WO2012092663A1

WO2012092663A1 - Monoclonal anti-anti-anti-mhc antibodies and uses thereof

Info

Publication number: WO2012092663A1
Application number: PCT/CA2012/000002
Authority: WO
Inventors: Geoffrey W. Hoffmann
Original assignee: Network Immunology Inc.
Priority date: 2011-01-04
Filing date: 2012-01-04
Publication date: 2012-07-12
Also published as: WO2012092665A1; WO2012092664A1

Abstract

This disclosure relates, at least in part, to monoclonal antibodies and uses thereof. The present antibodies include monoclonal anti-anti-anti-MHC antibodies. The uses may include the facilitation of organ transplantation, the treatment of degenerative disorders including autoimmune diseases and cancers. The present disclosure further relates to compositions, uses, methods, systems, processes, kits, antibodies, and the like.

Description

MONOCLONAL ANTI-ANTI-ANTI-MHC ANTIBODIES AND USES THEREOF FIELD

[0001] This disclosure relates, at least in part, to monoclonal antibodies and uses thereof. The present antibodies include monoclonal anti-anti-anti-MHC antibodies. The uses may include the facilitation of organ transplantation, the treatment of degenerative disorders including autoimmune diseases and cancers, and the like. The present disclosure further relates to compositions, uses, methods, systems, processes, kits, antibodies, and the like.

BACKGROUND

[0002] Monoclonal antibodies are important both as a tool in biotechnology and for therapeutic purposes as biological pharmaceuticals.

[0003] Many diseases and conditions may be caused by the immune system not functioning optimally. These include, for example, autoimmune diseases in which case the immune system may be too active, and cancers in which case the immune system may not be sufficiently active. Immune system stabilizers that are effective in aiding in the treatment of such disorders would be useful.

[0004] Although transplantation of organs, tissues or cells from one genetically distinct person (donor) to another (recipient) is relatively commonplace, a shortage of acceptable donors and immunologic rejection of the donated tissue by the recipient remain major hindrances. It is understood that the rejection of a donor's tissue involves both cellular and humoral mechanisms, mediated respectively by T cells and antibodies. The recipient's immune system especially targets histocompatibility antigens on the transplanted cells that are not seen as "self but rather as foreign entities. Except for cases of organ donation between immunologically identical individuals or the special instance of transplantation in individuals with severe combined immunodeficiency disease, the donor's histocompatibility antigens will not completely match the recipient's histocompatibility antigens, and the recipient's immune system will almost certainly react to the incompatible donor's organs, tissues or cells.

[0005] With respect to immunologically-mediated rejection, the most potent of the histocompatibility antigens are the major histocompatibility complex (MHC) antigens known in humans as the human leukocyte antigens (HLAs) which are present on virtually all of the nucleated cells of the human body. The MHC class I antigens include the HLA-A, HLA-B and HLA-C antigens. Since each person receives genes encoding one set of these antigens from each parent, human cells typically express six of these major HLA class I antigens. Organ donors and recipients can also differ in their MHC class II antigens (HLA class II antigens). In addition to the major histocompatibility antigens, there are several minor histocompatibility antigens and other antigens that may limit transplantation success including the ABO and Rh systems.

[0006] When tissue or cells are transplanted, it is desirable to match, to the maximum extent possible, the histocompatibility antigens of the donor and the recipient. The best

immunologic match between donor and recipient is between identical twins, since they share the same major HLA antigens and the same minor histocompatibility antigens; therefore, the recipient identical twin will immunologically tolerate the identical twin donor's organs, tissue or cells.

[0007] More commonly, however, the donor and recipient are not genetically identical resulting in some degree of rejection to the transplanted tissue. To minimize this rejection and permit survival of the engrafted tissue, efforts are routinely made to find the best match between donor and recipient. Even in the best case scenario, there is still a high probability that the minor histocompatibility antigens differ (and likely the major HLA antigens as well), and the donor and recipient will almost certainly be sufficiently distinct in terms of cellular antigens, which results in some degree of graft rejection. In some circumstances, a negative cross-match indicates a recipient has antibodies against the red blood cells of the donor, in which case the donor cannot donate tissue or cells to the recipient without the recipient's immune system responding. Due partly to these negative cross-matches, only a small percentage of available donor-organs or donor-tissues are actually suitable for any given potential recipient.

[0008] If transplantation is carried out, the adverse reactions following transplantation of an organ or tissue from one genetically distinct individual to another can cause difficulties. For example, immunologic rejection of a transplanted organ or tissue can be particularly dangerous if the organ is life-sustaining, such as a heart, liver or lung. The destruction of such an organ may lead directly to the death of the patient. In other circumstances, the quality of life of the recipient can be adversely affected by rejection of transplanted tissues such as insulin-producing pancreatic islet cells or kidneys.

[0009] In order to prevent or limit the rejection, various agents and therapies have been used including: (1) corticosteroids, such as prednisone; (2) cytotoxic drugs, such as azathioprine and cyclophosphamide; (3) x-ray irradiation therapy; (4) anti-lymphocyte and anti-thymocyte globulins; (5) cyclosponne; and (6) monoclonal antibodies, such as OKT3, which reacts specifically with the CD3 antigen-recognition structure of human T cells and blocks the T cell effector function involved in allograft rejection. These agents and therapies are all administered post-transplant and introduce their own undesirable side effects. For example, immunosuppressive drugs, such as prednisone and cyclosponne, are globally

immunosuppressive, which greatly increases the susceptibility of the recipient to serious infections and also increases the susceptibility of the recipients to opportunistic infections, against which normal individuals have strong defenses. High doses of corticosteroids may also cause cataracts, precipitate diabetes mellitus and hypertension, and/or cause

demineralization of supporting bones, leading to arthritis or osteoporosis. Cyclosponne may cause hypertension, tremors, anorexia and elevated low-density lipoprotein levels. It also has major toxic effects on the kidney, which may lead to decreased renal function. Cytotoxic agents may cause anemia and thrombocytopenia and sometimes hepatitis. The anti- lymphocyte globulins may cause fever, hypotension, diarrhea, or sterile meningitis. OKT3 may cause chills and fever, nausea, vomiting, dianhea, rash, headache, photophobia and occasional episodes of life- threatening acute pulmonary edema.

[0010] In addition to the issues of transplant rejection, the need for chronic immune suppression following transplantation and the resulting adverse effects of post-transplant treatment, there is a marked shortage of human organ and tissue donors compared to the number of patients requiring a transplant.

[001 1] Xenografts, herein defined as transplants from another species, could potentially resolve the shortage of transplantable organs and tissues. Xenografts have been used in the past for short term life support when a recipient urgently requires a transplant and no suitable donor is available. Such uses, however, have only been temporary measures to provide additional time to locate a suitable human donor. The potential use of xenografts as long-term grafts for human recipients is limited by the same major issues that affect allografts; i.e., rejection of the donor graft and the adverse effects of anti-rejection treatments. The problem of rejection is even heightened with xenografts as the risk of rejection of xenografts is considered to be even greater than for allografts.

[0012] Reducing the risk of rejection of donated tissue, xenograft and/or allograft, especially with few excessive adverse effects is desirable. For example, an immunologically-specific immune system suppressant which has few or no side-effects would be valuable. Previous methods aimed at modulating a recipient's response to a donor graft have been disclosed. See, for example, US Patent No. 6,060,049, US Patent No. 5,560,91 1, US Patent No.

5,728,812, International Patent Application No. WO 84/02848, US Patent Application No. 2008/0127357 and US Patent Application No. 2001/0053362).

