion" refers to the propagation of a cell or cells without differentiation. "Fanconi anemia" as used here, means the same as Fanconi's anemia, a hereditary disease. "GVHD" refers to graft-versus-host disease, which refers to processes that occur primarily in an immunocompromised host animal when it is recognized as non-self by the immunocompetent cells of a graft. "HVG" refers to host versus graft response, which means that they occur when a host animal rejects a graft. Typically, HVG is triggered when a graft is recognized as foreign (not own) by the immunocompetent cells of the host animal. "Isolated" refers to the cell or cells that are not associated with one or more cells or one or more cellular components that are associated with the cell or cells in vivo. "MAPC" is an acronym for "multipotent adult progenitor cells". It refers to cells other than ES, different from EG, different from germ cells that can cause cell lineages of more than one germinal layer, such as the totality of the three germ layers (ie, of the endoderm, mesoderm and ectoderm). MAPCs also have telomerase activity. They can be positive for oct-3/4 (for example, oct-3A human). They can also express rex-1 and rox-1. In addition, they can express sox-2, SSEA-4, and / or nanog. The term "adult" in MAPC is not restrictive. It only denotes that these cells are not ES, EG, or germinal cells. Typically, when used here, MAPC is singular and MAPCs is plural. MAPCs have also been referred to as multipotent adult stem cells (MASCs). See U.S. Pat. No. 7,015,037, which is incorporated herein for reference for the description of MAPC / MASC and methods of isolation and growth thereof. "MASC", see MAPC. "MNC" refers to mononuclear cells. "Modality" means a type, method, route, or method, such as, a therapeutic modality, ie, a type of therapy. "MSC" is an acronym for mesenchymal stem cells. "Multipotent" with respect to MAPCs, refers to the ability to cause or produce lineages of cells larger than a germ layer, such as all three primitive germ layers (ie, endoderm, mesoderm and ectoderm) during the differentiation. "Persistence" refers to the ability of cells to resist rejection and to remain and / or increase in number over time (eg, for days, weeks, months, or years) in vivo. "Progenitor" as used in multipotent adult progenitor cells (MAPCs) indicates that these cells can cause other cells such as additional differentiated cells. The term is not limiting and does not limit these cells to a particular lineage. "Self-renewable" refers to the ability to produce duplicate daughter stem cells that have a differentiation potential that is identical to those from which they arise. A similar term used in this context is "proliferation". A "subject" is a vertebrate, such as a mammal, such as a human being. Mammals include, but are not limited to, humans, farm animals, sports animals, and pets. Subjects in need of treatment by the methods of the present invention include those suffering from a disorder, dysfunction or disease (such as a deficiency or immune dysfunction, such as HVG and GVHD), or a side effect thereof, or a treatment thereof, that may benefit from the administration of the MAPCs either as a primary treatment or an additive treatment. "Transplantation" as used herein means introducing cells, tissues, or organs into a subject. He Transplantation can be derived from the subject, from the culture, or from a different source of the subject. "Treat", "treatment", or "treating" includes the treatment, prevention, improvement, inhibition, or cure of a deficiency, dysfunction, disease, or other process that leads to a detrimental effect, such as a deficiency, dysfunction, disease of the immune system, or another process that detrimentally affects the functions or properties of the immune system or that interferes with a therapy. MAPCs are very promising for the treatment of a disease by cell transplantation techniques, such as for the regeneration of tissue and organs, both when used alone and when used in combination with other treatments. Among the potential obstacles to obtaining the promise of MAPCs for the treatment of diseases, and for the regeneration of tissue and organs, are the adverse immune reactions that typically complicate or prevent success in transplant therapies, such as blood and bone marrow transplant therapies and solid organ transplantation. Prominent among these immune complications are graft rejection by the host animal's immune system (referred to herein as host versus graft response and as "HVG") and systemic damage to an immunocompromised host that results when immunocompetent cells in a graft They are activated by contact with non-animal host components (referred to herein as graft-versus-host disease and as "GVHD"). It has been found (as described in more detail here elsewhere) that MAPCs do not elicit an immune response in allogenic host animals. Accordingly, transplantation of MAPCs to an allogeneic host animal should not engender a rejection of the allogeneic graft (i.e., HVG). In addition, it has also been found that allogeneic MAPCs can be administered to a host animal at a high concentration without harmful effects on respiration, suggesting that undue clumping and / or deposition in the lungs will not occur. In addition, it has been found (as described in more detail elsewhere herein), that MAPCs can modulate immune responses. In particular in this regard, it has been found that MAPCs can suppress immune responses, including but not limited to the immune responses involved in, for example, HVG and GVHD, to name but two. In a still more detailed particular mode in this regard, it has been found that MAPCs can suppress the proliferation of T cells, even in the presence of potent T-cell stimulators, such as Concavalin A and allogeneic stimulator cells.

In addition, it has been found that even relatively small amounts of MAPCs can suppress these responses. Actually, only 3% of MAPCs in mixed lymphocyte reactions is sufficient to reduce the response of T cells to potent stimulators in 50% in vi tro. Accordingly, in certain aspects of the invention in this regard, certain of the embodiments provide compositions and methods and the like for the treatment, improvement, and / or curing or elimination of adverse immune reactions, such as those occurring in the transplant therapies. The low immunogenicity of allogeneic MAPCs, their ability to suppress immune responses, and their high specific activity make them particularly valuable for additive therapies in the treatment of diseases with an adverse immune component. Among such diseases are autoimmune diseases in which, typically, the dysfunction of the subject's own immune system causes the disease. MAPCs are also useful as immunosuppressive additive therapeutic substances for the treatment of adverse immune responses that occur in transplant therapy. Examples include HVG in immunocompetent host animals and GVHD in immunocompromised host animals. MAPCs can also be useful in the additive immunosuppressive therapy in the treatment of a variety of neoplasms, anemias and blood disorders, and in the treatment of certain inflammatory diseases. The diseases in this respect are described in more detail later. Using the methods described here for MAPC isolation, characterization, and expansion, along with the description here of the immunosuppressive properties of MAPCs, MAPCs can be used to prevent, suppress, or decrease disorders, dysfunctions, or immune diseases, including, for example, adverse immune reactions, such as those resulting from other therapies, including those that complicate transplantation therapies, such as HVG and GVHD. Such disorders, dysfunctions, and diseases also include congenital immune disorders and autoimmune diseases, among others. MAPCs are useful in this respect and others, both as primary therapeutic agents and additives as modalities. MAPCs can be used therapeutically alone or together with other agents. The MAPCs can be administered before, during, and / or after such agents. Similarly, whether used alone or with other agents, MAPCs can be administered before, during, and / or after a transplant. If they are administered during the transplant, the MAPCs can be administered together with the transplant material or separately. If they are administered separately, the MAPCs can be administered consecutively or simultaneously with the transplant. In addition, MAPCs can be administered prior to transplantation and / or after transplantation. Other agents that can be used in conjunction with MAPCs, in particular transplant therapies, include immunomodulatory agents. A variety of such agents are described here elsewhere. In certain embodiments of the invention, immunomodulatory agents are immunosuppressive agents, such as those described herein elsewhere. Among such agents are corticosteroids, cyclosporin A, immunosuppressive compounds similar to cyclosporine, azathioprine, cyclophosphamide, and methotrexate. MAPCs can be administered to host animals by a variety of methods as described elsewhere herein. In certain embodiments, MAPCs are administered by injection, such as by intravenous injection. In some modalities, MAPCs are encapsulated for administration. In some modalities, the MAPCs are administered in you. Examples include the in-situ administration of MAPCs in solid organ transplantation and in the repair of organs. These and other forms of administration are described later. In some embodiments of the invention, MAPCs are administered in doses measured by the ratio of MAPCs (cells) to mass (weight) of the body. Alternatively, MAPCs can be administered in doses of a fixed number of cells. The dosage, route of administration, formulations, and the like, are described in greater detail here elsewhere. Mechanism of action Without being limited to any one or more of the explanatory mechanisms for immunomodulatory properties and other properties, activities, and effects of MAPCs, it is noteworthy that they can modulate immune responses through a variety of modalities . For example, MAPCs can have direct effects on a graft or host animal. Such direct effects are mainly a matter of direct contact between MAPCs and the cells of the host animal or graft. The contact can be with the structural elements of the cells or with the constituents in their immediate environment. Such a direct mechanism may involve direct contact, diffusion, absorption, or other processes well known to those skilled in the art. The activities and direct effects of the MAPCs can be spatially limited, such as with respect to a local deposition area or a compartment of the body that is accessed by injection. MAPCs can also "self-direct" in response to "self-targeting" signals, such as those released at sites of injury or illness. Since self-targeting is often mediated by signals whose natural function is to recruit cells for sites where repairs are necessary, self-addressing behavior can be a powerful tool for the concentration of MAPCs with respect to therapeutic goals. . This effect can be stimulated by specific factors, as described later. MAPCs can also modulate immune processes by their response to factors. This may occur additionally or alternatively with respect to direct modulation. Such factors may include factors of self-targeting, mitogens, and other stimulating factors. They can also include factors of differentiation, and the factors that trigger the particular cellular processes. Among the latter are factors that cause the secretion by cells of other specific factors, such as those that are involved in the recruitment of cells, such as stem cells (including MAPCs), to a site of injury or illness. MAPCs can secrete, in addition to the previous ones or alternatively thereto, factors acting on endogenous cells, such as stem cells or progenitor cells. Factors can act on other cells to generate, improve, reduce, or suppress their activities. MAPCs can secrete factors that act on the stem, progenitor, or differentiated cells that cause these cells to divide and / or differentiate. MAPCs that self-direct to a site where repair is necessary can secrete trophic factors that attract other cells to the site. In this way, MAPCs can attract stem, progenitor, or differentiated cells to a site where they are needed. MAPCs can also secrete factors that cause such cells to divide or differentiate. The secretion of such factors, including trophic factors, may contribute to the effectiveness of MAPCs in, for example, limiting inflammatory damage, limiting vascular permeability, improving cell survival, and the act of spawning and / or or increase self-targeting of repair cells to damaged sites. Such factors