EP1572247A1 - Ablation par radiofrequence de populations de cellules hemolymphopoietiques - Google Patents

Ablation par radiofrequence de populations de cellules hemolymphopoietiques

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Publication number
EP1572247A1
EP1572247A1 EP02808232A EP02808232A EP1572247A1 EP 1572247 A1 EP1572247 A1 EP 1572247A1 EP 02808232 A EP02808232 A EP 02808232A EP 02808232 A EP02808232 A EP 02808232A EP 1572247 A1 EP1572247 A1 EP 1572247A1
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European Patent Office
Prior art keywords
acid
cells
edtmp
dotmp
bone marrow
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP02808232A
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German (de)
English (en)
Inventor
Luca A. Inverardi
Camillo Ricordi
Giovanni Paganelli
Aldo N. Serafini
Jaime Simon
Alan D. Strickland
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University of Miami
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University of Miami
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Publication of EP1572247A1 publication Critical patent/EP1572247A1/fr
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • A—HUMAN NECESSITIES
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
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Definitions

  • the invention relates to the use of bone agent radiopharmaceuticals, and more particularly those that target bone and can deliver a radiation dose to the bone marrow and bone marrow-derived cells so as to aid in inducing hemolymphopoietic chimerism.
  • Manipulation of the human immune system has provided several challenges for the medical community, including providing therapies for the treatment of refractory autoimmune diseases, and providing tolerance to organ, tissue and cell transplants.
  • Autoimmune diseases are those wherein a person's immune system mistakenly attacks the cells, tissues and organs of that person's own body.
  • Treatment of refractory autoimmune diseases has been an elusive goal.
  • Bone marrow transplantation is a commonly utilized procedure for the treatment of hematological disorders including malignancies, and has been recently proposed as a therapeutic option for refractory autoimmune diseases. See, for example, Saba N. et al., "Bone marrow transplantation for nonmalignant diseases",.
  • Transplantation tolerance defined as complete acceptance of a graft or organ, tissue or cell transplant by an otherwise fully immunocompetent host without the need for long-term immunosuppression, has also been an elusive goal.
  • both chronic and acute graft rejection are alleviated mainly by the use of non-specific immunosuppressive regimens that are often associated with severe complications including development of neoplasms and organ toxicity.
  • CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model.
  • U.S. Patent Nos. 5,514,364; 5,635,156; and 5,876,692 describe the use of cell type-specific antibodies directed to antigens localized on subsets of cells in combination with whole body radiation to enhance chimerism and to increase tolerance induction after donor bone marrow transplantation. These patents do not describe the use of non-immunological radioconjugated compounds, such as phosphonate compounds, for the induction of hemolymphopoietic chimerism.
  • U.S. Patent No. 5,902,825 discloses therapeutic compositions containing an active agent complex formed of a non-radioactive metal ion and an organic phosphonic acid ligand, wherein the metal ion may be a Lanthanide.
  • the '825 patent teaches that such compositions may be used in the treatment of bone diseases and in methods of reducing bone pain, but does not address issues related to bone marrow transplantation. In particular, no suggestion is made to therapeutically target bone marrow or bone marrow-derived cells to achieve chimerism via bone marrow or bone marrow- derived cell transplantation for the induction of tolerance to graft-related antigens.
  • U.S. Patent No. 5,697,902 discloses therapeutic compositions and their methods of use in destroying bone-marrow cells in a patient prior to regrafting with normal bone marrow cells.
  • the disclosed method comprises treating a patient with a cytotoxic amount of an antibody or antibody fragment specific to a marker associated with, or produced by, bone marrow cells and which is conjugated to a cytotoxic agent.
  • suitable antibodies are described as being NP-2, MN3, and other antibodies that react with bone marrow cells, such as progenitor cell types.
  • Radioisotopes preferred for therapeutic use with conjugated antibodies include 153 samarium.
  • This patent discloses a protocol for infusion of autologous bone marrow, but does not address the issues concerning successful induction of transplantation tolerance for achieving hemolymphopoietic chimerism via bone marrow transplantation.
  • U.S. Patent No. 6,241,961 discloses therapeutic radioimmunoconjugates for use in human therapy and methods for their production.
  • radioimmunoconjugates may consist of a monoclonal antibody having binding specificity for CD 19, CD20, CD22, HLL2, HLA DRIO ⁇ , and CD66, conjugated to a radioisotope, and is useful in treating hemolymphopoietic diseases.