SUMMARY

[0013] In part, the present disclosure describes monoclonal anti-anti-anti-MHC antibodies.

[0014] In part, the present disclosure describes methods of production of anti-anti-anti-MHC antibodies.

[0015] In part, the present disclosure describes uses of monoclonal anti-anti-anti-MHC antibodies.

[0016] In part, the present disclosure describes a use monoclonal anti-anti-anti-MHC antibodies in the treatment of degenerative diseases including autoimmune diseases and cancers.

[0017] In part, the present disclosure describes a use of monoclonal anti-anti-anti-MHC

[0018] In part, the present disclosure describes a use of antibodies in reducing a recipient's immune response to donated tissue. The present use comprises introducing monoclonal anti- anti-anti -(donor MHC) antibodies to the recipient's immune system.

[0019] In part, the present disclosure describes compositions comprising monoclonal anti- anti-anti-MHC antibodies.

[0020] In part, the present disclosure describes rodent monoclonal anti-anti-anti-MHC antibodies.

[0021] In part, the disclosure describes fragments of monoclonal anti-anti-anti-MHC antibodies.

[0022] In part, the present disclosure describes a method of producing rodent monoclonal anti-anti-anti-MHC antibodies.

[0023] In part, the present disclosurer describes a use of monoclonal anti-anti-anti-MHC antibodies to facilitate tissue donation between appropriate pairs of vertebrate organisms. For example, organ donation between spouses, other relatives, partners, or other individuals. Further, the present disclosure describes a means for preparing a vertebrate organism or organisms for possible tissue donation to another vertebrate, for example in situations where married or common-law spouses wish to donate organs to their spouse, is also desired. Each member of a couple could benefit from being made immunologically tolerant to the tissue of the other. Then each member would be available as an organ donor for the other, should the need arise. This would facilitate the use of living donors for transplantations.

[0024] In part, the present disclosure describes a use of monoclonal anti-anti-anti-MHC antibodies in making each member of a pair of vertebrate organisms ("partners")

immunologically tolerant to the tissue and organs of the other.

[0025] In part, the present disclosure describes a method of supplying monoclonal anti-anti- anti-(donor MHC) antibodies suitable for administration to an organ recipient, the method comprising: a) receiving input parameters, said parameters comprising donor lymphocytes; b) obtaining, based on the input parameters, an appropriate monoclonal anti-anti- anti-(donor MHC) antibodies for facilitating the transplantation of tissue from said donor to a recipient; and c) distributing said monoclonal anti-anti-anti-(donor MHC) antibodies to the

delivery location.

[0026] As used herein, the term "immune response" means the production of antibodies and/or the induction of cell mediated immunity specific for an antigen, including especially the production of antibodies or the induction of cell mediated immunity specific for transplantation antigens.

[0027] As used herein, the term "facilitating transplantation" means reducing the risk of rejection of donated tissue by a recipient. For example, when the donated tissue is an organ the term will refer to reducing the chance of rejection of the organ by the recipient and a consequent improvement in the chances of the transplantation being successful. The facilitation can include inducing transplantation tolerance by the administration of monoclonal anti-anti-anti-(donor MHC) antibodies in non-immunogenic form to a prospective donor recipient. This may be together with the application of a prospective donor skin graft. This process can induce transplantation tolerance in the recipient with respect to donor tissue such as donor organs, and organ transplantation can be attempted as needed. [0028] As used herein, the term "idiotype" means the unique set of antigenic determinants (or epitopes) of the V region of an antibody, lymphocyte receptor or specific T cell factor, wherein such idiotype can potentially induce the formation of anti-idiotypic antibodies.

[0029] As used herein, the term "anti-idiotype" means the V region of an antibody, lymphocyte receptor or specific T cell factor that is complementary to the V region of the respective idiotype.

[0030] As used herein, the term "anti-anti-self antibody" in an alloimmune serum is an antibody that binds to an idiotype in the converse alloimmune serum (see Figure 1). In the case of complementary alloimmune sera, as shown for example in Figure 1 , anti-anti-P antibodies in a P anti-Q serum bind specifically to anti-P and anti-anti-anti-P antibodies in a Q anti-P serum. Anti-anti-self antibodies, for example anti-anti-P in Figure 1, are

predominantly anti-anti-(self MHC), because of the strong role that MHC antigens play in alloimmunity, but other self antigens also play a role in the selction of anti-anti-self antibodies, including minor histocompatibility antigens.

[0031] As used herein, the term "anti-anti-anti-MHC antibody" in the context of a P anti-Q immune response, where P and Q are vertebrates, means an antibody present in a P anti-Q serum, or a monoclonal antibody, that binds to the V regions of the anti-anti-Q antibodies present in a Q anti-P serum, but does not substantially bind to vertebrate Q MHC antigens (see Figure 1). In Figure 1 anti-anti-anti-Q antibodies may be anti-anti-anti-(Q MHC).

Hybridomas that produce monoclonal anti-anti-anti-donor antibodies can be selected using alloimmune animals on the basis of their V regions having complementarity to anti-anti- donor antibodies without substantially binding to donor MHC antigens. These anti-anti-anti- MHC antibodies are believed to bind in ELISA assays to HIV antigens, and it is believed that hybridomas that make monoclonal anti-anti-anti-MHC antibodies can be selected using alloimmune animals and selecting hybridomas with V regions that bind to HIV antigens.

[0032] As used herein, an animal P that has made an anti-Q immune response, where P and Q are vertebrates, is "conversely alloimmune" to an animal Q that has made an anti-P immune response.

[0033] As used herein, the term "converse alloimmune serum" for a P anti-Q serum is a Q anti-P antiserum. [0034] As used herein, the term "monoclonal anti-anti-anti-graft antibody" is synonymous with "monoclonal anti-anti-anti-(donor MHC) antibody".

[0035] As used herein, "HIV" is the human immunodeficiency virus, including especially the HIV-1 human immunodeficiency virus.

[0036] As used herein, the term "monoclonal donor-specific anti-HIV antibodies" means monoclonal antibodies that are obtained by immunizing a vertebrate with donor lymphocytes and selecting hybridomas with V regions that bind to HIV antigens.

[0037] As used herein, "non-immunogenic" means delivery in a manner that does not induce significant production of antibodies that bind to the monoclonal anti-anti-anti-MHC antibodies being administered. For example, the delievery may be without an adjuvant, via a non-immunogenic route, and/or in non-immunogenic amounts.

[0038] As used herein, the term "anti-anti-(donor MHC) antibody" means an anti-idiotype antibody that is present in an alloimmune serum and that is directed against the idiotypes of anti-(donor MHC) antibodies and anti-(donor MHC) T cell receptors that are present in the converse antiserum, and can recognize and interact with anti-(donor MHC) antibodies and anti-(donor MHC) T cell receptors that are present in the converse antiserum.

[0039] As used herein, the term "recipient" refers to a vertebrate organism which receives transplanted tissue from a genetically distinct organism.

[0040] As used herein, the term "donor" refers to a vertebrate organism from which tissue is removed or otherwise derived by, for example, tissue culturing techniques, and introduced into the recipient organism. The donor may be of the same (allograft) or different (xenograft) species.

[0041] As used herein, the term "catalyst animal" refers to a vertebrate organism that provides tissue, preferably lymphocytes, that is used for the immunization of a potential organ donor vertebrate, such that the donor makes an immune response that includes the production of anti-anti-donor antibodies.