can also affect the proliferation of T cells directly. Such factors can also affect dendritic cells, by reducing their activities of antigen presentation and phagocytic activity, which can also affect the activity of T cells. By these and other mechanisms, MAPCs can provide beneficial immunomodulatory effects, including, but not limited to, the suppression of undesirable and / or deleterious reactions, responses, functions, and immune diseases, and similar. MAPCs in various embodiments of the invention provide beneficial immunomodulatory properties and effects that are useful by themselves or in an additive therapy to prevent, prevent, decrease, reduce, improve, mitigate, treat, eliminate and / or cure the processes and / or damaging immune conditions. Such processes and conditions include for example, autoimmune diseases, anemias, neoplasms, HVG, GVHD, and certain inflammatory disorders, as described more fully herein elsewhere. MAPCs are useful in this and other aspects, particularly in mammals. In various embodiments of the invention in this regard, MAPCs are used therapeutically in human patients, often additively for other therapies. Administration of MAPCs MAPC Preparations MAPCs preparations can be prepared from a variety of tissues, such as the cells of the average bone, as described hereinafter. In many modalities, MAPC preparations are derived by cloning. Initially, the MAPCs in these preparations are genetically identical to each other and, if properly prepared and maintained, are free of other cells. In some modalities, MAPC preparations that are less pure than these can be used. Although rare, less pure populations may arise when the initial cloning stage requires more than one cell. If these are not all MAPCs, the expansion will produce a mixed population in which the MAPCs are only one of at least two cell types. More frequently, mixed populations arise when the MAPCs are administered in a mixed manner with one or more other cell types. In many embodiments, the purity of the MAPCs for administration to a subject is approximately 100%. In other modalities, it is 95% to 100%. In some modalities it is 85% to 95%. Particularly in the case of mixtures with other cells, the percentage of MAPCs can be 25% -30%, 30% -35%, 35% -40%, 40% -45%, 45% -50%, 60 % - 70%, 70% - 80%, 80% - 90% or 90% -95%. The number of MAPCs in a given volume can be determined by routine and well-known procedures and instrumentation. The percentage of MAPCs in a given volume of a mixture of cells can be determined by many of the same procedures. The cells can be counted manually or using an automatic cell counter. Specific cells can be determined in a given volume using specific visual and staining examination and by automated methods that utilize a specific agglutination reagent, typically antibodies, fluorescent labels, and a fluorescent activated cell sorter. MAPC immunomodulation may involve undifferentiated MAPCs. MAPCs cells that are compromised with respect to a differentiation pathway can be involved. Such immunomodulation may also involve MAPCs that have differentiated into a less potent stem cell with a limited differentiation potential. It may also involve MAPCs that have differentiated into a terminally differentiated cell type. The best type or mixture of MAPCs will be determined by the particular circumstances of their use, and it will be a matter of routine design for those skilled in the art to determine an effective type or combination of MAPCs. Formulations The choice of formulation for the administration of MAPCs for a given application will depend on a variety of factors. Prominent among these are the species of the subject, the nature of the disorder, the dysfunction, or the disease that is treated and its status and distribution in the subject, the nature of other therapies and agents that are administered, the optimal route for the administration of the MAPCs, the survival of the MAPCs by means of the route, the dosage regimen, and other factors that will be evident to those skilled in the art. In particular, for example, the choice of suitable carriers and other additives will depend on the exact route of administration and the nature of the particular dosage form, for example, the liquid dosage form (e.g., whether the composition is to be formulated in a solution, a suspension, a gel or other liquid form, such as a release form with the passage of time or a form filled with a liquid). For example, the survival of cells can be an important determinant of the efficacy of cell-based therapies. This is true for both primary and additive therapies. Another issue arises when the target sites are uninhabitable for planting the cells and cell growth. This can impede access to the site and / or the graft there of the therapeutic MAPCs. Various embodiments of the invention comprise measures to increase the survival of the cells and / or to overcome the problems posed by barriers for planting and / or growth. Examples of the compositions comprising the MAPCs include liquid preparations, including suspensions and preparations for intramuscular or intravenous administration (e.g., injectable administration), such as sterile suspensions or emulsions. Such compositions may comprise a mixture of MAPCs with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, dextrose, or the like. The compositions can also be lyophilized. The compositions may contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity improving additives, preservatives, flavoring agents, colors, and the like, depending on the route of administration and the desired preparation. Standard texts, such as "REMINGTON'S PHARMACEUTICAL SCIENCE", 17 / a. Edition, 1985, incorporated herein for reference, can be consulted to prepare suitable preparations, without undue experimentation. The compositions of the invention are conveniently provided as liquid preparations, for example, isotonic aqueous solutions, suspensions, emulsions, or viscous compositions, which can be buffered to a selected pH. Liquid preparations are usually easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, Liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the viscosity range to provide longer contact periods with specific tissues. Various additives will often be included to improve the stability, sterility, and isotonicity of the compositions, such as antimicrobial preservatives, antioxidants, chelating agents, and buffers, among others. The prevention of the action of microorganisms can be ensured by various antimicrobial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents that retard absorption, for example, aluminum monostearate, and gelatin. In accordance with the present invention, however, any vehicle, diluent, or additive used may have to be compatible with the cells. MAPC solutions, suspensions, and gels usually contain a major amount of water (preferably sterilized, purified water) in addition to the cells. The smaller amounts of other ingredients such such as pH adjusters (eg, a base such as NaOH), emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents and gelatinization agents (eg, methylcellulose) may also be present. Typically, the compositions will be isotonic, ie they will have the same osmotic pressure as blood and tear fluid when properly prepared for administration. The desired isotonicity of the compositions of this invention can be effected using sodium chloride, or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, or other organic or inorganic solutes. Sodium chloride is particularly preferred for buffers that contain sodium ions. The viscosity of the compositions, if desired, can be maintained at the selected level using a pharmaceutically acceptable thickening agent. Methylcellulose is preferred because it is readily and inexpensively available and easy to work with. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickener will depend on the agent selected. Point important is to use a quantity, which will achieve the selected viscosity. Viscous compositions are usually prepared from the solutions by the addition of such thickening agents. A pharmaceutically acceptable cell stabilizer or stabilizer can be employed to increase the life of MAPC compositions. If such preservatives are included, it is well within the scope of the expert to select compositions that will not affect the viability or effectiveness of the MAPCs. Those skilled in the art will recognize that the components of the compositions must be chemically inert. This will not be a problem for those experts in chemical and pharmaceutical principles. The problems can easily be avoided by reference to standard texts or by simple experiments (which do not involve undue experimentation) using the information produced by the description, the documents cited here, and generally available in the art. Sterile injectable solutions can be prepared by incorporating the cells used in the practice of the invention in the required amount of the appropriate solvent with various amounts of the other ingredients, when desirable. In some modalities, MAPCs are formulated in an injectable unit dosage form, such as a solution, suspension, or emulsion. Pharmaceutical formulations suitable for injection of MAPCs are typically sterile aqueous solutions and dispersions. The carriers for the injectable formulations can be a solvent or a dispersion medium containing, for example, water, a saline solution, a phosphate buffered saline solution, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), and suitable mixtures thereof. The skilled person can easily determine the amount of cells and additives, carriers, and / or optional carriers in the compositions to be administered in the methods of the invention. Typically, any additives (in addition to cells) are present in an amount of 0.001 to 50% by weight in the solution, such as in phosphate buffered saline. The active ingredient is present in the order of micrograms up to milligrams, such as about 0.0001 to about 5% by weight, preferably about 0.0001 to about 1% by weight, even more preferably about 0.0001 to about 0.05% by weight or about 0.001 to about 20% by weight, preferably about 0.01 to about 10% by weight, and even more preferably about 0.05 to about 5% by weight. For any composition that is to be administered to a human or animal, and for any particular method of administration, it is therefore preferred to determine: toxicity, such as by determining the lethal dose (LD) and the LD50 in a suitable animal model, for example, a rodent such as a rat or a mouse; and, the dosage of the composition (s), the concentration of the components therein, and the timing of the administration of the composition (s), which will produce an adequate response. Such determinations do not require undue experimentation from the expert's knowledge, this description, and the documents cited herein. And, the time for consecutive administration can be ascertained without undue experimentation. In some embodiments, MAPCs are encapsulated for administration, particularly where encapsulation improves the efficacy of the therapy, or provides advantages in handling and / or storage duration. Encapsulation in some embodiments where the effectiveness of MAPC-mediated immunosuppression is increased, may also reduce, as a result, the need for an immunosuppressive drug therapy. Also, encapsulation in some embodiments provides a barrier to the immune system of a subject which can further reduce an immune response of the subject to MAPCs (which is generally not immunogenic or only weakly immunogenic in allogeneic transplants), whereby any graft rejection or inflammation that might occur during administration of the grafts is reduced. cells In a variety of embodiments in which MAPCs are administered in a mixture with cells of another type, which are more immunogenic typically in an allogeneic or xenogenic environment, encapsulation can reduce or eliminate adverse host immune responses to host animals. cells other than MAPC and / or GVHD that could occur in an immunocompetitive host animal if the mixed cells are immunocompetent and recognize the host animal as non-self. The MAPCs can be encapsulated by the membranes, as well as by capsules, prior to implantation. It is contemplated that any of many available cell encapsulation methods may be employed. In some embodiments, cells are encapsulated individually. In some embodiments, many cells are encapsulated within the same membrane. In the modalities in which the cells are to be removed after implantation, a relatively large size structure that encapsulates many cells, such as within a single membrane, can provide a convenient means of recovery.