  • the '961 patent does not suggest the use of non-antibody mediated targeting of bone marrow cells for chimerism induction via bone marrow or bone marrow-derived cell transplantation for tolerance to alloantigens,
  • U.S. Patent No. 4,898,724 (hereinafter the '724 patent) teaches the use of Sm-153 with aminophosphonic acid chelators for the treatment of calcific tumors.
  • Administration of chelates such as Sm-153-EDTMP is used to deliver a beta radiation dose to bone tumors.
  • a dose to bone marrow occurs resulting in a transient bone marrow suppression.
  • the '724 patent does not teach or suggest the use of such chelates for chimerism induction.
  • U.S. Patent No. 4,882,142 (hereinafter the '142 patent) teaches the use of aminophosphonic acid complexes of radioactive rare earth metal ions such as Sm-153 and Ho-166 for the suppression of bone marrow.
  • a preferred embodiment is the complex formed between the macrocyclic aminophosphonic acid DOTMP and the radioactive metal Ho-166. I.V. injections of these chelates resulted in accumulation of the radioactivity in bone with the effect of suppressing or ablating bone marrow.
  • the ' 142 patent does not teach or suggest induction of chimerism.
  • radioactive bone agents including ablation of the marrow, treating of calcific tumors, and treating autoimmune disease.
  • this reference does not teach induction of chimerism. Rather, Fritzberg et. al propose the use of growth stimulating hormones that would speed up the recovery of bone marrow and as a result would not be conducive to the induction of chimerism..
  • the present invention is a method of achieving hemolymphopoietic chimerism comprising administering to a recipient a bone seeking radiopharmaceutical; transplanting bone marrow or bone marrow-derived cells into the recipient; and transiently suppressing lymphocyte response so as to induce hemolymphopoietic chimerism.
  • the present invention is a method for decreasing rejection of transplanted organs, tissues or cells comprising administering to a recipient a bone seeking radiopharmaceutical; transplanting bone marrow or bone marrow-derived cells into the recipient; transiently suppressing lymphocyte response; and transplanting one or more organs, tissues or cells.
  • the present invention is a method to treat autoimmune disease comprising administering to a recipient a bone seeking radiopharmaceutical; transplanting bone marrow or bone marrow-derived cells into the recipient; and transiently suppressing lymphocyte response.
  • the present invention has the advantage of inducing hemolymphopoietic chimerism without the need for lethal or sub-lethal conditioning regimens as used in some of the methods described in the above identified prior art.
  • the use of bone-seeking radioactive compounds represents a viable approach to creating the "space" required for the donor stem cellengraftment and hemolymphopoietic chimerism without the need for external radiation or harsh cytotoxic drugs.
  • the method of the present invention also provides more certainty that hemolymphopoietic chimerism will indeed result, as opposed to some of the methods of the prior art that do not provide an environment allowing induction of chimerism to an adequate degree. And, using the method of the present invention, tolerance to an organ, cell, or tissue transplant can be achieved.
  • FIGURE 1 graphically depicts the results of treating mice with a single dose, IV, of 153 Sm- EDTMP, 150 ⁇ Ci or 500 ⁇ Ci, prior to administration of 20x10 6 or 100x10° allogeneic donor bone marrow-derived cells (BMC) as a single intravenous (TV) dose;
  • FIGURE 2 graphically shows that a single administration of BMC resulted in bone marrow engraftment in all recipients analyzed
  • FIGURE 3 graphically shows the percentage of donor-derived cells in recipients treated with 20x10 BMC, anti-CD 154 mAb, and one of 4 conditioning approaches;
  • FIGURE 4 shows the percentage of donor-derived cells in control animals treated with 100x10° BMC and one of the 4 conditioning approaches
  • FIGURE 5 shows the percentage of donor-derived cells in the control animals treated with 20x10 BMC, and one of the 4 conditioning approaches;
  • FIGURE 6 shows the percent of donor-derived cells in the control animals treated with 20xl0 6 BMC or 100x10° BMC along with anti-CD154 mAb (in the absence of 153 Sm- EDTMP treatment);
  • FIGURE 7 depicts a two-color flow cytometric analysis of the proportion of donor-derived lymphoid (B cells), NK, and myeloid (granulocytes) lineages in representative mixed chimeras prepared using a non-lethal conditioning regiment of 20x10 6 BMC, 153 Sm- EDTMP, and anti-CD154 mAb (upper panels) as well as 20x10° BMC and anti-CD154 mAb (lower panels);
  • FIGURE 8 depicts a two-color flow cytometric analysis of the proportion of donor-derived lymphoid (B cells), NK, and myeloid (granulocytes) lineages in representative mixed chimeras prepared using a non-lethal conditioning regiment of 100x10° BMC, 153 Sm- EDTMP, and anti-CD 154 mAb (upper panels) as well as 100x10° BMC and anti-CD 154 mAb (lower panels);
  • FIGURE 9 graphically shows the survival of full thickness tail-derived skin grafts placed on the recipients treated with 20x10 6 BMC, I53 Sm-EDTMP, and anti-CD 154 mAb, or the indicated control groups;
  • FIGURE 10 graphically depict the survival of full thickness tail-derived skin grafts placed on the recipients treated with 100x10° BMC, 153 Sm-EDTMP, and anti-CD 154 mAb, or the indicated control groups.