[0042] As used herein, the term "tissue" means one or more nucleated cells. Frequently, the tissue will be from an organ such as, for example, skin, heart, lung, kidney, liver, spleen, thymus, lymph node, blood, bone marrow, pancreas, intestine, gall bladder, prostate, ovary, muscle, limbs, or the like. The tissue may be a whole or partial organ. [0043] This summary does not necessarily describe the entire scope of the present invention. Other aspects, features and advantages of the invention will be apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 shows a system by which anti-, anti-anti-, and anti-anti-anti- antibodies are defined and are believed to be present as polyclonal antibodies in alloimmune or

xenoimmune vertebrates. A vertebrate "P" with MHC antigens P that is alloimmune or made alloimmune to a vertebrate "Q" with MHC antigens Q is believed to make anti-Q, anti-anti-P and anti-anti-anti-Q antibodies. If the vertebrate "Q" is alloimmune or is made alloimmune to the vertebrate "P", "Q" is believed to make anti-P, anti-anti-Q and anti-anti-anti-P antibodies. The anti-anti-Q antibodies in the Q anti-P serum are believed to have specificity for anti-Q and anti-anti-anti-Q polyclonal antibodies in the P anti-Q serum. The monoclonal anti-anti- anti-MHC antibodies of this invention are believed to have specificity for anti-anti-MHC antibodies without binding to MHC antigens, as shown here.

[0045] Figure 2 illustrates the IJ phenomenon in the context of the symmetrical immune network theory.

[0046] Figure 3 shows a possible mechanism for an anti-anti-(MHC class II) monoclonal antibody in immunogenic form being a vaccine for the prevention of infection with HIV.

[0047] Figure 4 shows a possible mechanism for the induction of transplantation tolerance using anti-anti-(graft MHC) antibodies.

[0048] Figure 5 shows a method for the induction of transplantation tolerance between two vertebrates P and Q using the immune system of a third party "catalyst" vertebrate C in the production of anti-anti-self polyclonal antibodies.

[0049] Figure 6 shows a method for obtaining monoclonal anti-anti-anti-MHC antibodies and their use in a transplantation technology.

[0050] Figure 7 shows a possible mechanism by which anti-anti-anti-(graft MHC) antibodies mediate transplantation tolerance.

[0051] Figure 8 shows a possible mechanism for the stabilization of an immune system by monoclonal anti-anti-(self MHC) antibodies. [0052] Figure 9 shows a possible mechanism for the stabilization of an immune system by monoclonal anti-anti-anti-MHC antibodies.

DETAILED DESCRIPTION

[0053] In part, the present disclosure describes monoclonal anti-anti-anti-MHC antibodies and uses thereof. The present disclosure furthermore describes methods for the production of monoclonal anti-anti-anti-MHC antibodies and uses of monoclonal anti-anti-anti-MHC antibodies such as the treatment of degenerative disorders including autoimmune diseases and cancers. In the case of autoimmunity the immune system may be considered too active, and cancers may proliferate when the immune system is not active enough.

[0054] In part, the present disclosure describes a method of reducing the risk of the rejection of tissue transplanted into a recipient animal from a donor animal. In an embodiment, the present disclosure provides a method of producing anti-idiotypic antibodies against antigen receptors on the surface of a recipient's lymphocytes and the use of such anti-idiotypic antibodies in preventing transplant rejection by a recipient by inducing a state of the recipient's immune system that is suppressed with regard to responding immunologically against the transplanted organ. The present disclosure further relates to compositions, uses, kits, and the like.

[0055] As shown in Figure 1, the serum of an animal P that has been immunized with Q lymphocytes contains anti-Q, anti-anti-P, and anti-anti-anti-Q antibodies, while the serum of an animal Q that has been immunized with lymphocytes of an animal P contains anti-P, anti- anti-Q, and anti-anti-anti-P antibodies. In the context of the symmetrical immune network theory, the anti-anti-anti-P antibodies and anti-anti-anti-Q antibodies are called anti-IJ^p and anti-IJ^Q antibodies in mice. The diagonal lines in this diagram indicate that all of the specific antibodies induced in the P anti-Q serum have complementarity to antibodies in the Q anti-P serum. Hence as used herein, the term "anti-anti-anti-MHC antibody" in the context of an P anti-Q immune response, where P and Q are vertebrates, means an anti-anti-anti-(Q MHC) antibody, or a monoclonal antibody, that binds to the V regions of anti-anti-(Q MHC) antibodies present in a Q anti-P serum, but not to vertebrate Q MHC antigens.

[0056] As used herein, the term "co-selection" means the mutual positive selection of individual members from within two diverse populations, such that selection of members within each population is dependent on interaction with (recognition of) one or more members within the other population. Figure 2 shows how helper T cells and suppressor T cells are co-selected and can give rise to IJ determinants that are expressed on suppressor T cells. See Hoffinann, G. W. 1994. Immunol. Cell Biol, 72:338.

[0057] Figure 3 shows how monoclonal anti-anti-MHC antibodies in immunogenic form may induce an anti-anti-anti-MHC immune response that is also an anti-HIV immune response, and hence monoclonal anti-anti-MHC antibodies may function as a vaccine for protection against HIV infection. While not wishing to be bound by theory it is believed that HIV preferentially infects HIV-specific helper T cells (Hoffmann, G. W. 1994. Immunol. Cell Biol, 72:338-346; Douek D.K., et al. 2002. Nature, 417: 95-98), thus HIV could be selected to be similar to anti-anti-MHC antibodies.

[0058] Immunization with protein antigens in immunogenic form can result in the production of antibodies that are both specific for the antigen and antiidiotypic. Hsu et al. (1989) Int. Immunol. 1, 197-204; Forsyth et al. (1990) J. Immunol. 145, 215-223. This dual specificity could mean an anti-anti-anti-MHC antibody may induce an anti-HIV immune response, and hence may also be effective as a vaccine in protection against HIV.

[0059] While not wishing to be bound by theory, the present method is believed to work based on the symmetrical immune network theory, according to which the variable regions (the "V regions") of antibodies, specific T cell factors, and specific lymphocyte receptors recognize each other, and according to which such recognition is a key element in the regulation of the immune system. The V regions of antibodies, lymphocyte receptors and specific T cell factors each have a set of antigenic determinants (or epitopes) that characterize each type of antibody, receptor and specific T cell factor. These sets of antigenic

determinants are referred to as idiotypes and function in their own right as antigenic stimuli, which can induce the formation of anti-idiotypic antibodies. An anti-idiotype is a set of antigenic determinants complementary to its respective idiotypes. The interactions between idiotypes and anti-idiotypes and the interaction between idiotypic receptors and anti-idiotypic receptors is thought to be a major factor in regulating a specific immune response (see, for example, Wigzell, H. and Binz, H. 1980. Progress in Immunology IV, eds. Fougereau, M. and Dausset, J. Academic Press, N.Y., p. 94-103; Infante, et al. 1982. J. Exp. Med. 155: 1100; Bona, C. and Paul, E. 1980. Regulatory T Lymphocytes, eds., Pernis, B. and Vogel, H.J. Academic Press, N.Y., p. 292). The interactions between idiotypes and anti-idiotypes is thought to be symmetrical. The symmetrical interactions are thought to include symmetrical stimulation, inhibition, and elimination interactions. The symmetrical immune network theory is described in "Immune Network Theory" by Hoffmann, G. W., published at online at www.networkimmunologyinc.com. However, for a variety of reasons symmetrical immune network theory has been largely discounted by the scientific community and the vast majority of immunologists are not further pursuing or researching the theory. One issue with the theory is that it is based on the presumed existence of molecules called specific T cell factors, or "tabs", which are integral to the symmetrical immune network theory, but are not part of the reigning paradigm of adaptive immunity in the year 2010. A second cause for the unpopularity of the symmetrical immune network theory is known as the IJ paradox. Tabs were shown experimentally to express IJ determinants, and IJ was clearly mapped in mice to within the MHC, but no gene for IJ could be found there. This was the IJ paradox. The IJ paradox led to the widespread conclusions that "IJ does not exist" and "suppressor tabs do not exist". Since tabs are important in the symmetrical immune network theory, it has been widely concluded that the symmetrical immune network theory is wrong.