A wide variety of materials can be used in various modalities for the microencapsulation of MAPCs. Such materials include, for example, polymer capsules, alginate-poly-L-lysine-alginate microcapsules, poly-L-lysine barium alginate capsules, barium alginate capsules, polyacrylonitrile-polyvinyl chloride (PAN / PVC) in the form of hollow fibers, and hollow polyethersulfone fibers (PES). The techniques for microencapsulation of cells that can be used for the administration of MAPCs are already known to those skilled in the art and are described, for example, in Chang, P., et al., 1999; Matthew, H.W., et al., 1991; Yanagi, K., et al., 1989; Cai Z.H., et al., 1988; Chang, T.M., 1992 and in the U.S. patent. No. 5,639,275 (which, for example, describes a compatible capsule for the long-term maintenance of cells that stably express biologically active molecules.) Additional encapsulation methods are in European Patent Publication No. 301,777 and US Pat. Nos. 4,353,888, 4,744,933, 4,749,620, 4,814,274, 5,084,350, 5,089,272, 5,578,442, 5,639,275, and 5,676,943, all of which are incorporated herein for reference in the relevant parts for the encapsulation of the MAPCs. polymer, such as a biopolymer or synthetic polymer. Examples of the biopolymers include, but are not limited to, fibronectin, fibrin, fibrinogen, thrombin, collagen, and proteoglycans. Other factors, such as the cytokines described above, can also be incorporated into the polymer. In other embodiments of the invention, the MAPCs can be incorporated in the interstices of a three-dimensional gel. A large polymer or gel, typically, will be surgically implanted. A polymer or gel that can be formulated into sufficiently small particles or fibers can be administered by other non-surgical, more convenient, common routes. The pharmaceutical compositions of the invention can be prepared in many forms including tablets, hard or soft gelatin capsules, aqueous solutions, suspensions, and liposomes and other slow release formulations, such as shaped polymer gels. Oral liquid pharmaceutical compositions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as dry products for constitution with water or other suitable vehicle before use. Such liquid pharmaceutical compositions may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles, (which may include non-aqueous oils). edibles), or conservatives. An oral dosage form can be formulated in such a way that the cell is released into the intestine after it passes through the stomach. Such formulations are described in U.S. Pat. No. 6,306,434 and in the references contained therein. Pharmaceutical compositions suitable for rectal administration can be prepared as unit dose suppositories. Suitable carriers include a saline solution and other materials commonly used in the art. For administration by inhalation, the cells can be conveniently administered from an insufflator, nebulizer, or a pressurized pack or other convenient means of delivering an aerosol spray solution. The pressurized containers may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosing unit can be determined by the provision of a valve to supply a measured quantity. Alternatively, for administration by inhalation or insufflation, a medium may take the form of a dry powder composition, for example, a powder mixture of a modulator and a suitable powder base such as lactose. or starch. The powder composition can be presented in the unit dosage form, for example, in capsules or cartridges or, for example, gelatin or ampoule containers from which the powder can be supplied with the aid of an inhaler or insufflator . For intranasal administration, the cells can be administered by means of a liquid, spray solution, such as an atomizer from a plastic bottle. Other active ingredients MAPCs can be administered with other pharmaceutically active agents. In some embodiments, one or more such agents are formulated together with the MAPCs for administration. In some embodiments, the MAPCs and one or more agents are in separate formulations. In some embodiments, the compositions comprising the MAPCs and / or one or more agents are formulated with respect to the additive use with each other. MAPCs can be administered in a formulation comprising an immunosuppressant agent, such as any combination of any number of a corticosteroid, cyclosporin A, an immunosuppressive agent similar to cyclosporin, cyclophosphamide, antithymocyte globulin, azathioprine, rapamycin, FK-506, and an immunosuppressive agent similar to the macrolide other than KF-506, and rapamycin. In certain modalities, such agents include a corticosteroid, cyclosporin A, azathioprine, cyclophosphamide, rapamycin, and / or FK-506. The immunosuppressive agents according to the above may be the only one of such additional agents or may be combined with other agents, such as other agents noted herein. Other immunosuppressive agents include tacrolimus, mycophenolate mofetil, and sirolimus. Such agents also include antibiotic agents, antifungal agents, and antiviral agents, to name just a few other substances and pharmacologically active compositions that can be used according to the embodiments of the invention. Typical antibiotics or antifungal compounds include, but are not limited to, penicillin, streptomycin, amphotericin, ampicillin, gentamicin, kanamycin, mycophenolic acid, nalidixic acid, neomycin, nystatin, paromomycin, polymyxin, puromycin, rifampicin, spectinomycin, tetracycline, tylosin, zeocin, and cephalosporins, aminoglycosides, and echinocandins. Additional additives of this type refer to the fact that the MAPCs, similar to other stem cells, after administration to a subject, can be "sent" to an environment favorable for their growth and function. Such "targeting" frequently concentrates the cells at sites where they are needed, such as sites of disorder, dysfunction, or immune disease. A number of substances that stimulate self-addressing are already known. They include growth factors and trophic signaling agents, such as cytokines. They can be used to promote the self-targeting of the MAPCs to the sites located as a therapeutic target. They can be administered to a subject prior to treatment with MAPCs, together with MAPCs, or after the MAPCs are administered. Certain cytokines, for example, alter or affect the migration of MAPCs or their differentiated counterparts to sites that have a need for therapy, such as immunocompromised sites. Cytokines that may be used in this regard include, but are not limited to, factor 1 derived from stromal cells (SDF-1), stem cell factor (SCF), angiopoietin 1, derived growth factor of the placenta (PIGF), the stimulating factor of the granulocyte colony (G-CSF), cytokines that stimulate the expression of endothelial adhesion molecules such as ICAMs and VCAMs, and the cytokines that generate or facilitate self-targeting. They can be administered to a subject as a pre-treatment, in the company of the MAPCs or after the MAPCs have been administered, to promote self-addressing to the desired sites and to achieve effects therapeutic improvements, either by improved self-targeting or by other mechanisms. Such factors can be combined with the MAPCs in a suitable formulation for them to be administered jointly. Alternatively, such factors can be formulated and administered separately. The order of administration, formulations, dosage, frequency of dosing, and routes of administration of the factors (such as the cytokines described above) and the MAPCs will generally vary with the disorder or disease being treated, its severity, the subject , other therapies that are being administered, the stage of the disorder or illness, and the prognostic factors, among others. The general regimens that have been established for other treatments provide a support to determine the appropriate dosage in the additive or direct therapy mediated by MAPC. These, together with the additional information provided herein, will make it possible for the expert to determine the appropriate administration procedures according to the embodiments of the invention, without undue experimentation. Routes MAPCs can be administered to a subject by any of a variety of routes known to those skilled in the art that can be used to administer cells to a subject.

Among the methods that can be used in this regard in the embodiments of the invention are methods for the administration of the MAPCs by a parenteral route. Parenteral routes of administration, useful in various embodiments of the invention include, inter alia, administration by intravenous, intraarterial, intracardiac, intraspinal, intrathecal, intraosseous, intraarticular, intrasynovial, intracutaneous, intradermal, subcutaneous, and / or intramuscular injection. In some embodiments, intravenous, intraarterial, intracutaneous, intradermal, subcutaneous, and / or intramuscular injections are used. In some embodiments, intravenous, intraarterial, intracutaneous, subcutaneous, and / or intramuscular injections are used. In various embodiments of the invention, MAPCs are administered by systemic injection. Systemic injection, such as intravenous injection, offers one of the simplest and least invasive routes for the administration of MAPCs. In some cases, these routes may require high MAPC doses to provide optimal efficacy and / or auto-addressing by the MAPCs to the target sites. In a variety of modalities MAPCs can be administered by localized injections and / or target sites to ensure an optimal effect at the target sites. MAPCs can be administered to the subject by means of a hypodermic needle by a syringe in some embodiments of the invention. In several embodiments, the MAPCs are administered to the subject by means of a catheter. In a variety of modalities, the MAPCs are administered by surgical implant. In addition to this aspect, in various embodiments of the invention, the MAPCs are administered to the subject by implant using an arthroscopic process. In some embodiments, the MAPCs are administered to the subject on or on a solid support, such as a polymer or a gel. In various embodiments, the MAPCs are administered to the subject in an encapsulated form. In the further embodiments of the invention, the MAPCs are suitably formulated for oral, rectal, epicutaneous, ocular, nasal, and / or pulmonary delivery, and are administered accordingly. Dosage The compositions can be administered in dosages and by techniques well known to those skilled in the medical and veterinary arts taking into consideration such factors as the age, sex, weight, and condition of the particular patient, and the formulation that will be administered ( for example, solid versus liquid). Doses for humans or other mammals can be determined without undue experimentation by the skilled person, from this description, the documents cited here, and the knowledge in the art. The dose of appropriate MAPCs that will be used according to various embodiments of the invention will depend on numerous factors. The same can vary considerably for different circumstances. The parameters that will determine the optimal doses of MAPCs will be administered for primary and additive therapy, they will generally include some or all of the following: the disease that is treated and its stage; the subject's species, health, sex, age, weight, and metabolic rate; the immunocompetence of the subject; other therapies that are administered; and the potential complications expected from the subject's or genotype's history. The parameters can also