  • the present invention focuses on a novel approach of attaining a profound, but transient myelodepression by selectively targeting the recipient bone marrow in order to achieve multilineage chimerism.
  • the present invention can be used to obtain multilineage hemolymphopoietic chimerism.
  • multilineage is defined herein to mean that more than one cell lineage derived from bone marrow-contained precursors is detectable in the recipient.
  • the present invention has particular applicability to inducing transplantation tolerance in a recipient of an organ, tissue or cell transplant, and to treating autoimmune diseases.
  • hemolymphopoietic chimerism is induced so as to provide immunological tolerance to at least one member of the group consisting of alloantigens, autoantigens and xenoantigens.
  • Alloantigens are those antigens recognized by the immune system that are expressed on cells, tissues or organs of a non-identical individual of the same species.
  • Autoantigens are those antigens expressed by an individual's tissues, cells or organs that elicit an autoimmune response or that are the target of an autoimmune disease.
  • Xenoantigens are those antigens recognized by the immune system that are expressed on cells, tissues or organs of an individual of a different species.
  • the method of the present invention includes the step of administering a bone seeking radiopharmaceutical to a recipient.
  • a bone seeking radiopharmaceutical is defined herein to mean a complex of a radionuclide and a ligand which targets bone rather than soft tissue.
  • the radiopharmaceutical comprises a rare earth radionuclide complexed with an aminophosphonic acid.
  • Preferred radionuclides include Sm-153, Ho-166, Gd-159, Lu-177, Dy-165, Y-90, In-155m, Re-186, Re-188, Sn-117m, La-140,I-131, Cu-67, Ac-225, Bi-212, Bi-213, At-211, Ra-223, Pm-149, Rh-105; Au-198, Au-199, Dy-166, Sc-47, Yb-175, P-32, Sr-89, Ir-192, Tb-149, and Ra-224.
  • Preferred ligands include aminophosphonic acids and lower carboxylic acids. More preferably, the ligand is selected from the group consisting of ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), tris(2- aminoethyl)aminehexamethylenephosphonic acid (TTHMP), 1- carboxyethylenediaminetetramethylenephosphonic acid (CEDTMP) and bis(aminoethylpiperazine)tetramethylenephosphonic acid (AEPTMP),.
  • ETMP ethylenediaminetetramethylenephosphonic acid
  • DTPMP diethylenetriaminepentamethylenephosphonic acid
  • HEDTMP hydroxyethylethylenediaminetrimethylenephosphonic acid
  • NTMP nitrilotrimethylenephosphonic acid
  • TTHMP tris(
  • Ethylenediaminetetraacetic acid l,4,7,10-tetraazacyclododecane-N,N',N",N'"- tetramethylenephosphonic acid (DOTMP), hydroxyethyldiphosphonic acid (HEDP), methylenediphosphonic acid (MDP), diethylenetriaminepentaacetic acid (DTP A), hydroxethylethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).
  • DOTMP Ethylenediaminetetraacetic acid
  • HEDP hydroxyethyldiphosphonic acid
  • MDP methylenediphosphonic acid
  • DTP A diethylenetriaminepentaacetic acid
  • HEDTA hydroxethylethylenediaminetriacetic acid
  • NTA nitrilotriacetic acid
  • the bone seeking radiopharmaceutical complex is chosen from the group consisting of Sm-153-EDTMP, Sm-153-DOTMP, Ho-166-EDTMP, Ho-166-DOTMP, Gd- 159-EDTMP, Gd-159-DOTMP, Dy-165-EDTMP, Dy-165-DOTMP, Re-186-HEDP, Re- 188-HEDP, and Sn-117m-DTPA.