[0060] In spite of the technical prejudice that exists against immune network theory , the present disclosure describes anti-anti-anti-MHC antibodies and uses thereof.

[0061] In part, the present disclosure comprises obtaining monoclonal anti-anti-anti-MHC and/or fragments of monoclonal anti-anti-anti-MHC antibodies. These antibodies may be produced in any suitable method such methods being well known in the art. Preferred methods of producing monoclonal anti-anti-anti-MHC mAbs are described below in

Examples 1 and 2.

[0062] In part, the present use of monoclonal anti-anti-anti-MHC antibodies comprises administering the antibodies to the recipient in non-immunogenic form. The dose of monoclonal anti-anti-anti-MHC antibodies is determined by one skilled in the art. Preferably, the recipient is given monoclonal anti-anti-anti-(donor MHC) antibodies intravenously or intra-peritoneal without an adjuvant, in amounts preferably between about 10 ng and about 10 μg of anti-anti-(donor MHC) antibody per kilogram weight of the recipient per dose, even more preferably about 1 μ of anti-anti-(donor MHC) antibody per kilogram of the recipient per dose.

[0063] In an embodiment, donor serum comprising anti-anti-(donor MHC) antibodies is administered to the recipient, which administration comprises: (i) obtaining serum or purified IgG antibodies from an immunized donor; (ii) adsorbing the donor's serum or purified IgG antibodies using recipient tissue in order to remove any anti-(recipient MHC) antibodies; and (iii) administering the resulting serum or purified IgG antibodies containing anti-anti-(donor MHC) activity to the recipient to facilitate acceptance of the donor's graft.

[0064] Figure 4 shows how a possible mechanism for how anti-anti-graft antibodies, which are also known as anti-anti-(donor MHC) antibodies, are believed to facilitate the induction of transplantation tolerance. The anti-anti-graft antibodies, when administered to the recipient, stimulate T cells of the recipient. The anti-anti-graft antibodies stimulate anti-anti- anti-graft T cells and anti-graft T cells, which causes the secretion of specific T cell factors. These T cell factors are protein molecules that are postulated to be monovalent (i.e., having only one V region). The V regions of specific T cell factors mediate the T cell factors' specificity. Since T cell factors are monovalent, T cell factors in soluble form cannot crosslink complementary receptors; however, such soluble T cell factors can be stimulatory when presented on the surface of non-specific accessory cells ("A cells") including macrophages.

[0065] The T cell factors that are secreted by the anti-anti-anti-graft T cells and anti-graft T cells have anti-anti-anti-graft specificity and anti-graft specificity. These T cell factors of a given specificity are adsorbed by and presented on the surface of macrophages. The surface of the macrophage is a highly immunogenic surface, and the presence of the specific T cell factors on the surface of macrophages stimulate T cells bearing receptors that are

complementary to the T cell factors on the macrophage surface. While not wishing to be bound by theory, it is believed that the anti-anti-anti-graft T cell factors and anti-graft T cell factors specifically stimulate anti-anti-graft T cells. These anti-anti-graft T cells secrete anti- anti-graft specific T cell factors, which in turn are presented on the surface of macrophages, resulting in the proliferation of anti-graft T cells and anti-anti-anti-graft T cells. As a result of the symmetric stimulation of T cells, the macrophages of the recipient become armed with a mixture of anti-graft, anti-anti- graft and anti-anti-anti-graft T cell factors. Consequently, the immune system of the recipient goes into a state in which there are elevated levels of anti- graft, anti-anti-graft and anti-anti-anti-graft T cells, and their mutual stimulation leads to a significant level of these cells and their corresponding antigen-specific T cell factors. In the context of the symmetrical immune network theory, this is thought to be a specifically suppressed state for the recipient especially with regard to the MHC antigens of the organ donor. The recipient's immune system is therefore selectively suppressed with respect to any immunity against the antigens of the donor, while still leaving the remainder of the immune system intact and not injuring other important organs, tissues or cells. [0066] The present disclosure may involve a donor animal that is a different species from the recipient animal, i.e., a xenogeneic transplantation. Many species could potentially be used as donor animals and different animals offer advantages for select uses. Preferably, donor animals are of the class Mammalia. Of the class Mammalia, five orders are particularly suitable for human recipients: primates, artiodactyls, carnivores, rodents, and lagamorphs.

[0067] In an embodiment a potential transplant recipient receives either anti-anti-donor antibodies or monoclonal anti-anti-anti-donor antibodies. The antibodies may be given substantially simultaneously with the transplant. An additional dose or doses may be delivered at intervals thereafter. The antibodies may also be given prior to the transplant. In a variation, the antibodies are given substantially simultaneously with a skin graft, and optionally at intervals thereafter. The anti-anti-donor or monoclonal anti-anti-anti-donor antibodies may also be given prior to the time of a skin graft. When the skin graft is stably accepted, the potential transplant recipient is transplantation tolerant with respect to the tissue of the potential donor, and can receive a transplant as needed.

[0068] An embodiment of the present method involves immunizing a prospective organ donor A with tissue of a prospective transplant recipient B, preferably including lymphocytes. The prospective donor A is immunized with tissue of the organ recipient B. The tissue of the recipient used for the immunization is preferably lymphocytes. For safety, the tissue of the recipient used for immunization can be gamma irradiated, for example with 3000 rads of gamma irradiation. Polyclonal IgG obtained from the immunized donor can be absorbed using B tissue, for example B lymphocytes, removing the anti-B and anti-anti-anti-B antibodies, and leaving serum or IgG containing anti-anti-A antibodies. These polyclonal antibodies can be given to the potential organ recipient in non-immunogenic form preferably starting at the time point of a skin graft from the potential organ donor. Administration of the anti-anti-A antibodies may also be given prior to the time of skin tissue transplantation. The number of administrations that are needed may vary depending on circumstances but, for example, there may be two or more, three or more, four or more, ten or more, or twenty or more administrations of anti-anti-A antibodies. The administrations may be at any suitable time interval. For example, the time between administrations may be initially relatively short, e.g. one or two days, then after a week or so the time intervals can be extended, e.g. doubled, and then systematically increased as needed. The dose in each given case can be varied depending on the response of the recipient. For example any inflammation at the site of the skin graft is indicative of the need for more doses of anti-anti-A antibodies or of larger doses of the anti-anti-A antibodies. Following stable acceptance of the skin graft, the prospective organ recipient B is able to accept an organ transplant from the ogan donor A at any time that this is needed. This method allows for the induction of one way transplantation tolerance, since the donor A becomes immune to the tissue of the recipient B and cannot also be made transplantation tolerant with respect to tissue of the recipient.