include: if the MAPCs are syngeneic, autologous, allogenic, or xenogeneic; its potency (specific activity); the site and / or distribution that must be labeled for the MAPCs that are going to be effective; and characteristics such as those of the site such as the accessibility to the MAPCs and / or the grafting of the MAPCs. Additional parameters include co-administration with MAPCs of other factors (such as growth factors and cytosine). The optimal dose in a given situation will also take into account the manner in which the cells are formulated, the manner in which they are administered, and the degree to which the cells will be located at the target sites after the treatment. administration. Finally, the determination of the optimal dosage will necessarily provide an effective dose that is not below the threshold of the maximum beneficial effect or above the threshold where the detrimental effects associated with the MAPC dose are worth more than the advantages of the increased dose. The optimal dose of MAPCs for some modalities will be in the range of doses used for the transplantation of the mononuclear, autologous bone marrow. For fairly pure preparations of MAPCs, optimal doses in various modalities will vary from 104 to 108 MAPC cells / kg of receptor mass per administration. In some embodiments, the optimum dose for administration will be between 105 to 107 MAPC cells / kg. In many embodiments, the optimal dose for administration will be from 5 x 105 to 5 x 10 6 MAPC cells / kg. By way of reference, the higher doses in the preceding part are analogous to the doses of the nucleated cells used in an autologous mononuclear bone marrow transplant. Some of the lower doses are analogous to the number of CD34 + cells / kg used in autologous mononuclear bone marrow transplantation. It will be appreciated that a single dose may be delivered once, in fractions, or continuously over a period of time. The full dose can also be delivered in a single location or dispersed from split way over several locations. In several embodiments, MAPCs can be administered in an initial dose, and thereafter maintained by additional administration of MAPCs. MAPCs can be administered by a method initially, and thereafter administered by the same method or one or more other methods. The MAPC levels of the subject can be maintained by the ongoing administration of the cells. Several modalities administer the MAPCs either initially or to maintain their level in the subject or both by intravenous injection. In a variety of modalities, other forms of administration are used, depending on the condition of the patient and other factors, described herein elsewhere. It is pointed out that human subjects are generally treated more extensively than experimental animals; but, the treatment usually has a duration proportional to the duration of the disease process and the effectiveness of the treatment. Those skilled in the art will take this into account in the use of the results of other procedures carried out on humans and / or animals, such as rats, mice, non-human primates, and the like, to determine the doses appropriate for human beings. Such determinations, based on these considerations and taking into account the guidance provided by the present description and the prior art will make it possible for the expert to do so without undue experimentation. Appropriate regimens for initial administration and additional doses or for consecutive administration, all may be identical or may be variable. The appropriate regimes can be ascertained by the expert, from this description, the documents cited here, and knowledge in the art. The dose, frequency, and duration of treatment will depend on many factors, including the nature of the disease, the subject, and other therapies that may be administered. Consequently, a wide variety of regimes can be used to administer MAPCs. In some embodiments, the MAPCs are administered to a subject in a dose. In other embodiments, the MAPCs are administered to a subject in a series of one or more doses in succession. In some other embodiments where the MAPCs are administered in a single dose, in two doses or in more than two doses, the doses may be the same or different, and may be administered with equal or unequal intervals between them. MAPCs can be administered at many frequencies over a wide range of time intervals. In some modalities, MAPCs are administered for a period of less than one day. In other modalities they are administered for two, three, four, five, or six days. In some modalities, MAPCs are administered one or more times per week, over a period of weeks. In other modalities they are administered over a period of weeks for one to several months. In several modalities they can be administered during a period of months. In other modalities they can be administered for a period of one or more years. In general, the durations of the treatment will be proportional to the duration of the disease process, the effectiveness of the therapies that are applied, and the condition and response of the subject being treated. Therapeutic uses of immunomodulatory MAPCs The immunomodulatory properties of MAPCs can be used in the treatment of a wide variety of disorders, dysfunctions and diseases, such as those which, intrinsically, as a side effect or as a side effect of treatment, are presented with several processes and effects on the immune system, harmful. Several illustrations are described later. Many modalities in this regard involve the administration of MAPCs to a subject who has a weakened (or compromised) immune system, either as the sole therapy or as an additive therapy with another treatment. In a variety of modalities in this regard, MAPCs are administered to a subject additively to the therapy of radiation or chemotherapy or a combination of radiation and chemotherapy that either, have been, are being, or will be administered to the subject. In many such modalities, radiation therapy, chemotherapy, or a combination of radiation and chemotherapy, are part of a transplant therapy. And in a variety of modalities, MAPCs are administered to treat a deleterious immune response, such as HVG or GVHD. In a variety of embodiments in this regard, the subject is the recipient of a transplant of bone marrow cells or blood cells, typically allogeneic, non-syngeneic, the subject's immune system has been weakened or ablated by therapy of radiation, chemotherapy, or a combination of radiation and chemotherapy, immunosuppressive drugs that are administered to the subject, the subject that is at risk of developing or that has developed graft-versus-host disease, and the MAPCs are administered to the subject in addition to any one or more of the transplant, radiation therapy and / or chemotherapy, and immunosuppressive drugs to treat, such as to ameliorate, arrest, or eliminate, graft-versus-host disease in the subject. Neoplasms The term "neoplasm" generally denotes disorders that involve the clonal proliferation of cells. The Neoplasms can be benign, that is, they are not progressive and are not recurrent, and, if so, they will not generally be life threatening. Neoplasms can also be malignant, meaning that they will progressively worsen, disperse, and, as a rule, threaten life and are often fatal. In several modalities, the MAPCs are administered to a subject suffering from a neoplasm, in an additive manner to a treatment thereof. For example, in some embodiments of the invention in this regard, the subject is at risk of or is suffering from a neoplasm of the blood or bone marrow cells and has undergone or will undergo a blood or bone marrow transplant. Using the methods described herein for MAPC isolation, characterization, and expansion, together with the descriptions here of the immunosuppressive properties of MAPCs, MAPCs are administered to treat, such as to prevent, suppress, or reduce immune reactions. harmful, such as HVG and GVHD, which can complicate transplant therapy. In a variety of modalities that involve transplant therapies, MAPCs can be used alone for an immunosuppressive purpose, or together with other agents. MAPCs can be administered before, during, or after one or more transplants. If they are administered during the transplant, the MAPCs can be administered in a separately or together with the transplant material. If administered separately, the MAPCs can be administered consecutively or simultaneously with the other transplant materials. In addition, the MAPCs may be administered either prior to transplantation and / or afterwards, alternatively to or in addition to the administration at or about the same time as the administration of the transplant. Other agents that can be used in conjunction with MAPCs, in particular transplant therapies, include immunomodulatory agents, such as those described herein elsewhere, particularly immunosuppressive agents, more particularly those described elsewhere herein, especially in this regard, one or more of a corticosteroid, cyclosporin A, an immunosuppressive compound similar to cyclosporin, azathioprine, cyclophosphamide, methotrexate, and an immunosuppressive monoclonal antibody agent. Among the neoplastic disorders of the bone marrow that are treated with MAPCs in the embodiments of the invention in this regard, are the myeloproliferative disorders ("MPDs"); myelodysplastic syndromes (or states) ("MDSs"), leukemias, and lymphoproliferative disorders that include multiple myeloma and lymphomas. MPDs are distinguished by proliferation aberrant and autonomic cells in the bone marrow. The disorder may involve only one type of cell or several. Typically, MPDs involve three cell lineages and are erythrocytic, granulocytic, and thrombocytic. The involvement of the three lineages varies from one MPD to another and between the presentations of the individual types. Typically, they are affected differently and a cell lineage is predominantly affected in a given neoplasm. The MPDs are clearly non-malignant, but they are classified as neoplasms and are characterized by the aberrant self-replication of hematopoietic precursor cells in the bone marrow. MPDs have the potential, however, to develop into acute leukemias. MDSs similar to MPDs are clonal disorders, and they are characterized by the aberrant self-replication of hematopoietic precursor cells in the bone marrow. Similar to the MPDs, they can develop in acute leukemias. Most, but not totally, MDSs manifest peripheral blood cytopenias (chronic myelomonocytic leukemia is the exception), while MPDs do not. The clinical and laboratory manifestations of these disorders may vary with their course and between individual presentations. The demonstrations can overlap, and it can be difficult to make a certain diagnosis that distinguishes one disease from all the others. The diagnosis of neoplasms of the hematopoietic cells of the bone marrow requires special caution, so as not to misdiagnosis as a benign disorder, one that is, in reality, fatally malignant. The following diseases are among the myeloproliferative disorders (MPDs) that can be treated with MAPCs, typically or additively, in various embodiments of the invention: chronic myelocytic leukemia ("CML") / chronic granulocytic leukemia ("CGL"), myelofibrosis agnogenic, essential thrombocythemia, and polycythemia vera. The following diseases are among the myelodysplastic syndromes: (MDSs) that can be treated with MAPCs, typically or additively, in various embodiments of the