Abstract
Hematopoietic macrochimerism, established by bone marrow transplantation, can be used as an approach for treating autoimmune disease and inducing transplant tolerance. In this study, we investigated whether a stable, high level of fully MHC-mismatched hematopoietic macrochimerism can be induced by using irradiation-free protocols, and whether rapamycin and T cell costimulatory blockades (anti-CD40L monoclonal antibody (mAb) and CTLA4Ig) as post-transplant treatment promote bone marrow engraftment. Donor-specific blood transfusion (DST), anti-lymphocyte serum (ALS), busulfan, and cyclophosphamide were given pretransplantation. Balb/c (H-2d) bone marrow cells, at a dose of 4 × 107, were infused into each C57BL/6 mouse (H-2b). Rapamycin, anti-CD40L mAb, and CTLA4Ig were then administered, either alone or in combination. Without ALS or busulfan and cyclophosphamide, macrochimerism can only rarely be induced. Donor-specific transfusion (DST) enhances induction of hematopoietic macrochimerism. Rapamycin, anti-CD40L mAb and CTLA4Ig, alone or in combination, induce a stable and high level of hematopoietic macrochimerism. In the chimeric mice, donor-derived cells were detected in all lymphohematopoietic tissues and donor-specific tolerance was induced in vitro. We conclude that a stable and high level of fully MHC-mismatched hematopoietic macrochimerism can be induced in mice after transplanting a single modest dose of bone marrow cells without irradiation. Rapamycin and T cell costimulatory blockade as post-transplant treatment promote bone marrow engraftment.
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References
Ildstad ST, Sachs DH . Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts Nature 1984 307: 168 170
Cobbold SP, Martin G, Qin S, Waldmann H . Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance Nature 1986 323: 164 166
Wekerle T, Sykes M . Mixed chimerism as an approach for the induction of transplantation tolerance Transplantation 1999 68: 459 467
Sachs DH . Mixed chimerism as an approach to transplantation tolerance Clin Immunol 2000 95: S63 S68
Wekerle T, Kurtz J, Ito H et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment Nat Med 2000 6: 464 469
Durham MM, Bingaman AW, Adams AB et al. Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning J Immunol 2000 165: 1 4
Hale DA, Gottschalk R, Umemura A et al. Establishment of stable multilineage hematopoietic chimerism and donor-specific tolerance without irradiation Transplantation 2000 69: 1242 1251
Tomita Y, Sachs DH, Sykes M . Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow Blood 1994 83: 939 948
Tomita Y, Yoshikawa M, Zhang QW et al. Induction of permanent mixed chimerism and skin allograft tolerance across fully MHC-mismatched barriers by the additional myelosuppressive treatments in mice primed with allogeneic spleen cells followed by cyclophosphamide J Immunol 2000 165: 34 41
Guo Z, Wu T, Kirchhof N et al. Immunotherapy with nondepleting anti-CD4 monoclonal antibodies but not CD28 antagonists protects islet graft in spontaneously diabetic nod mice from autoimmune destruction and allogeneic and xenogeneic graft rejection Transplantation 2001 71: 1656 1665
Matesic D, Lehmann PV, Heeger PS . High-resolution characterization of cytokine-producing alloreactivity in naive and allograft-primed mice Transplantation 1998 65: 906 914
Acha-Orbea H, Palmer E . Mls – a retrovirus exploits the immune system (see comments) Immunol Today 1991 12: 356 361
Dyson PJ, Knight AM, Fairchild S et al. Genes encoding ligands for deletion of V beta 11 T cells cosegregate with mammary tumour virus genomes (see comments) Nature 1991 349: 531 532
Sykes M, Szot GL, Swenson KA, Pearson DA . Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning Nat Med 1997 3: 783 787
Wekerle T, Sayegh MH, Hill J et al. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance J Exp Med 1998 187: 2037 2044
Mayumi H, Himeno K, Tanaka K et al. Drug-induced tolerance to allografts in mice. IX. Establishment of complete chimerism by allogeneic spleen cell transplantation from donors made tolerant to H-2-identical recipients Transplantation 1986 42: 417 422
Eto M, Mayumi H, Tomita Y et al. Intrathymic clonal deletion of V beta 6+ T cells in cyclophosphamide-induced tolerance to H-2-compatible, Mls-disparate antigens J Exp Med 1990 171: 97 113
Tomita Y, Nishimura Y, Harada N et al. Evidence for involvement of clonal anergy in MHC class I and class II disparate skin allograft tolerance after the termination of intrathymic clonal deletion J Immunol 1990 145: 4026 4036
Adams AB, Durham MM, Kean L et al. Costimulation blockade, busulfan, and bone marrow promote titratable marochimerism, induce transplantation tolerance and correct genetic hemoglobinopathies with minimal myelosuppression J Immunol 2001 167: 1103 1111
Sehgal SN . Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression Clin Biochem 1998 31: 335 340
Blazar BR, Taylor PA, Snover DC et al. Murine recipients of fully mismatched donor marrow are protected from lethal graft-versus-host disease by the in vivo administration of rapamycin but develop an autoimmune-like syndrome J Immunol 1993 151: 5726 5741
Blazar BR, Taylor PA, Sehgal SN, Vallera DA . Rapamycin prolongs survival of murine recipients of fully allogeneic donor grafts when administered during the graft-versus-host disease process Ann NY Acad Sci 1993 685: 73 85
Chen BJ, Morris RE, Chao NJ . Graft-versus-host disease prevention by rapamycin: cellular mechanisms Biol Blood Marrow Transplant 2000 6: 529 536
Abraham RT, Wiederrecht GJ . Immunopharmacology of rapamycin Annu Rev Immunol 1996 14: 483 510
Bierer BE, Mattila PS, Standaert RF et al. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin Proc Natl Acad Sci USA 1990 87: 9231 9235
Li Y, Li XC, Zheng XX et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance Nat Med 1999 5: 1298 1302
Wells AD, Gudmundsdottir H, Turka LA . Following the fate of individual T cells throughout activation and clonal expansion. Signals from T cell receptor and CD28 differentially regulate the induction and duration of a proliferative response J Clin Invest 1997 100: 3173 3183
Li Y, Zheng XX, Li XC et al. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment Transplantation 1998 66: 1387 1388
Quesenberry PJ, Zhong S, Wang H, Stewart M . Allogeneic chimerism with low-dose irradiation, antigen presentation, and costimulator blockade in H-2 mismatch mice Blood 2001 98: 557 564
Taylor PA, Lees CJ, Waldmann H et al. Requirements for the promotion of allogeneic engraftment by anti-CD154 (anti-CD40L) monoclonal antibody under nonmyelablative conditions Blood 2001 98: 467 474
Sykes M, Bukhari Z, Sachs DH . Graft-versus-leukemia effect using mixed allogeneic bone marrow transplantation Bone Marrow Transplant 1989 4: 465 474
Tomita Y, Khan A, Sykes M . Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a nonmyeloablative regimen J Immunol 1994 153: 1087 1098
Acknowledgements
This work was partly supported by grants awarded by the Juvenile Diabetes Foundation International and by the American Diabetes Association.
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Wu, T., Sozen, H., Luo, B. et al. Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy. Bone Marrow Transplant 29, 949–956 (2002). https://doi.org/10.1038/sj.bmt.1703574
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DOI: https://doi.org/10.1038/sj.bmt.1703574