[0069] An embodiment of the present method involves the induction of reciprocal transplantation tolerance between two vertebrates, for example between two members of a couple A and B. This embodiment allows for both A and B to become potential organ donors for each other if and when the need should arise. This embodiment involves a third party catalyst vertebrate C as shown in Figure 5. Both A and B are immunized with tissue of C, preferably including lymphocytes. A makes anti-C, anti-anti-A and anti-anti-anti-C antibodies, while B makes anti-C, anti-anti-B and anti-anti-anti-C antibodies. The A and B immune sera are absorbed using C tissue to remove anti-C and anti-anti-anti-C antobodies, leaving anti-anti-A and anti-anti-B serum respectively. The anti-anti-A antibodies are administered in non-immunogenic form to B at the time of the application of a B skin graft and at intervals following the application of the skin graft. Similarly, the anti-anti-B antibodies are administered in non-immunogenic form to A at the time of the application of a B skin graft and at intervals following the application of the skin graft. Following stable acceptance of the skin grafts, A and B are mutually transplantation tolerant with respect to the other, and each can receive an organ transplant from the other if and when needed. The skin grafts are stably accepted when there is no evidence of rejection within a suitable period, for example when the skin grafts have not been rejected and there is no inflammation at the site of the skin graft three months after the application of the skin graft.

[0070] Figure 6 shows a method for obtaining monoclonal anti-anti-anti-MHC antibodies and their use in a transplantation technology. A vertebrate CI is immunized with lymphocytes of a vertebrate P and a vertebrate C2 is immunized with lymphocytes of a vertebrate Q. The B lymphocytes of vertebrate CI are used to make hybridomas. Hybridomas are selected that have V regions that bind to HIV antigens. These hybridomas make monoclonal HIV-specific anti-anti-anti-(P MHC) antibodies. The B lymphocytes of vertebrate C2 are used to make hybridomas. Hybridomas are selected that have V regions that bind to HIV antigens. These hybridomas make monoclonal HIV-specific anti-anti-anti-(Q MHC) antibodies. P receives a Q skin graft together with anti-anti-anti-Q antibodies and Q receives a P skin graft together with anti-anti-anti-P antibodies. When the skin grafts are stably accepted, P and Q are each ready to receive a transplant from the other, should the need arise.

[0071] Figure 7 shows a possible mechanism by which monoclonal anti-anti-anti-graft MHC antibodies mediate transplantation tolerance. Alpha (a) is an abbreviation for "anti-" and "tab" means specific T cell factor. Small doses of the anti-anti-anti-graft antibodies in non- immunogenic form stimulate anti-anti-graft T cells that secrete anti-anti-graft specific T cell factors (tabs). These specific T cell factors bind to the surface of non-specific accessory cells including macrophages (A cells), where they present an array that is stimulatory for anti-graft T cells and anti-anti-anti-graft T cells that secrete anti-graft tabs and anti-anti-anti-graft tabs respectively. The A cells thus become armed with a mixture of anti-graft, anti-anti-graft and anti-anti-anti-graft tabs, and the immune system is stimulated to go to a state with elevated levels of anti-graft, anti-anti-graft and anti-anti-anti-graft T cells, which in the context of the symmetrical immune network theory is believed to be a specifically suppressed state with regard to making an immune response to the graft.

[0072] Figure 8 shows a possible mechanism for the stabilization of an immune system by monoclonal anti-anti-(self MHC) antibodies. Such stabilization is for the prevention and treatment of degenerative diseases including autoimmunity and cancers. The Greek letter alpha (a) is an abbreviation for "anti-" and "tab" means specific T cell factor. Anti-anti-(self MHC) antibodies (aaself) stimulate aself and aaaself T cells. The aself T cells are also stimulated by the self. The aself and aaaself T cells secrete aself and aaaself tabs respectively. The aself and aaaself tabs bind to the surface of A cells. The a(self MHC) and aaaself tabs on the A cells stimulate aaself T cells. The aaself T cells secrete aaself tabs that also bind to the surface of A cells. Thus the A cells become armed with a mixture of aself, aaself and aaaself tabs. The armed A cell stimulates the proliferation of aself, aaself and aaaself T cells. The resulting state of the system with elevated levels of aself, aaself and aaaself T cells is stabilized and is believed to be resistant against making immune responses against self, without being compromised regarding making immune responses to substances that cause a disease or disorder such as cancer cells.

[0073] Figure 9 shows a possible mechanism for the stabilization of an immune system by monoclonal anti-anti-anti-MHC antibodies. Such stabilization is for the prevention and treatment of degenerative diseases including autoimmunity and cancers. Alpha (a) is an abbreviation for "anti-" and "tab" means specific T cell factor. Small doses of the anti-anti- anti-(self MHC) antibodies in non-immunogenic form stimulate anti-anti-self T cells that secrete anti-anti-self specific T cell factors (tabs). These specific T cell factors bind to the surface of non-specific accessory cells including macrophages (A cells), where they present an array that is stimulatory for anti-self T cells and anti-anti-anti-self T cells that in turn secrete anti-self tabs and anti-anti-anti-self tabs respectively. The A cells thus become armed with a mixture of anti-self, anti-anti-self and anti-anti-anti-self tabs, and the immune system goes to a specifically stabilized state with regard to making immune responses against self, on account of an increase in the level of the centrally important anti-anti-self T cells, without being compromised regarding making immune responses to substances that cause a disease or disorder such as cancer cells.

[0074] The monoclonal anti-anti-anti-MHC antibodies described herein can be used to prevent and/or treat degenerative disorders for example autoimmune disorders and cancers.

[0075] Any suitable autoimmune disorder may be prevented, treated, or the prevention or treatment of the disorder may be aided with the present monoclonal anti-anti-anti-MHC antibodies. Examples of identified autoimmune disorders include, but are not limited to, Achlorhydra; Autoimmune Active Chronic Hepatitis; Acute Disseminated

Encephalomyelitis; Acute hemorrhagic leukoencephalitis; Addison's Disease;

Agammaglobulinemia; Alopecia areata; Amyotrophic Lateral Sclerosis; Ankylosing

Spondylitis; Anti-GBM/TBM Nephritis; Antiphospholipid syndrome; Antisynthetase syndrome; Arthritis; Atopic allergy; Atopic Dermatitis; Autoimmune Aplastic Anemia;

Autoimmune cardiomyopathy; Autoimmune hemolytic anemia; Autoimmune hepatitis;

Autoimmune inner ear disease; Autoimmune lymphoproliferative syndrome; Autoimmune peripheral neuropathy; Autoimmune pancreatitis; Autoimmune polyendocrine syndrome Types I, II, & III; Autoimmune progesterone dermatitis; Autoimmune thrombocytopenic purpura; Autoimmune uveitis; Balo disease/Balo concentric sclerosis; Bechets Syndrome; Berger's disease; Bickerstaff s encephalitis; Blau syndrome; Bullous Pemphigoid;

Castleman's disease; Chagas disease; Chronic Fatigue Immune Dysfunction Syndrome;

Chronic inflammatory demyelinating polyneuropathy; Chronic recurrent multifocal ostomyelitis; Chronic lyme disease; Chronic obstructive pulmonary disease; Churg-Strauss syndrome; Cicatricial Pemphigoid; Coeliac Disease; Cogan syndrome; Cold agglutinin disease; Complement component 2 deficiency; Cranial arteritis; CREST syndrome; Crohns Disease; Cushing's Syndrome; Cutaneous leukocytoclastic angiitis; Dego's disease; Dercum's disease; Dermatitis herpetiformis; Dermatomyositis; Diabetes mellitus type 1 ; Diffuse cutaneous systemic sclerosis; Dressler's syndrome; Discoid lupus erythematosus; Eczema; Endometriosis; Enthesitis-related arthritis; Eosinophilic fasciitis; Epidermolysis bullosa acquisita; Erythema nodosum; Essential mixed cryoglobulinemia; Evan's syndrome;