invention: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts , refractory anemia with blasts in excess in transformation, and chronic myelomonocytic leukemia. The following diseases are among the lymphoproliferative disorders, including multiple myelomas and lymphomas that can be treated with MAPCs, typically additively, in various embodiments of the invention: acute pre-B lymphoblastic leukemia, chronic lymphocytic leukemia ("CLL"), lymphoma of B cells, leukemia of the hair cells, myeloma, multiple myeloma, acute T-cell lymphoblastic leukemia, peripheral T-cell lymphoma, other lymphoid leukemias, and other lymphomas. Also among the neoplasms that can be treated with MAPCs, typically additively, in a variety of embodiments of the invention, are the following: a benign neoplasm of bone marrow cells, a myeloproliferative disorder, a myelodysplastic syndrome, a leukemia acute chronic myelocytic leukemia ("CML") (also called chronic leukemia ("CGL")), agnogenic myelofibrosis, essential thrombocythemia, polycythemia vera, other myeloproliferative disorders, acute multiple myeloma, myeloblastic leukemia, acute promyelocytic leukemia, pre-B lymphoblastic leukemia acute, chronic lymphocytic leukemia ("CLL"), B-cell lymphoma, hair cell leukemia, myeloma, acute T-cell lymphoblastic leukemia, peripheral T-cell lymphoma, other lymphoid leukemias, other lymphomas, or other acute leukemia. The MAPCs can be administered additively to a treatment for any of the following diseases. Treatments Involving Immunoablation or Immunocompromised Therapy Acute leukemias are often difficult to treat by methods that have been effective for others. malignancies This is partially due to the mobility of bone marrow cells, including those of a neoplasm. Partially this may be due to the diffuse distribution of the bone marrow from beginning to end of the skeleton. And this is partly due, no doubt, to the nature of the cells and their transformation. At present, a standard treatment for hematological malignancies involves the ablation of all hematopoietic cells in the patient. There is no way to do this without also ablating the healthy hematopoietic cells of the patient. Typically, the patient is treated using chemo-radiotherapy in sufficiently high doses to exterminate virtually all cells of the bone marrow, both normal and neoplastic. The side effects of treatment are severe, and their effects on patients are unpleasant, painful, and debilitating physically and emotionally. The treatment not only ablates tissue and diseased cells, but also attacks the hematopoietic system and the patient's immune system. The treatment leaves them compromised, dependent on transfusions, and thus highly susceptible to infection so that even an otherwise minor exposure to an infectious agent can be fatal. Normal hematopoietic capacity is restored after this either by transplants of bone marrow or peripheral blood, autologous or allogeneic. Unfortunately, the patient's immune system is not only severely compromised by the ablation treatment but, also in the case of allogeneic transplantation, by immune suppression, to prevent rejection of the transplant and to ensure graft and proliferation of the stem cells new hematopoietic agents that will repopulate the patient's bone marrow and regenerate the patient's immune and hematopoietic systems. Many complications have been found to carry out such transplants to regenerate the hematopoietic and immune systems in an immunocompromised host animal. One is the rejection by competent immune cells and the processes in the host animal, referred to herein as the HVG response. Another is triggered by the immunocompetent cells in the graft, referred to herein as GVHD. These complications could be avoided by the use of a syngenic or autologous donor material. However, syngeneic donors are usually rare and autologous transplants have an increased risk of recurrence of the disease. Therefore, transplants generally use allogeneic cells and tissues obtained from an HLA-compatible donor. Unfortunately, this procedure leads to GVHD, which varies from light to severe in the preponderance of those who receive this form of therapy. If they are not at least improved, these immune reactions will lead to failure of transplant therapy, and by themselves can be fatal to the patient. A variety of agents have been developed to suppress immune responses that improve graft complications, such as HVG and GVHD, as described above. Some are effective enough to reduce adverse immune reactions to a manageable level in some transplant therapies, such as transplantation of the bone marrow and peripheral blood. These agents have improved the prognosis for transplant patients, to some degree; but none of them is totally effective, and all of them have rather substantial disadvantages. It has been found (as described more fully here elsewhere) that MACPs do not elicit an immune response in allogenic host animals. The transplantation of MAPCs to the allogeneic host animal does not, therefore, engender a rejection of the allogeneic graft (ie, HVG). In addition, it has also been found that allogeneic MAPCs can be administered to a host animal at a high concentration without any perceptual effects on the breathing. In addition, it has been found, (as described in more detail here elsewhere) that MAPCs can modulate immune responses. In particular in this regard, it has been found that MAPCs can suppress immune responses, including but not limited to the immune responses involved, for example, in response to HVG and GVHD, to name but two. In a still more detailed particular mode in this regard, it has been found that MAPCs can suppress the proliferation of T cells, even in the presence of potent T-cell stimulators, such as Concavalin A and allogeneic and xenogeneic stimulator cells. . In addition, it has been found that even relatively small amounts of MAPCs can suppress these responses. Actually, only 3% of MAPCs in mixed lymphocyte reactions is sufficient to reduce the T cell response by 50% in vi tro. Accordingly, embodiments of the invention provide compositions and methods and the like for the treatment, such as for the improvement, and / or curing or elimination, of neoplasms, such as neoplasms of hematopoietic cells, particularly those of the bone marrow. that is. Among these are those that are myeloproliferative disorders (MPDs), such as chronic myelocytic leukemia (also called "chronic granulocytic leukemia" and "CGL"), agnogenic myelofibrosis, essential thrombocythemia, polycythemia vera; myelodysplastic syndromes (MDSs), such as refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia; and clearly malignant neoplasms - acute leukemias - such as acute myeloblastic leukemia, chronic myelogenous leukemia (CML), acute promyelocytic leukemia, acute lymphoblastic leukemia B, B-cell lymphoma, hair cell leukemia, myeloma, lymphoblastic leukemia acute T-cell lymphoma, peripheral T-cell lymphoma, and other lymphoid leukemias and lymphomas. The MAPCs can be administered additively to a treatment for any of the preceding diseases. Anemias and Other Blood Disorders In various embodiments of the invention, MAPCs can be used to treat an anemia or other blood disorder, often in an additive manner. Among several modalities in this regard are the modalities in which MAPCs are used to treat the following anemias and / or blood disorders, either uniquely or, typically, additively: hemoglobinopathies, thalassemia, bone marrow failure syndrome, sickle cell anemia, aplastic anemia, or immune hemolytic anemia. Also, the disorders include refractory anemia, refractory anemia with ringed sideroblasts, refractory with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia; or another myelodysplastic syndrome, and in some modalities, Fanconi's anemia. The MAPCs can be administered additively to a treatment for any of the preceding diseases. Immune Diseases The embodiments of the invention relate to the use of MAPC immunomodulation to treat a dysfunction, disorder, or immune disease, either uniquely, or as an additive therapy. The modalities in this regard refer to congenital immune deficiencies and dysfunctions, disorders, and autoimmune diseases. Several modalities refer, in this regard, to the use of MAPCs to treat, in a unique or additive manner, Crohn's disease, Guillain-Barré syndrome, lupus erythematosus (also called "SLE" and systemic lupus erythematosus), multiple sclerosis. , myasthenia gravis, optic neuritis, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's disease, Ord's thyroiditis, diabetes mellitus (type 1), Reiter's syndrome, autoimmune hepatitis, primary biliary cirrhosis, antiphospholipid antibodies ("APS"), opsoclonia-myoclonus syndrome ("OMS"), temporal arteritis, acute disseminated encephalomyelitis ("ADEM" and "ADE"), Goodpasture syndrome, Wegener's granulomatosis, celiac disease, pemphigus, polyarthritis , and autoimmune hemolytic anemia by hot antibodies. Particular modalities among these refer to Crohn's disease, lupus erythematosus (also called "SLE" and systemic lupus erythematosus), multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's disease, diabetes mellitus (from type 1), Reiter's syndrome, primary biliary cirrhosis, celiac disease, polyarthritis, and autoimmune hemolytic anemia due to hot antibodies. In addition, MAPCs are used in a variety of modalities in this regard, uniquely, and, typically, additively, to treat a variety of diseases that are thought to have an autoimmune component, including but not limited to modalities. which can be used to treat endometriosis, interstitial cystitis, neuromyotonia, scleroderma, progressive systemic scleroderma, vitiligo, vulvodynia, Chagas disease, sarcoidosis, chronic fatigue syndrome, and deautonomy. Immune system disorders, inherited, include Combined Immunodeficiency (SCID) including but not limited to SCID with Adenosine Deminase Deficiency (ADA-SCID), SCID that is X-linked, SCID with absence of T and B cells, SCID with absence of cells T, Normal B Cells, Omenn Syndrome, Neutropenia including but not limited to Kostmann's Syndrome, Myelocatexis; Ataxia-Telangiectasia, Nude Lymphocyte Syndrome, Common Variable Immunodeficiency, DiGeorge Syndrome, Leukocyte Adhesion Deficiency; and phagocyte disorders (phagocytes are cells of the immune system that can swallow and kill foreign organisms) including but not limited to Chediak-Higashi Syndrome, Chronic Granulomatous Disease, Actin Deficiency of Neutrophils, Reticular Dysgenesis. The MAPCs can be administered additively to a treatment for any of the preceding diseases. Inflammatory diseases In addition, in a variety of embodiments of the invention, MAPCs can be used to treat inflammatory diseases, either with a single agent or additively. In many such embodiments, MAPCs can be used to treat serious inflammatory conditions, such as those arising from the acute allergic reaction, or as adjuvants for other diseases or treatments. For the most part, at present, the use of MAPCs in this regard is limited to acute cases in which the subject is at risk of greater disability or loss of life. The MAPCs can be administered additively to a treatment for any of the preceding diseases. MAPCs as described in U.S. Pat. No. 7,015,037 Human MAPCs are described in the art. Methods of MAPC isolation for humans and mice are already known in the art. Therefore it is now possible for a person skilled in the art to obtain aspirated materials from the bone marrow, brain or liver biopsies, and other organs, and isolate the cells using