  • Certain bone seeking radiopharmaceuticals which can be used in the method of the present invention do not require the use of a chelating agent.
  • P-32 can be used alone as a bone seeking radiopharmaceutical without a ligand.
  • Sr-89 as the chloride can be used, as indicated in Robinson R G, Spicer J A, Preston D F, et al., "Treatment of Metastatic Bone Pain With Strontium-89,” Nucl. Med. Biol. 14:219-222 (1987).
  • Preferred radiopharmaceuticals for use with the present invention include Sm-153-EDTMP, Sm-153- DOTMP, Ho-166-EDTMP, Ho-166-DOTMP, Gd-159-EDTMP, and Gd-159-DOTMP. Examples of these complexes are described in U.S Patents 4,976,950, 4,882,142, 5,059,412, 5,066,478, 5,064,633, 4,897,254, 4,898,724, and 5,300,279. More preferred radiopharmaceuticals for use with the present invention do not include Sm-153-EDTMP, but rather include complexes of Sm-153 with ligands other than EDTMP and complexes of EDTMP with radionuclides other than Sm-153. Most preferred radiopharmaceuticals include Sm-153-DOTMP, Ho-166-EDTMP, Ho-166-DOTMP, Gd-159-EDTMP, and Gd- 159-DOTMP.
  • the bone seeking radiopharmaceutical may be introduced to a human bone marrow recipient in dosages ranging from 1 mCi/Kg to 50 mCi/Kg.
  • the dose of the bone seeking radiopharmaceutical will depend upon the nuclear properties of the radionuclide, the localization of the radiopharmaceutical in bone, and the localization in other tissues. For example, an isotope with a long half life and a high energy emission would deliver a higher dose than one with a short half life and low energy emissions.
  • a lower, diagnostic dose of the radiopharmaceutical may be used to determine the biodistribution of the bone seeking radiopharmaceutical allowing for an estimation of the dose prior to administration of the higher doses.
  • a dose of from 3 miCi/Kg (111 MBq Kg) to 20 mCi/Kg (740 MBQ) is preferred. More preferred is a dose of 6 mCi/Kg (222 MBq/Kg) to 10 mCi/Kg (370 MBq/Kg) body weight.
  • Each radionuclide and the form that it is administered will give a different dose. The dose is dependent on the decay properties of the radionuclide and the biodistribution.
  • Preferred doses to the red bone marrow are from 800 rads (8 Grey) to 5,000 rads (50 Grey). More preferred is from 1600 Rads (16 Grey) to 3,000 rads (30 Grey).
  • Radioactivity will remain in recipient bone, thereby affecting the bone marrow or bone marrow-derived cells therein, for the life of the isotope.
  • Sm-153, Ho-166, and Gd-159 are preferred, other radioactive isotopes having relatively short, but clinically appropriate, half-lives may also be employed in complexes useful for the invention.
  • Suitable complexes may be prepared according to known protocols optionally utilizing complex forming agents, or may be obtained from commercial sources.
  • the radiopharmaceuticals may be formulated into any pharmaceutically acceptable dosage form, including liquids, emulsions, and suspensions. Liquid solutions for injection are particularly preferred. Pharmaceutical compositions of the complexes for use according to the invention may also contain suitable diluents, excipients, buffers, stabilizers and carriers. Sterile water or sterile isotonic saline solutions are particularly preferred. Another step in the method of the present invention entails transplanting the bone marrow- derived cells into a recipient.
  • bone marrow-derived cells is defined herein to mean bone marrow cells, stem cells and precursors as well as cells obtained from the bone marrow and selected or manipulated in vitro (for example, cultured, enriched etc) as well as cells with stem cell/precursor cell properties obtained from other anatomical sources (peripheral blood after mobilization, cord blood etc). Bone marrow-derived cells are transplanted into the recipient via protocols known to those of skill in the art.
  • the method of the present invention further comprises the step of transiently suppressing the lymphocyte response.
  • Transient lymphocyte response suppression is defined to mean that the treatment is transient, or of a relatively short duration, as opposed to being chronic in duration.