Fibrodysplasia ossificans progressiva; Fibromyalgia; Fibromyositis; Fibrosing aveolitis;

Gastritis; Gastrointestinal pemphigoid; Giant cell arteritis; Glomerulonephritis; Goodpasture's syndrome; Graves' disease; Guillain-Barre syndrome (GBS); Hashimoto's encephalitis;

Hashimoto's thyroiditis; Haemolytic anaemia; Henoch-Schonlein purpura; Herpes gestationis; Hidradenitis suppurativa; Hughes syndrome (Antiphospholipid syndrome);

Hypogammaglobulinemia; Idiopathic Inflammatory Demyelinating Diseases; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic purpura (Autoimmune thrombocytopenic purpura); IgA nephropathy (Berger's disease); Inclusion body myositis; Inflammatory demyelinating polyneuopathy; Interstitial cystitis; Irritable Bowel Syndrome (IBS); Juvenile idiopathic arthritis; Juvenile rheumatoid arthritis; Kawasaki's Disease; Lambert-Eaton myasthenic syndrome; Leukocytoclastic vasculitis; Lichen planus; Lichen sclerosus; Linear IgA disease (LAD); Lou Gehrig's Disease (Amyotrophic lateral sclerosis); Lupoid hepatitis; Lupus erythematosus; Majeed syndrome; Meniere's disease; Microscopic polyangiitis;

Miller-Fisher syndrome; Mixed Connective Tissue Disease; Morphea; Mucha-Habermann disease; Muckle- Wells syndrome; Multiple Myeloma; Multiple Sclerosis; Myasthenia gravis; Myositis; Narcolepsy; Neuromyelitis optica (Devic's Disease); Neuromyotonia; Occular cicatricial pemphigoid; Opsoclonus myoclonus syndrome; Ord thyroiditis; Palindromic rheumatism; PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal

hemoglobinuria (PNH); Parry Romberg syndrome; Parsonnage- Turner syndrome; Pars planitis; Pemphigus; Pemphigus vulgaris; Pernicious anaemia; Perivenous encephalomyelitis; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatica; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy;

Psoriasis; Psoriatic Arthritis; Pyoderma gangrenosum; Pure red cell aplasia; Rasmussen's encephalitis; Raynaud phenomenon; Relapsing polychondritis; Reiter's syndrome; Restless leg syndrome; Retroperitoneal fibrosis; Rheumatoid arthritis; Rheumatoid fever; Sarcoidosis; Schizophrenia; Schmidt syndrome; Schnitzler syndrome; Scleritis; Scleroderma; Sjogren's syndrome; Spondyloarthropathy; Sticky blood syndrome; Still's Disease; Stiff person syndrome; Subacute bacterial endocarditis (SBE); Susac's syndrome; Sweet syndrome;

Sydenham Chorea; Sympathetic ophthalmia; Takayasu's arteritis; Temporal arteritis (Giant cell arteritis); Tolosa-Hunt syndrome; Transverse Myelitis; Ulcerative Colitis; Undifferentiated connective tissue disease; Undifferentiated spondyloarthropathy; Vasculitis; Vitiligo; Wegener's granulomatosis; Wilson's syndrome; Wiskott-Aldrich syndrome.

[0076] Any suitable cancer may be prevented, treated, or the prevention or treatment of the cancer may be aided with the present monoclonal anti-anti-anti-MHC antibodies. Examples of identified or suspected cancers include, but are not limited to, Acute lymphoblastic leukemia; Acute myeloid leukemia; Adrenocortical carcinoma; AIDS-related cancers; AIDS- related lymphoma; Anal cancer; Appendix cancer; Astrocytoma, childhood cerebellar or cerebral; Basal cell carcinoma; Bile duct cancer, extrahepatic; Bladder cancer; Bone cancer, Osteosarcoma/Malignant fibrous histiocytoma; Brainstem glioma; Brain tumor; Brain tumor, cerebellar astrocytoma; Brain tumor, cerebral astrocytoma/malignant glioma; Brain tumor, ependymoma; Brain tumor, medulloblastoma; Brain tumor, supratentorial primitive neuroectodermal tumors; Brain tumor, visual pathway and hypothalamic glioma; Breast cancer; Bronchial adenomas/carcinoids; Burkitt lymphoma; Carcinoid tumor, childhood; Carcinoid tumor, gastrointestinal; Carcinoma of unknown primary; Central nervous system lymphoma, primary; Cerebellar astrocytoma, childhood; Cerebral astrocytoma/Malignant glioma, childhood; Cervical cancer; Childhood cancers; Chronic lymphocytic leukemia; Chronic myelogenous leukemia; Chronic myeloproliferative disorders; Colon Cancer;

Cutaneous T-cell lymphoma; Desmoplastic small round cell tumor; Endometrial cancer; Ependymoma; Esophageal cancer; Ewing's sarcoma in the Ewing family of tumors;

Extracranial germ cell tumor, Childhood; Extragonadal Germ cell tumor; Extrahepatic bile duct cancer; Eye Cancer, Intraocular melanoma; Eye Cancer, Retinoblastoma; Gallbladder cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Gastrointestinal Stromal Tumor (GIST); Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Adult; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; Gastric Carcinoid; Hairy cell leukemia; Head and neck cancer; Heart cancer; Hepatocellular (liver) cancer; Hodgkin lymphoma; Hypopharyngeal cancer; Hypothalamic and visual pathway glioma, childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas);

Kaposi sarcoma; Kidney cancer (renal cell cancer); Laryngeal Cancer; Leukemias; Leukemia, acute lymphoblastic (also called acute lymphocytic leukemia); Leukemia, acute myeloid (also called acute myelogenous leukemia); Leukemia, chronic lymphocytic (also called chronic lymphocytic leukemia); Leukemia, chronic myelogenous (also called chronic myeloid leukemia); Leukemia, hairy cell; Lip and Oral Cavity Cancer; Liver Cancer (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphomas; Lymphoma, AIDS-related; Lymphoma, Burkitt; Lymphoma, cutaneous T-Cell; Lymphoma, Hodgkin; Lymphomas, Non-Hodgkin (an old classification of all lymphomas except Hodgkin's); Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom; Malignant Fibrous Histiocytoma of Bone/Osteosarcoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma; Mesothelioma, Adult Malignant; Mesothelioma, Childhood; Metastatic Squamous Neck Cancer with Occult Primary; Mouth Cancer; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplasia Syndromes; Myelodysplastic/Myeloproliferative Diseases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple (Cancer of the Bone-Marrow);

Myeloproliferative Disorders, Chronic; Nasal cavity and paranasal sinus cancer;

Nasopharyngeal carcinoma; Neuroblastoma; Non-Hodgkin lymphoma; Non-small cell lung cancer; Oral Cancer; Oropharyngeal cancer; Osteosarcoma/malignant fibrous histiocytoma of bone; Ovarian cancer; Ovarian epithelial cancer (Surface epithelial-stromal tumor); Ovarian germ cell tumor; Ovarian low malignant potential tumor; Pancreatic cancer; Pancreatic cancer, islet cell; Paranasal sinus and nasal cavity cancer; Parathyroid cancer; Penile cancer; Pharyngeal cancer; Pheochromocytoma; Pineal astrocytoma; Pineal germinoma;

Pineoblastoma and supratentorial primitive neuroectodermal tumors, childhood; Pituitary adenoma; Plasma cell neoplasia/Multiple myeloma; Pleuropulmonary blastoma; Primary central nervous system lymphoma; Prostate cancer; Rectal cancer; Renal cell carcinoma (kidney cancer); Renal pelvis and ureter, transitional cell cancer; Retinoblastoma;