positive or negative selection techniques available to those with experience in the art. art, which are based on genes that are expressed (or not expressed) in these cells (for example, by functional or morphological assays such as those described in the applications referred to above, which have been incorporated herein for reference). Such methods are described, for example, in U.S. Pat. No. 7,015,037, the contents of which are incorporated herein for reference for their description of MAPCs and preparation methods. Isolation and Growth of MAPCs as described in PCT / US00 / 21387 Methods of MAPC isolation for humans and the mouse are already known in the art. They are described, for example, in US Patent No. 7,015,037, PCT / US00 / 21387 (published as WO 01/11011), and PCT / US02 / 04652 (published as WO 02/064748), and these methods, in the company of the characterization of MAPCs described therein, are incorporated herein for reference. The MAPCs were initially isolated from the bone marrow, but were subsequently established from other tissues, including the brain and muscles (Jiang, Y. et al., 2002). Accordingly, MAPCs can be isolated from multiple sources, including from the bone marrow, placenta, umbilical cord and cord blood, muscles, brain, liver, spinal cord, blood or skin. For example, MAPCs can be derived from bone marrow aspirate materials, which can be obtained by standard means available to those skilled in the art (see, eg, Muschler, GF, et al., 1997; Batinic, D ., et al., 1990). Phenotype of human MAPCs under the conditions described in U.S. Pat. No. 7,015,037 Immunophenotypic analysis by FACS of the human MAPCs obtained after 22-25 duplications of the cells indicated that the cells do not express CD31, CD34, CD36, CD38, CD45, CD50, CD62E and -P, HLA-DR, Mucl8 , STRO-1, cKit, Tie / Tek; and expresses low levels of CD44, HLA-class 1, and β2-microglobulin, but expresses CD10, CD13, CD49b, CD49e, CDw90, Flkl (N > 10). Once the cells suffered > 40 duplications in the re-seeded cultures at approximately 2 x 103 / cm2, the phenotype became more homogeneous, and no cell expressed HLA class-I or CD44 (n = 6). When the cells were grown to a higher confluence, they expressed high levels of Mucl8, CD44, HLA class 1 and β2-microglobulin, which are similar to the phenotypes described for MSC (N = 8) (Pittenger, 1999). Immunohistochemistry showed that human MAPCs grown at approximately 2 x 103 / cm2 of sowing density expressed EGF-R, TGF-R1 and -2, BMP-R1A, PDGF-Rla and B, and that a small subpopulation (between 1 and 10%) of the MAPCs stained with anti-SSEA4 antibodies (Kannagi, R, 1983). Using the Clontech cDNA arrays, the expressed genetic profile of the human MAPCs cultured at planting densities of approximately 2 x 10 3 cells / cm 2 for 22 and 26 duplicates of the cells were determined: A. The MAPCs did not express CD31, CD36, CD62E, CD62P, CD44-H, cKit, Tie, the receptors for IL1, IL3, IL6, IL11, G CSF, GM-CSF, Epo, Flt3-L, or CNTF, and the levels below HLA-class- I, CD44-E and Muc-18 mRNA. B. MAPCs expressed mRNA for cytokines BMP1, BMP5, VEGF, HGF, KGF, MCP1; the cytokine receptors Flkl, EGF-R, PDGF-Rla, gpl30, LIF-R, activin-R1 and -R2, TGFR-2, BMP-R1A; the adhesion receptors CD49c, CD49d, CD29; and CD10. C. The MAPCs expressed the mRNA for hTRT and TRF1; the transcription factor of the POU domain oct-4, sox-2 (required with oct-4 to maintain the undifferentiated state of ES / EC, Uwanogho D., 1995), sox 11 (neural development), sox 9 (chondrogenesis) ) (Lefebvre V., 1998); transcription factors of homeodeomaine: Hox-a4 and -a5 (specification of the cervical and thoracic skeleton, organogenesis of the respiratory tract) (Packer AI, 2000), Hox-a9 (myelopoiesis (Lawrence H, 1997), Dlx4 (specification of structures peripheral and forebrain of the head) (Akimenko MA, 1994), MSX1 (osteogenesis of the embryonic mesoderm, muscles and heart, adult and chondro and osteogenesis) (Foerst-Potts L. 1997), PDX1 (pancreas) (Offield MF , 1996) D. The presence of oct-4 mRNA, LIF-R, and hTRT was confirmed by RT-PCR, E. In addition, RT-PCR showed that the rex-1 mRNA and the Rox-1 mRNAs were expressed in MAPCs. Oct-4, rex-1 and rox-1 were expressed in MAPCs derived from the bone marrow of the human being and the murine and brain and liver of the murine. Human MAPCs expressed LIF-R and stained positively with SSEA-4. Finally, the Oct-4, LIF-R, rex-1 and rox-1 mRNA levels were found to be increased in cultured human MAPCs beyond 30 duplicates of cells, which led to phenotypically more homogeneous cells. In contrast, MAPCs cultured at high density lost the expression of these markers. This was associated with senescence before 40 duplicates of cells and loss of differentiation for cells other than chondroblasts, osteoblasts, and adipocytes. Therefore, the presence of oct-4, combined with rex-1, rox-1, and sox-2, correlates with the presence of more primitive cells in the MAPC cultures. Methods for cultivating MAPCs are well known in the art. (See, for example, U.S. Patent No. 7,015,037, which is incorporated herein for reference with respect to methods for growing MAPCs). The density for the culture of the MAPCs can vary from about 100 cells / cm 2 or about 150 cells / cm 2 to about 10,000 cells / cm 2, including about 200 cells / cm 2 to about 1,500 cells / cm 2 to about 2,000 cells / cm 2. The density can vary between species. Additionally, the optimum density may vary depending on the conditions of the culture and the source of the cells. It is within the experience of the expert to determine the optimum density for a given set of conditions and cells of the culture. Also, effective concentrations of atmospheric oxygen of less than about 10%, including about 3-5%, can be used at any time during isolation, growth, and differentiation of the MAPCs in the culture. The present invention is further described by means of the following non-limiting, illustrative examples. EXAMPLES Example 1: Human MAPCs (from Bone Marrow Mononuclear Cells) Bone marrow mononuclear cells were obtained from materials aspirated from the bone marrow of the posterior iliac crest of > 80 healthy human volunteers. Ten to 100 cubic centimeters of bone marrow were obtained from each subject. Mononuclear cells ("MNCs") were obtained from the bone marrow by centrifugation over a Ficoll-Paque density gradient (Sigma Chemical Co., St. Louis, MO). The bone marrow MCNs were incubated with CD45 and Glicoforin A microbeads (Miltenyi Biotec, Sunnyvale, CA) for 15 minutes and the CD45 + GlyA + cells were removed by placing the sample in the front of a SuperMACS magneto. The eluted cells are 99.5% of CD45"GlyA".

The depletion of CD45 + GlyA + cells led to the recovery of CD45 ~ GlyA ~ cells that constituted approximately 0.05 to 0.10% of the mononuclear cells of the bone marrow. The cells were selected so as not to express the CD45 antigen of the common leukocyte, or the glycophorin A of the marker of the erythroid precursor (GlyA). CD45"GlyA ~ cells make up 1/103 cells of the bone marrow CD45" GlyA "cells were plated in fibronectin-coated cavities in 2% FCS, EGF, PDGF-BB, dexamethasone, insulin, linoleic acid , and ascorbic acid After 7-21 days, small groups of adherent cells were developed.Using limiting dilution assays, the frequency of the cells that cause these adherent groups is 1/5 x 10 3 CD45 ~ GlyA cells ". When the colonies appeared (approximately 103 cells), the cells were recovered by trypsinization and plated again every 3-5 days in a 1: 4 dilution under the same culture conditions. The cell densities were maintained between 2-8 x 103 cells / cm2. Example 2: Mouse MAPCs All tissues were obtained according to the rules of the University of Minnesota IACUC. The BM mononuclear cells (BMMNC) were obtained by Ficoll Hypaque separation. BM were obtained from ROSA26 mice or from C57 / BL6 mice 5-6 weeks old. Alternatively, Brain and muscle tissue was obtained from 129 3-day-old mice. The muscles of the proximal parts of the front and rear legs were cut and shredded completely. The tissue was treated with 0.2% collagenase (Sigma Chemical Co., St Louis MO) for 1 hour at 37 ° C, followed by 0.1% trypsin (Invitrogen, Grand Island, NY) for 45 minutes. The cells were vigorously ground and passed through a 70 μm filter. The suspensions of the cells were collected and centrifuged for 10 minutes at 1600 rpm. The brain tissue was completely dissected and shredded. The cells were dissociated by incubation with 0.1% trypsin and 0.1% DNAse (Sigma) for 30 minutes at 37 ° C. The cells were then vigorously ground and passed through a 70 μm filter. The suspensions of the cells were collected and centrifuged for 10 minutes at 1600 rpm. BMMNC or muscle or brain suspensions were placed on plates at 1 x 105 / cm2 in the expansion medium [2% FCS in the Dulbecco low glucose minimum essential medium (LG-DMEM), 10 ng / ml of each of the platelet derived growth factor (PDGF), epidermal growth factor (EGF) and leukemia inhibitory factor (LIF)] and was maintained at 5 x 103 / cm2. After 3-4 weeks, the cells recovered by trypsin / EDTA were depleted of CD45 + GlyA + cells with micromagnetic beads. The resulting CD45 ~ GlyA "cells were plated to 10 cells / well in 96-well plates coated with FN and expanded to cell densities between 0.5 and 1.5 x 10 3 / cm 2 The potential expansion of MAPCs was similar regardless of the tissue from which they were derived Example 3: Rat MAPCs BM and MNCs from Sprague Dawley, Lewis, or Wistar rats were obtained and plated under conditions similar to those described for mMAPCs. Cloning of Rat and Mouse MAPCs To demonstrate that differentiated cells were derived from a single cell and MAPCs are actually "clonal" multipotent cells, cultures were made in which MAPCs have been transduced with a retroviral vector. Undifferentiated MAPCs and their progeny were found to have the retrovirus inserted in the same site in the genome.The studies were done using two ROSA26 MAPCs derived indep in particular, two MAP57 of C57BL / 6, and a population of rMAPC expanded for 40 up to > 90 PDs, as well as with the "clonal" and "clonal" mouse transducidas with eGFP. No difference was observed between the transduced and non-transduced cells with eGFP. It is notable that the expression of eGFP persisted in the MAPCsDifferentiated Specifically, the murine and rat BMMNCs cultured on FN with EGF, PDGF-BB, and LIF for three weeks were transduced on two consecutive days with an oncorretroviral vector of eGFP. After this, the CD45 + and GlyA + cells were depleted and the cells were subcultured in 10 cells / well. The rat BMMNCs transduced with eGFP were expanded for 85 PDs. Alternatively, expanded mouse MAPCs were used for 80 PDS. Subcultures of undifferentiated MAPCs were generated by placing 100 MAPCs of the crops maintained for 75 PDs and re-expanding them up to > 5 x 106 cells. The expanded MAPCs were induced to differentiate in vi tro with respect to the endothelium, neuroectoderm, and endoderm. Lineage differentiation was shown by staining with antibodies specific for these cell types. Example 5: Human MAPCs are not immunogenic Mesenchymal stem cells have demonstrated low immunogenicity in vitro and the ability to be grafted through allogeneic receptors (Di Nicola, M. et al. (2002) Blood 99: 3838-3843 Jorgensen, C. et al. (2002) Gene Therapy 10: 928-931, Le Blanc, K. et al. (2003) Scandinavian Journal of Immunology 57: 11-20; Mclntosh, K. et al. (2000) Graft 6: 324-328; Tse, W. et al. (2003) Transplantation 75: 389-397).