  • chronic lymphocyte response suppression is avoided with the use of the present invention, so as to minimize the side effects associated with such chronic lymphocyte suppression.
  • a biological modifier is administered to the host.
  • suitable biological modifiers include antibodies, cytokines, immunosuppressive drugs, peptides, proteins, nucleic acids or a combination thereof.
  • the bone marrow-derived cells are transplanted in conjunction with at least one antibody raised against an antigen selected from the group consisting of CD4, CD8, CD3, CD5, CD55, CD40, CD40L, B7.1, B7.2, CD28, and LFA-1.
  • Appropriate dosage levels and length of administration of the biological modifier can be determined by those of ordinary skill in the art and will depend upon factors such as histocompatability matching, dose of transplanted cells, age of the patient, and so forth.
  • the method of the present invention is useful for decreasing rejection of transplanted organs, tissues or cells.
  • the organs, tissues or cells can be transplanted using procedures known to those skilled in the art.
  • Organs, tissues or cells for which transplantation tolerance can be enhanced by the present invention include liver, heart, lung, kidney, intestine, pancreas, larynx, blood vessels limbs, endocrine organs, skin, islet cells, cornea, nerves, muscles, keratinocytes and keratynocyte precursors , chondrocytes and condrocyte precursors hepatocytes and hepatocyte precursors, myocytes and myoblasts including cardiomyocytes and cardiomyoblasts, neural cells and neural cell precursors, endothelial cells, endocrine cells and endocrine cell precursors, stem cells and cells of different lineage derived from stem cells.
  • the method of the present invention can be used to treat autoimmune disease.
  • the bone marrow- derived cells that are transplanted during the bone marrow-derived cell transplantation step can be autologous or homologous.
  • the bone marrow-derived cells can be either unmanipulated or depleted of mature T-lymphocytes prior to transplantation.
  • autoimmune diseases typically affect the nervous system, cardiac system, the eye, cardiac system, respiratory system, urogenital system, gastrointestinal system, blood, blood vessels, endocrine glands, skin, and musculoskeletal system, including connective tissue diseases.
  • the autoimmune diseases that can be treated using the method of the present invention include rheumatoid arthritis, ankylosing spondilytis polymyositis and dermatomyositis systemic lupus erythematosus, vasculitides, Goodpasture's syndrome Wegener granulomatosis uveitis Sjogren's syndrome Bechet's disease, autoimmune myocarditis and perycarditis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune gastritis, autoimmune hepatitis primary biliary chirrosis, diabetes, autoimmune thyroid disease Graves disease, Hashimoto thyroiditis, Addison's disease, ipoparat
  • mice All animal procedures were performed under the supervision and approval of the University of Miami Institutional Animal Care and Use Committee (IACUC). Mice (7-8 week old Balb/c (H-2 d ), C57BL/6 (B6; H-2 b ) and C3H/HeJ (C3H; H-2 k )) were purchased from Jackson Laboratories (Bar Harbor, Maine). Recipient C57BL/6 mice were used at 9- 10 weeks of age. All animals were housed in pathogen-free room in sterile microisolator cages with autoclaved feed and autoclaved acidified water.
  • IACUC University of Miami Institutional Animal Care and Use Committee
  • Bone marrow-derived Cell Transplantation Balb/c mice, 8-9 weeks old, used as donors, were sacrificed on the day of the transplant.
  • Bone marrow cells were prepared according to a previously published regimen. Briefly, after removing femura and tibiae, and cleaning them from muscle tissue and cartilage, BMC were flushed with sterile RPMI-1640 (Mediatech, Inc, Herndon, Virginia) supplemented with 0.8 mg/ml Gentamycin (Gibco, Gaithersburg, Maryland), using 23G needle. BMC were filtered through a sterile nylon mesh and counted.
  • the grafts were first inspected on the eighth-day following grafting, and every third day thereafter. Graft rejection was considered complete when no viable graft tissue was detected by visual inspection. Recipient mice were considered to be tolerant when donor- specific skin grafts survived in perfect condition for ⁇ 150 days.