Rhabdomyosarcoma, childhood; Salivary gland cancer; Sarcoma, Ewing family of tumors; Sarcoma, Kaposi; Sarcoma, soft tissue; Sarcoma, uterine; Sezary syndrome; Skin cancer (nonmelanoma); Skin cancer (melanoma); Skin carcinoma, Merkel cell; Small cell lung cancer; Small intestine cancer; Soft tissue sarcoma; Squamous cell carcinoma

(nonmelanoma); Squamous neck cancer with occult primary, metastatic; Stomach cancer; Supratentorial primitive neuroectodermal tumor, childhood; T-Cell lymphoma, cutaneous (Mycosis Fungoides and Sezary syndrome); Testicular cancer; Throat cancer; Thymoma, childhood; Thymoma and Thymic carcinoma; Thyroid cancer; Thyroid cancer, childhood; Transitional cell cancer of the renal pelvis and ureter; Trophoblastic tumor, gestational;

Unknown primary site, carcinoma of, adult; Unknown primary site, cancer of, childhood; Ureter and renal pelvis, transitional cell cancer; Urethral cancer; Uterine cancer, endometrial; Uterine sarcoma; Vaginal cancer; Visual pathway and hypothalamic glioma, childhood;

Vulvar cancer; Waldenstrom macroglobulinemia; and Wilms tumor (kidney cancer), childhood.

[0077] The present anti-anti-anti-MHC antibodies may aid in the treatment, prevention, and/or cure of other degenerative diseases or conditions. Such antibodies may act as immune system stabilizers. Examples of other degenerative diseases or conditions include, but are not limited to, acne, adenoid problems, AIDS, allergies, Alzheimer's disease, asthma,

atherosclerosis, blisters, bronchitis, bunions, burns, canker sores, cataracts, celiac disease, cervical problems, cholesterol problems, chronic fatigue syndrome, chronic pain, circulatory problems, cirrhosis, cold sores, colitis, dermatitis, diverticulitis, eczema, emphysema, endometriosis, epilepsy, fever, gastritis, goiter, gout, hay fever, heart disease, haemorrhoids, hepatitis, hives, inflammation, itching skin, kidney disease, lactose intolerance, Meniere's disease, neuralgia, Parkinson's disease, pelvic inflammatory disease, phlebitis, pleurisy, pregnancy problems, premenstrual syndrome, prostate problems, rashes, sinusitis, tendonitis, thyroid problems, uterine problems, vaginal problems, varicose veins, and warts.

[0078] The present disclosure provides the use of the monoclonal or polyclonal anti-anti-anti- graft or anti-anti-graft antibodies antibodies to reduce the risk of transplant rejection in a recipient by administering to the recipient animal an effective amount of monoclonal or polyclonal anti-anti-anti-graft or anti-anti-graft antibodies in a non-immunogenic form.

[0079] If desired, and not counter-productive, administration of the compound according to the invention may be combined with more traditional and existing therapies for treating or preventing the disorder e.g. transplant rejection.

[0080] An "effective amount" of a compound according to the invention refers to a non- immunogenic amount, for the number and periods of time necessary, to achieve the desired result; that is, selective suppression of the recipient's immune response to the donor graft. An effective amount of the compound may vary according to factors such as the health, age, sex and weight of the individual, and the species of the donor and recipient animals. The effective amount may be adjusted to provide the optimum result. It is preferred that the amount be between about 1 ng and about 10 μg of the monoclonal or polyclonal anti-anti-anti-graft or anti-anti-graft antibody per kilogram per administration to the recipient, or alloimmune immunogen absorbed serum containing approximately the same total amount of anti-anti- graft IgG. For example, about 1 μg of the monoclonal or polyclonal anti-anti-anti-graft or anti-anti-graft antibody per kilogram per administration to the recipient, or alloimmune immunogen absorbed serum containing approximately the same total amount of IgG.

[0081] In part, the present disclosure provides a composition comprising the monoclonal or polyclonal anti-anti-anti-graft or anti-anti-graft antibody in combination with a

pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier will depend on the mode of administration of the compound. The carrier may, for example, be non- immunogenic. Suitable carriers are those known in the art for use in such modes of administration.

[0082] The pharmaceutical compositions may be formulated by means known in the art and their mode of administration.

[0083] The pharmaceutical composition may comprise anti-anti-anti-MHC monoclonal or polyclonal antibodies or fragments of antibodies in combination with a pharmaceutically acceptable carrier.

[0084] The dose of the pharmaceutical composition may be determined by the skilled practitioner. It is preferred that each dose contain between about 10 ng and about 10 μg of the monoclonal anti-anti-anti-graft antibody per kilogram weight of the recipient. For example, about 1 μg of the monoclonal or polyclonal anti-anti-anti-graft or anti-anti-MHC antibody per kilogram weight of the recipient per dose, or alloimmune immunogen absorbed serum containing the same total amount of IgG.

[0085] The present invention further discloses a kit comprising a pharmaceutical composition of the monoclonal or polyclonal anti-anti-anti-MHC or anti-anti-MHC antibody with a pharmaceutically acceptable carrier together with instructions for administration to recipients of donor tissue.

[0086] In part, the present disclosure further provides a method of supplying monoclonal or polyclonal anti-anti-anti-MHC or anti-anti-MHC antibodies, the method comprising: a) receiving input parameters, said parameters comprising a sample of lymphocytes from a tissue donor and a delivery location; b) obtaining, based on the input parameters, an appropriate monoclonal or

polyclonal anti-anti-anti-MHC or anti-anti-MHC antibodies for facilitating the transplantation of tissue from said donor to a recipient; and c) distributing said monoclonal or polyclonal anti-anti-anti-MHC or anti-anti-MHC antibodies to the delivery location.

[0087] The present method can be used also for non-human vertebrates. For example, the method may include the production of monoclonal or polyclonal anti-anti-anti-graft or anti- anti-graft antibodies suitable for using dogs as donors for dogs that are in need of an organ transplant, and the production of monoclonal or polyclonal anti-anti-anti-graft or anti-anti- graft antibodies suitable for using cats as donors for cats.

[0088] The present method comprises distributing the antibodies to a delivery location. The distribution may be done by any suitable means. Given the time sensitivity of organ donation it is preferred that the distribution is performed in an expeditious manner.

[0089] In part, the present disclosure provides a method, use, pharmaceutical composition and kit for preventing rejection of a transplanted tissue from a donor. The present disclosure provides a highly efficacious way of attaining selective suppression of the recipient's immune system. In certain embodiments administration of monoclonal or polyclonal anti-anti-anti- graft or anti-anti-graft antibodies obtained from an immunized donor can specifically and robustly suppress the immune response of the recipient against the foreign antigens of the transplanted graft, without comprising the immune response of the recipient against other antigens. Further, the risk of adverse effects associated with immunosuppressant drugs currently used in preventing graft rejection is reduced. Transplantation of organs, tissues or cells from donors of a species different from that of the recipient may also be used as a long- term, sustainable therapy for organ or tissue failure.

[0090] It is contemplated that any embodiment discussed in this specification can be implemented or combined with respect to any other embodiment, method, composition or aspect of the invention, and vice versa.

[0091] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, all patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth in this section prevails over the definition that is incorporated herein by reference. Citation of references herein is not to be construed nor considered as an admission that such references are prior art to the present invention.