Figure 3 shows that human MAPCs exhibit low immunogenicity in vi tro and are immunosuppressive when they are added to the MLRs of otherwise potent T cells (Tse, W. et al (2003)). The results were consistent across all donor pairs and responders tested. The responder and stimulator cells were prepared for these experiments and the MLRs were performed according to the procedures described by Tse, W. et al. (2003). Example 6: MAPCs modulate T-cell responses The ability of MAPCs to modulate, and in this case suppress, the immune responsiveness, is illustrated by T-cell proliferation assays, for example, which may be carried out as follows. Preparation of Responding T Cells Responding cells were prepared from the lymphatic nodes of Lewis rats. The lymph nodes were surgically removed from the rats and immediately placed in 3 to 5 ml of the medium (complete RPMI or complete DMEM) in 60 x 15 mm Petri dishes. The lymph nodes were dispersed through a nylon filter (using the manual plunger of a syringe). The dispersions were loaded into 50 ml tubes and centrifuged at 1,250 rpm for 8 minutes. The supernatants (from the medium) results. The pellets (containing the cells) were resuspended in fresh medium (complete RPMI or complete DMEM). The cells were washed three times, and then resuspended in a fresh medium. The resuspended cell densities were determined by counting the number of cells in a known volume thereof. The cells were kept on ice. Prior to its use, the cells were resuspended in the medium (complete RPMI or complete DMEM) at a density of 1.25 x 106 cells / ml. Preparation of the MAPCs The MAPCs were prepared from the Lewis or Sprague-Dawley rats and then frozen as described above. They were thawed and then irradiated at 3000 rad. The irradiated cells were then resuspended in medium (complete RPMI or complete DMEM) at densities of 0.4 × 10 6 cells / ml, 0.8 × 10 6 cells / ml, and 1.6 × 10 6 cells / ml. Preparation of Concavalin A Concavalin A ("ConA") was used to activate T cells. ConA was dissolved in PBS (complete RPMI or complete DMEM) at final concentrations of 0 (PBS only), 10, 30, and 100 μg / ml. Test Procedure Each point of the data is based on at least three determinations. μl of each of the solutions of ConA were added to the cavities of the microtitre plates (96 cavities), flat bottom), followed by 80 μl / cavity of the responder cells and 100 μl / cavity of the MAPCs. Plates were incubated at 37 ° C in humidified incubators under 5% C02 for 4-5 days. The plates were supplied with pulses of 1 μCi / cavity of 3H-thymidine during the last 14-18 hours of the culture. After this, the cells were automatically collected on glass fiber filters using a Tomtec collection machine. Thymidine uptake was quantified in a microplate scintillation counter. The results were expressed as average counts per minute (CPM) +/- SD. The final concentrations of ConA in the growth medium in the cavities were 0, 1, 3.16, and 10 μg / ml. The MAPCs were present in the cavities in the amounts of 0, 0.4, 0.8, and 1.6 x 105 cells / cavity. The results, described below, are illustrated in Figure 4. Resulted The increasing amounts of ConA led to a dose-dependent stimulation of T cell proliferation (Figure 4, LN only). The Lewis MAPCs inhibited the proliferation of T cells stimulated with ConA. Inhibition was dependent on the dose of the MAPCs. The maximum inhibition, 50%, occurred at the highest dose of MAPCs used in these experiments and with the low and intermediate doses of ConA. These results are shown graphically in Figure 4 and show that MAPCs suppress the proliferation of activated T cells. Example 7: MAPCs Suppress Proliferation of Stimulated T Cells The ability of MAPCs to suppress the proliferation of syngeneic and non-corresponding (allogenic) T cell proliferative responses is demonstrated by the results of mixed lymphocyte reactions. The following example shows the suppressive effects of MAPCs on the T cells of Lewis rats stimulated by the irradiated splenocytes of DA rats. The MAPCs of syngeneic Lewis rats and non-corresponding (allogenic) Sprague-Dawley rats both inhibited T cell responses in a dose-dependent manner. The experiments were carried out as follows. Preparation of Responding T Cells Responding cells were prepared from the lymph nodes of the Lewis rats as described above. Bazo Stimulatory Cells, Irradiated Spleens were surgically removed from AD rats. The splenocytes were then isolated from the spleens essentially as described above for the isolation of the responder cells of the lymphatic nodes of Lewis rats. The isolated spleen cells were irradiated at 1800 rad. The cells were resuspended up to 4 x 106 / ml and kept on ice until they were used. Preparation of MAPCs Syngeneic MAPCs were prepared from the Lewis rats as described above. The non-corresponding (allogenic) MAPCs were prepared from the Sprague-Dawley rats in the same manner. The MAPCs of the Lewis and Sprague-Dawley rats were irradiated at 3000 rad, then resuspended in the RPMI medium at densities of 0.03 x 106 / ml, 0.06 x 106 / ml, 0.125 x 106 / ml, 0.25 x 106 / ml, 0.5 x 106 / ml, 1 x 106 ml, and 2 x 106 / ml. Assay Procedure The cavities of a 96-well microtiter plate were loaded with: 100 μl of MAPCs (at the dilutions indicated above) or 100 μl of the medium; 50 μl of a storage material of the stimulating or control cells; 50 μl of each of the storage materials of the responder or control cells; and the medium (complete RPMI or complete DMEM) when required to equalize the total volumes up to a final volume of 200 μl / well. 96-well flat-bottom microtiter plates cavities were used for all trials. Each data point is based on at least three determinations. Plates were incubated at 37 ° C in humidified incubators under 5% C02 for 4-5 days. The plates were supplied with pulses of 1 μCi / cavity of 3H-thymidine during the last 14-18 hours of the culture. After this, the cells were automatically collected on glass fiber filters using a Tomtec collection machine. Thymidine uptake was quantified in a microplate scintillation counter. The results were expressed as average counts per minute (CPM) +/- SD. Resulted The exposure of T cells derived from lymph nodes of Lewis rats (Responders) to stimulator cells consisting of irradiated splenocytes from DA rats (Stimulators) led to very robust proliferative responses of responder cells, as shown in Figures 5A and 5B, for "without MAPC". The addition of the increasing doses of the syngeneic Lewis MAPCs (Figure 5A) and the third part of the non-corresponding (allogenic) Sprague-Dawley MAPCs (Figure 5B) led to a significant and dose-dependent inhibition of the activation of the T cells. The levels Maximum inhibition were ~ 80%. Even at the lowest doses of MAPCs, there was 40-50% inhibition. There was no 3H-thymidine incorporation in the controls, which shows that the incorporation was due solely to the proliferation of the activated responder T cells, as shown in Figures 5A and 5B. In summary, the results show that syngeneic and third-party (allogenic) MAPCs suppress T-cell proliferation even in the presence of potent activator splenocytes from non-corresponding rats. In these experiments, the inhibition had a maximum value when there were similar numbers (200,000 cells) of each of the stimulators, responders, and MAPCs in the reaction. Under these conditions, there was an inhibition of ~ 80%. There was a very substantial inhibition at much lower ratios of the MAPCs with respect to the other cells in the reaction. For example, at 1.5% of the MAPCs, there was a 50% inhibition (3,000 MAPCs against 200,000 of each of the cell types). The results demonstrated not only that MAPCs have a strong immunosuppressive effect, but also a relatively small number of MAPCs is sufficient to inhibit a relatively large number of competent T cells even in the presence of cell activators.

T very powerful. Example 8: MAPCs are Safe The main intermediate risk of intravenous injection of large numbers of cells is the accumulation of cell clumps in the lungs that led to respiratory stress and can cause cardiac arrest. To demonstrate the safety of MAPCs in this regard, the effects of intravenous injection of MAPCs on respiratory rates in Buffalo rats were measured. The MAPCs were prepared from the rats of Lewis as described above ("Lewis MAPCs"). Splenocytes were also prepared from the Lewis rats as described above for use as controls ("Lewis Splenocytes"). A female Lewis rat served as the donor of splenocytes for each group (experimental condition). Two female Buffalo rats were used as recipients for each group (experimental condition). The cells were administered to the rats as indicated below. The data are graphically displayed in Figure 6. The agreement of the data points for the individual rats as they are numbered subsequently, is listed in the vertical legend to the right of Figure 6. All the rats were Buffalo rats. 1.1, 1.2 10 x 106 Lewis MAPC per rat 2. 1, 2.2 5 x 106 Lewis MAPC per rat 3.1, 3.2 2.5 x 106 Lewis MAPC per rat 4.1, 4.2 1.2 x 106 Lewis MAPC per rat 5.1, 5.2 10 x 106 Lewis splenocytes per rat 6.1, 6.2 5 x 106 Lewis splenocytes per rat 7.1, 7.2 2.5 x 106 Lewis splenocytes per rat 8.1, 8.2 1.2 x 106 Lewis splenocytes per rat As indicated above, the rats were injected with 1.2, 2.5, 5, or 10 million MAPCs or 1.2 , 2.5, 5, or 10 million splenocytes. This corresponded to 5, 10, 25, or 50 million cells / kg. Respiratory rates were measured before (0 minutes) and at 1, 5, and 10 minutes after the intravenous injection of MAPCs or splenocytes. Respiratory rates were measured for 20 seconds and counts were multiplied by 3 to derive respiratory rates per minute. The normal rat respiratory rates are between 60 and 140 / min. Resulted All animals survived after intravenous cell injections. No difference or trends in respiratory rates were observed under different conditions. The results are shown in Figure 6. The initial respiratory rates (0 minutes) were slightly reduced because the animals were anesthetized before the cells were 1 injected. At each moment of time, the measurements were grouped without any apparent tendency. In summary, intravenous injection of 5-50 million MAPCs / kg did not cause changes in respiratory rates or mortality at any of the rates under any of the conditions. The results show that the intravenous injection of MAPCs is safe even at high doses. Example 9: MAPC Expression of Immune Markers The immunomodulatory nature of MAPCs was further characterized by the determination of immune regulatory markers in MAPCs, such as those described by Barry et al. (2005). The markers were determined using antibodies specific for the marker and FACS analysis. The MAPCs from the rat bone marrow were isolated, cultured, and collected as described above. For the FACS analysis, the cells were suspended at 1-2 x 10 8 cells / ml in PBS. 200 μl of the suspension of the cells were added to each of a series of 12 x 75 propylene tubes. An antibody specific for the marker or a control was added to each of the tubes, and they were then incubated for 15-20 minutes at room temperature. At the end of the incubation period, 2 ml of PBS is added to each tube and they were then centrifuged at 400 x g for 5 hours. minutes The supernatants were discarded and the cells were resuspended in each tube in 100 μl of PBS. A fluorescently labeled secondary antibody was added to each tube in an appropriate volume, and the tubes were again incubated for 15-20 minutes at room temperature, this time in the dark. After this, 2 ml of PBS was added to each tube and they were centrifuged again at 400 x g for 5 minutes. The supernatants were discarded, and the cells in each tube were resuspended in 200 μl of PBS and then kept on ice until analyzed by FACS. The results are listed and presented graphically in Table 1. As shown in the table, the MAPCs of the rat are: (a) positive for MHC class I, CDllc, CD29, and CD90, and (b) negative for MHC class II, CDllb, CD31, CD40, CD45, CD54, CD80, CD86, CD95, and CD106. Negative results were validated for each antibody by positive staining of the control cells, including the endothelial and peripheral blood cells of the rat. These configurations of marker expression, in terms of the markers that are detected in the MAPCs as those that were not detected, are totally consistent with the immunostimulatory cross-section of the MAPCs.