  • Cells were also assessed for non-specific staining using an Ig isotype control (FITC-conjugated mouse IgG 2a and Cy-Chrome-conjugated rat IgG 2b ), and the percentage of cells stained with this Ab was subtracted from the values obtained from staining with the specific Ab to determine the relative number of positive cells. Reconstitution of various cell lineages was assessed using FITC-conjugated anti-mouse H- 2K b or H-2K d and PE-conjugated anti-mouse CD19/CD22 in the B cell, PE-conjugated anti- mouse Ly-6G in the granulocyte, and PE-conjugated anti-mouse Mac-3 in the macrophage compartments.
  • Ig isotype control FITC-conjugated mouse IgG 2a and Cy-Chrome-conjugated rat IgG 2b
  • Reconstitution of various cell lineages was assessed using FITC-conjugated anti-mouse H- 2K
  • Recipient animals were first tested 1 week after BMC-Tx, every 2 weeks up to 6 weeks, and every 4 weeks thereafter.
  • Purified anti-mouse CD16/CD32 (Fc ⁇ III/II) was used to block non-specific binding to the Fc receptors.
  • FCM analyses were preformed using Cell Quest software on a FACScan cytometer purchased from Becton Dickinson & Co. (Mountain View, California).
  • Splenocytes were used to analyze the expression of Vb3 + , Vb5 + , Vbl 1 + and Vbl4 + families in the chimeras at the time of sacrifice.
  • cells were blocked with purified anti-mouse CD16/CD32 (Fc ⁇ III/II) (PharMingen), and then incubated with FITC-conjugated H-2K d and PE- conjugated anti-Vb3 + , Vb5 + , Vbl 1 + or Vbl4 + (PharMingen) for 30 minutes on ice.
  • FITC- conjugated mouse IgG2a, PE-conjugated Armenian Hamster IgG, group 2, mouse IgGl, rat IgG2b and rat IgM antibodies were used as negative controls.
  • Splenocytes depleted of red blood cells were incubated at 37°C in 5 percent CO for 3 days in quintuplicate wells containing 2 x 10 5 responders with 2 x 10 5 stimulators treated with Mytomicin C (Sigma, St. Louis, Missouri) in Iscove's tissue culture media (Gibco, Gaithersburgh, Maryland) containing 10 percent heat-inactivated FCS, 2 mM L-Glutamine (Mediatech), 25mM HEPES (Mediatech) and 0.05 mM ⁇ - mercaptoethanol.
  • splenocytes isolated from na ⁇ ve Balb/c donors were incubated with several different dilutions (1 :3; 1: 10; 1:30; 1: 100) of plasma from the chimeric recipients at 4°C for 60 minutes.
  • Cells were washed with PBS supplemented with 1 percent BSA, 0.02 percent sodium azide, and then incubated with FITC-conjugated goat anti-mouse IgG (H+L) (Jackson ImmunoResearch Laboratories, West Grove, Pennsylvania) and PE-conjugated anti-mouse CD22 for 30 minutes on ice.
  • the cells were then washed with PBS and analyzed on a Becton Dickinson F AC Scan. Plasma from a na ⁇ ve C57BL/6 incubated with splenocytes from na ⁇ ve Balb/c donors was used as a baseline.
  • Recipient animals C57BL/6, H-2 b
  • BMC allogenic donor bone marrow cells
  • BMC transplantation BMC-Tx
  • MR-1 hamster anti-murine CD154 mAb
  • the lower dose of 153 Sm, 150 ⁇ Ci proved to be as effective as the higher dose, 500 ⁇ Ci.
  • Treatment with 153 Sm- EDTMP resulted in transient myelodepression that occurred one week post administration of the compound and was spontaneously resolved by 4-6 weeks post-administration, as shown in FIGURE 1.
  • Both the 150 ⁇ Ci and 500 ⁇ Ci doses of 153 Sm-EDTMP have similar effect on hemolymphopoietic elements.
  • WBC white blood cell counts
  • administration of 153 Sm-EDTMP does not have significant effect on red blood cell (RBC), hemoglobin (Hb), and Platelet (PLT) counts.
  • FIGURE 2 shows percentages of donor-derived cells in the recipients treated with lOOxlO 6 BMC, anti-CD 154 mAb, and one of 4 conditioning approaches- 153 Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 7; 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 7, Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 14; and 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 14.
  • FIGURE 3 is shown the percentage of donor-derived cells in the recipients treated with 20x10 6 BMC, anti-CD 154 mAb, and one of the 4 conditioning approaches: 153 Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 7; 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 7; I53 Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 14; and 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day
  • the conditioning regimens were 153 Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 7; 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 7; 153 Sm- EDTMP 150 ⁇ Ci, followed by administration of BMC on day 14; and 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 14.