[0092] Use of examples in the specification, including examples of terms, is for illustrative purposes only and is not intended to limit the scope and meaning of the embodiments of the invention herein. Numeric ranges are inclusive of the numbers defining the range. In the specification, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to," and the word "comprises" has a corresponding meaning.

[0093] The invention includes all embodiments, modifications and variations substantially as hereinbefore described and with reference to the examples and figures. It will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. Examples of such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way.

[0094] The present invention will be further illustrated in the following examples. However it is to be understood that these examples are for illustrative purposes only, and should not be used to limit the scope of the present invention in any manner.

EXAMPLES

[0095] Example 1. A method for producing anti-anti-anti-MHC antibodies using the immune systems of two animals P and Q, whereby the anti-anti-anti-MHC antibodies are believed to be functionally the equivalent of anti-IJ^p antibodies in mice. The method comprises the steps of: a. an animal P is multiply immunized with lymphocytes of an animal Q; b. an animal Q is multiply immunized with lymphocytes of an animal P;

c. IgG is obtained from the said immunized animal P is absorbed using Q

lymphocytes, producing anti-anti-(MHC P)IgG; d. hybridomas are produced using B lymphocytes of the the immunized animal Q; e. hybridomas from step d. are selected that have V regions that bind to the V

regions of the anti-anti-(MHC P)IgG antibodies obtained in step c. and do not bind to MHC antigens of P, and are consequently anti-anti-anti-(MHC) antibodies;

f. the hybridomas selected in step e. are used to make the monoclonal anti-anti-anti- (MHC P) antibodies.

[0096] Example 2. A method for producing monoclonal anti-anti-anti-MHC antibodies, whereby the anti-anti-anti-MHC antibodies are believed to be functionally the equivalent of anti-IJ^p antibodies in mice and are believed to bind to the HIV antigens gpl20, gp41 and p24. The method comprises the steps of: a. an animal Q is multiply immunized with lymphocytes of an animal P; b. lymphocytes of the immunized animal Q are used to make hybridomas; c. the hybridomas are used to produce monoclonal antibodies, which are assayed for binding to HIV antigens; d. the monoclonal antibodies that bind to the said HIV antigens are believed to be the desired anti-anti-anti-MHC antibodies.

[0097] Example 3. The use of monoclonal anti-anti-anti-MHC antibodies in the treatment of a patient with an autoimmune disease comprising the administration of monoclonal anti-anti- anti-(patient MHC) antibodies in non-immunogenic form and in non-immunogenic amounts and a pharmaceutically acceptable carrier.

[0098] Example 4. The use of monoclonal anti-anti-anti-MHC antibodies in the treatment of a patient with a cancer comprising the administration of monoclonal anti-anti-anti-(patient MHC) antibodies in non-immunogenic form and in non-immunogenic amounts and a pharmaceutically acceptable carrier.

[0099] Example 5. The use of monoclonal anti-anti-anti-MHC antibodies in the treatment of the recipient of an organ transplant comprising the administration to the recipient of monoclonal anti-anti-anti-(donor MHC) antibodies in non-immunogenic form and in non- immunogenic amounts and a pharmaceutically acceptable carrier, where the donor is the donor of the organ, starting at the time of a skin graft, and at intervals thereafter, until the skin graft is stably accepted. Then the recipient is believed to be tolerant to tissue of the organ donor, and the organ transplant is carried out. Additional administrations of the anti-anti-anti- donor antibodies may optionally be given following the transplantation of the organ from the donor to the recipient.

Claims

A monoclonal antibody that specifically binds to the variable region of an anti-anti- MHC antibody.

A monoclonal antibody according to claim 1 wherein the monoclonal antibody and the anti-anti-MHC antibody are derived from conversely alloimmune animals.

A monoclonal antibody according to claim 1 or 2 that also binds to the HIV antigens gpl20, gp41 , p24, or a combination thereof.

A method for producing a hydridoma capable of producing monoclonal anti-anti-anti- MHC antibodies, said method comprising: a. Immunizing an animal P with lymphocytes of an animal Q; b. Immunizing animal Q with lymphocytes of animal P; c. Obtaining IgG from the immunized animal P; d. Treating said IgG with Q lymphocytes to absorb out anti-(MHC Q) and anti- anti-anti-(MHC Q) antibodies and thus to produce IgG enriched with anti-anti- (MHC P) IgG; e. Producing hybridomas using B lymphocytes of the immunized animal Q; f. Selecting hybridomas that make monoclonal anti-anti-anti-(P MHC) antibodies i.e. have V regions that bind to the V regions of the anti-anti-(MHC P)IgG antibodies of step d. and do not substantially bind to P MHC antigens; and g. Optionally producing monoclonal anti-anti-anti-(MHC P) antibodies from said hydridomas.

A method for producing hydridomas capable of producing monoclonal anti-anti-anti- MHC antibodies comprising the steps of:

a. Immunizing an animal Q with lymphocytes of an animal P; b. Making hydridomas from lymphocytes of the immunized animal Q; c. Producing antibodies from said hybridomas; d. Assaying said antibodies for their binding to the HIV antigens gpl20, gp41 and/or p24; and e. Optionally, confirming the anti-anti-anti-MHC specificity by testing for binding to anti-anti-P antibodies and/or lack of binding to P MHC antigens.

6. The use of the monoclonal anti-anti-anti-MHC antibodies of claims 1 to 3 in the

treatment of a vertebrate animal (X) having or at risk of developing a degenerative disease comprising the administration to said animal of an effective, non- immunogenic, amount of monoclonal anti-anti-anti-(X MHC) antibodies.

7. The use of claim 6 when en the degenerative disease is an autoimmune disease.

8. The use of claim 6 wherein the degenerative disease is a cancer.

9. The use of claim 6, in which the vertebrate (X) is administered more than one dose of monoclonal anti-anti-anti-(X MHC) antibodies.

10. The use of claim 6, wherein about 10 ng to about 10 μg of the anti-anti-anti-donor antibodies per kilogram of the vertebrate is administered per dose.

1 1. The use of monoclonal anti-anti-anti-MHC antibodies in the treatment of the recipient of a tissue transplant, said use comprising the administration to the recipient an effective amount of monoclonal anti-anti-anti-(donor MHC) antibodies in non- immunogenic form and a pharmaceutically acceptable carrier, where the donor is the prospective tissue donor.

12. The use of claim 1 1, wherein said recipient animal and said donor animal are of the same species.

13. The use of claim 1 1, wherein said recipient animal and said donor animal are different species.

14. The use of claim 11 , wherein said monoclonal anti-anti-anti-(donor MHC) antibodies are administered to the recipient animal at the time of, and/or following

transplantation of tissue from the donor animal to the recipient animal.

15. The use of claim 1 1 , wherein said monoclonal anti-anti-anti-(donor MHC) antibodies are administered to the recipient prior to and/or at the time of and/or following transplantation of tissue from the donor animal to the recipient animal.

16. The use of claim 11 , wherein about 10 ng to about 10 μg of the anti-anti-anti-donor antibodies per kilogram of the recipient is administered per dose.

17. A kit comprising:

(a) a composition comprising monoclonal anti-anti-anti-MHC antibodies and a pharmaceutically acceptable carrier; and

(b) instructions for use in an animal.

18. A use for monoclonal anti-anti-anti-MHC antibodies in inducing mutual

transplantation tolerance between two vertebrates "A" and "B" comprising administering anti-anti-anti-(B MHC) antibodies to A and applying a B skin graft to A; administering anti-anti-anti-(A MHC) antibodies to B and applying an A skin graft to B; and assessing when the skin grafts are stably accepted as an indication of transplantation tolerance.