Table 1 - Detection of Markers Related to Immune Cells in MAPCs Example 10: MAPCs suppress T cells previously stimulated in the MLRs Cells Responding cells were prepared from the lymph nodes of the Lewis rats as described above. Splenocytes, prepared from Buffalo or DA rats, as described above, were used as stimulators. The MAPCs were prepared as described above. PROCEDURES The MAPCs were added to a first group of MLRs at the same time as the splenocytes (as was done in the preceding examples). In addition, the MAPCs were added to a second group of MLRs that were identically adjusted to the first group. However, the MAPCs in the second group were added 3 days after the addition of the splenocytes (or control). Therefore, in the first group, the MAPCs were added before the T cells start to proliferate in response to the splenocytes. In the second group, the MAPCs were added when the response of the T cells to the splenocytes has been suffered for 3 days. All plates were incubated for a total of 4 days, then pulsed with 3H-thymidine and collected, as described in the preceding examples. The examples were carried out in another manner as described for the MLRs in the preceding examples. Each of the data points was based on the least three determinations. Resulted As can be seen from the right side of the Figure 7, MAPCs strongly suppressed the proliferation of T cells in MLRs when they are added three days after stimulation by allogeneic splenocytes. The comparison of the left and right sides of Figure 7 show that the MAPCs suppress strongly the proliferation reaction in progress. Quantitatively, the results show that for the cells of the Buffalo rats that were supplied with MAPCs 3 days post-stimulation, they suppressed the proliferation of the T cells in 50% compared with the controls (right side of the figure), and in 75 % when they were added at the same time as stimulating splenocytes (left side of the figure). Similarly, for DA cells, MAPCs added 3 days post-stimulation suppressed the proliferation of T cells in 33% when compared to controls (right side of the figure), and in 70% when added at the same time as stimulating splenocytes (left side of the figure). In all cases, the degree of immunosuppression by MAPCs depends, in general, on the number of MAPCs that were added to the reaction. In other words, immunosuppression depends on the doses of MAPCs added to the MLRs. The publications cited above are incorporated here for reference in their entirety as for the specific subject matter for which they have been cited. Example 11: Inhibition by MAPCs of T lymphocytes is reversible. T cells were cultured with allogeneic splenocyte stimulators for 13 days in the presence or absence of irradiated MAPCs. After the 13 day culture, the T cells were recovered and plated with the irradiated allogeneic splenocytes, with or without the MAPCs, and cultured for 4 days. The proliferation of T cells that was inhibited by the presence of irradiated MAPCs during the primary culture period was restored when the MAPCs were absent during secondary culture. The presence of MAPCs in the secondary culture inhibited the proliferation of T cells comparable to that in the primary culture, with up to 90% inhibition at a 1: 2 ratio of MAPCs with respect to T cells. The results, presented in Figure 8, they clearly demonstrate that the inhibition of T cell proliferation by MAPCs in MLRs is reversible, and that MAPCs inhibit the proliferative responses of both primary and secondary T cells. Example 12: MAPCs prevent GVHD The ability of MAPCs to suppress GVHD was demonstrated in a rat model as follows. The donor T cells of the Buffalo rats served as the "graft" in the receptors of the Lewis x Buffalo rats. The graft cells of the Buffalo rats were activated by the "foreign" Lewis cells in the host animal, leading to GVHD in the model. The recipient rats Fl (Lewis x Buffalo) were irradiated subletically on day 0 with a single dose of 600 rad. On the same day they were injected intravenously with 2 x 107 bone marrow cells and 10 x 107 T cells (splenocytes) from the Buffalo donor rats. Rats were checked 3x / week to verify the signs of GVHD, evaluated by posture, activity, fur texture, skin, and weight loss. Group 1 did not receive MAPCs. Group 2 received 2.5 x 106 MAPCs on day 1. Group 3 received 2.5 x 106 MAPCs each of the days of day 1 and day 8. There were five rats in each group. The results are shown in Figure 9. Administration of MAPC clearly improved survival rates. Forty percent of the rats in Group 2 and sixty percent of the rats in Group 3 survived at the end of the experiment (42 days), while all the rats that did not receive the MAPCs (Group 1) succumbed to GVHD for the day 21. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (27)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A method of additive treatment of a subject, characterized in that it comprises: administering to a subject at risk of or suffering from an immune dysfunction, for a effective route and in an effective amount to treat immune dysfunction, cells that: are not embryonic stem cells, embryonic germ cells, or germ cells; they can be differentiated into at least one cell type from each of at least two of the endodermal, ectodermal, and mesodermal embryonic lineages; they do not provoke a harmful immune response in the subject; and are effective for treating immune dysfunction in the subject, wherein the cells are administered additively to one or more other treatments administered to the subject to treat the same thing, to treat something different, or both.
2. 2. A method according to claim 1, characterized in that the cells can be differentiated into at least one cell type from each of the endodermal, ectodermal, and mesodermal embryonic lineages.
3. 3. A method according to claim 1, characterized in that the cells express telomerase.
4. 4. A method in accordance with the claim 1, characterized in that the cells are positive for oct-3/4.
5. 5. A method according to claim 1, characterized in that the cells have suffered at least 10 to 40 duplications of the cells in the culture prior to their administration to the subject.
6. 6. A method according to claim 1, characterized in that the cells are allogeneic with respect to the subject.
7. 7. A method in accordance with the claim 1, characterized in that the cells are administered to the subject additively with respect to another treatment that is administered before, at the same time as, or after the cells are administered.
8. 8. A method in accordance with the claim 1, characterized in that the cells are mammalian cells.
9. 9. A method according to claim 8, characterized in that the cells are human cells.
10. 10. A method according to claim 8, characterized in that the cells are derived from cells isolated from the placental tissue, umbilical cord tissue, umbilical cord blood, bone marrow, blood, tissue from the spleen, thymus tissue, spinal cord tissue, or liver tissue.
11. 11. A method according to claim 1, characterized in that the subject is a mammal.
12. 12. A method according to claim 9, characterized in that the subject is a human being.
13. 13. A method in accordance with the claim 12, characterized in that the cells are administered to the subject in one or more doses comprising 104 to 108 of the cells per kilogram of the mass of the subject.
14. A method according to claim 12, characterized in that the subject will receive or have received a transplant and will be at risk for or has developed a host response against graft or graft-versus-host disease, and the cells are administered additively to the transplant.
15. 15. A method in accordance with the claim 14, characterized in that the transplant is an organ transplant, the subject is at risk of or has developed a host versus graft response, and the cells are addively administered to the transplant to treat the host versus graft response.
16. 16. A method according to claim 14, characterized in that the subject is being treated or will be treated by radiation or chemotherapy or a combination of radiation and chemotherapy, weakening the immune system of the subject, and the treatment with the cells is additive with Regarding radiation, chemotherapy, or the combination of the two.
17. 17. A method in accordance with the claim 14, characterized in that the cells are administered to a subject having a compromised immune system.
18. 18. A method in accordance with the claim 17, characterized in that the transplant is a bone marrow or blood transplant, the subject is at risk for or has developed graft-versus-host disease, and the cells are addively administered to the transplant to treat graft-versus-host disease.
19. 19. A method in accordance with the claim 15, characterized in that the subject will be or is being treated with an immunosuppressant agent, and the treatment with the cells is additive with respect thereto.
20. 20. A method in accordance with the claim 18, characterized in that the subject will be or is being treated with an immunosuppressive agent, and the treatment with the cells is additive with respect thereto.
21. 21. A method in accordance with the claim 1, characterized in that the subject is at risk of or is suffering from one or more of a neoplasm, an anemia or other blood disorder, and an immune dysfunction, wherein the treatment with the cells is additive with respect to a treatment of the same.
22. 22. A method according to claim 1, characterized in that the subject is at risk of or is suffering from one or more of a myeloproliferative disorder, a myelodysplastic syndrome, leukemia, multiple myeloma, a lymphoma, a hemoglobinopathy, a thalassemia, a syndrome of bone marrow failure, sickle cell anemia, aplastic anemia, Fanconi anemia, an immune haemolytic anemia, a congenital immune deficiency, or an autoimmune dysfunction, where the treatment with the cells is additive with respect to a treatment thereof.
23. 23. A method of adjunctive treatment of a human subject, characterized in that it comprises: administering to a subject at risk of or suffering from a graft-versus-host or host-versus-graft disease, by an effective route and in an effective amount to treat the disease, cells that: are not embryonic stem cells, embryonic germ cells, or germ cells; they can be differentiated into at least one cell type from all three of the endodermal, ectodermal, and mesodermal embryonic lineages; they do not provoke a harmful immune response in the subject; and are effective for treating the disease in the subject, wherein the cells are administered additively to one or more other treatments administered to the subject to treat the same disease, to treat something different, or both.
24. 24. A method in accordance with the claim 23, characterized in that the cells have a telomerase activity, are positive to oct-3/4, and have suffered at least 10 to 40 duplications of the cells in the culture prior to their administration to the subject.
25. 25. A method in accordance with the claim 24, characterized in that the cells are allogenic with respect to the subject.
26. 26. A method according to claim 25, characterized in that the subject will receive or have received a transplant and the cells are administered additively to the transplant.
27. 27. A method of compliance with the claim 25, characterized in that the subject is at risk of or is suffering from one or more of a myeloproliferative disorder, a myelodysplastic syndrome, leukemia, multiple myeloma, a lymphoma, a hemoglobinopathy, a thalassemia, a syndrome of bone marrow failure, anemia falciform, aplastic anemia, Fanconi anemia, an immune haemolytic anemia, a congenital immune deficiency, or an autoimmune dysfunction, where the treatment with the cells is additive with respect to a treatment thereof.