  • This fourth regimen differs from the previous, since no anti-CD 154 mAb to induce costimulatory blockade was used.
  • FIGURE 5 shows the percent of donor-derived cells in the control animals treated with 20x10 6 BMC, and one of the 4 conditioning approaches: 153 Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 7; 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 7; 153 Sm-EDTMP 150 ⁇ Ci, followed by administration of BMC on day 14; and 153 Sm-EDTMP 500 ⁇ Ci, followed by administration of BMC on day 14 (this regimen differs from the previous, since no anti-CD 154 mAb to induce costimulatory blockade was used).
  • the percentage of donor-derived cells in the control animals treated with 20x10 6 BMC or 100x10° BMC along with anti-CD154 mAb is shown in FIGURE 6.
  • FIGURE 7 shows a two-color flow cytometric analysis of the proportion of donor-derived lymphoid (B cells), NK, and myeloid (granulocytes) lineages in representative mixed chimeras prepared using a non-lethal conditioning regiment of 20x10 BMC, Sm- EDTMP, and anti-CD 154 mAb (upper panels) as well as 20x10 6 BMC and anti-CD 154 mAb (lower panels). Analysis was performed using Class I H-2 d -FITC and either CD22 (B cells), NK, or GRAN1 (granulocytes), all PE. Analysis was performed on the lymphoid gate, and the values were normalized to 100 percent.
  • FIGURE 8 is shown a two-color flow cytometric analysis of the proportion of donor- derived lymphoid (B cells), NK, and myeloid (granulocytes) lineages in representative mixed chimeras prepared using a non-lethal conditioning regiment of 100 10 BMC, Sm- EDTMP, and anti-CD 154 mAb (upper panels) as well as 100x10° BMC and anti-CD 154 mAb (lower panels). Analysis was preformed using Class I H-2 d -FITC and either CD22 (B cells), NK, or GRAN1 (granulocytes), all PE. Analysis was performed on the lymphoid gate, and the values were normalized to 100 percent.
  • FIGURE 9 The survival of full thickness tail-derived skin grafts placed on the recipients treated with 20xl0 6 BMC, 153 Sm-EDTMP, and anti-CD154 mAb, or indicated control groups is shown in FIGURE 9. Grafts were prepared 30 days following the last administration of anti- CD154 mAb in the treated animals. Two different donor strain combinations, BALB/c (H- 2 d ) and C3H/J (H-2 k ) were used. Each recipient received skin grafts from both strains: donor-type, BALB/c (H-2 d ), as well as third-party, C3H/J (H-2 k ). Third party grafts were rejected within the same time frame as were donor-specific grafts placed on na ⁇ ve recipients.
  • FIGURE 10 The survival of full thickness tail-derived skin grafts placed on the recipients treated with 100x10° BMC, 153 Sm-EDTMP, and anti-CD 154 mAb, or indicated control groups is depicted graphically in FIGURE 10. Grafts were prepared 30 days following the last administration of anti-CD 154 mAb in the treated animals. Two different donor strain combinations, BALB/c (H-2 d ) and C3H/J (H-2 k ) were used. Each recipient received skin grafts from both strains: donor-type, BALB/c (H-2 d ), as well as third-party, C3H/J (H-2 k ).
  • allogeneic bone marrow-derived cells may be infused in the presence of a transient T cell co-stimulatory blockade obtained by administration of anti-CD 154 monoclonal antibodies (mAb).
  • mAb monoclonal antibodies

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Abstract

L'invention concerne une méthode permettant d'obtenir un chimérisme hémolymphopoïétique. Ladite méthode consiste à administrer à un receveur un pharmaceutique ostéotrope ; à greffer des cellules issues de la moelle osseuse chez le receveur ; et à supprimer la réponse lymphocytaire de manière transitoire afin d'induire un chimérisme hémolymphopoïétique. Ladite méthode est utile pour diminuer le rejet d'organes, de tissus ou de cellules greffés ou pour traiter des maladies auto-immunes. La présente invention présente l'avantage d'induire un chimérisme hémolymphopoïétique sans recourir à l'irradiation externe ou à des médicaments cytotoxiques durs. La présente invention présente l'avantage supplémentaire de prolonger de manière significative la tolérance d'une greffe d'organe, de cellule ou de tissu.
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