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Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation

Bone Marrow Transplantation volume 50, pages S82–S86 (2015)Cite this article

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Abstract

The success of allogeneic hematopoietic cell transplantation (HCT) has been limited by transplant-associated toxicities related to the conditioning regimens used and to graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has greatly impeded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. This paper reviews an approach to HCT involving reduced intensity conditioning that demonstrated sufficient safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting, to be applied for the induction of kidney allograft tolerance in humans with no other indication for HCT. These studies provided the first successful example of intentional organ allograft tolerance induction across HLA barriers in humans. Current data and hypotheses on the mechanisms of tolerance in these patients are reviewed.

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References

  1. Owen RD . Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102: 400–401.

    Article  CAS  PubMed  Google Scholar 

  2. Sharabi Y, Sachs DH, Sykes M et al. T cell subsets resisting induction of mixed chimerism across various histocompatibility barriers. In: Gergely J, Benczur M, Falus A, Füst Gy, Medgyesi G, Petrányi Gy et al (eds) Progress in Immunology VIII Proceedings of the Eighth International Congress of Immunology. Budapest, 1992, 801–805.

    Google Scholar 

  3. Hayashi H, LeGuern C, Sachs DH, Sykes M . Alloresistance to K locus mismatched bone marrow engraftment is mediated entirely by CD4+ and CD8+ T cells. Bone Marrow Transplant 1996; 18: 285–292.

    CAS  PubMed  Google Scholar 

  4. Tomita Y, Khan A, Sykes M . Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantion in mice conditioned with a non-myeloablative regimen. J Immunol 1994; 153: 1087–1098.

    CAS  PubMed  Google Scholar 

  5. Tomita Y, Sachs DH, Khan A, Sykes M . Additional mAb injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Transplantation 1996; 61: 469–477.

    Article  CAS  PubMed  Google Scholar 

  6. Tomita Y, Khan A, Sykes M . Mechanism by which additional monoclonal antibody injections overcome the requirement for thymic irradiation to achieve mixed chimerism in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Transplantation 1996; 61: 477–485.

    Article  CAS  PubMed  Google Scholar 

  7. Khan A, Tomita Y, Sykes M . Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Peripheral mechanisms do not contribute to maintenance of tolerance. Transplantation 1996; 62: 380–387.

    Article  CAS  PubMed  Google Scholar 

  8. Manilay JO, Pearson DA, Sergio JJ, Swenson KG, Sykes M . Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation 1998; 66: 96–102.

    Article  CAS  PubMed  Google Scholar 

  9. Ramsdell F, Fowlkes BJ . Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science 1990; 248: 1342–1348.

    Article  CAS  PubMed  Google Scholar 

  10. Lee LA, Sergio JJ, Sykes M . Natural killer cells weakly resist engraftment of allogeneic long-term multilineage-repopulating hematopoietic stem cells. Transplantation 1996; 61: 125–132.

    Article  CAS  PubMed  Google Scholar 

  11. Kean LS, Hamby K, Koehn B, Lee E, Coley S, Stempora L et al. NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Am J Transplant 2006; 6: 292–304.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    CAS  PubMed  Google Scholar 

  13. Ramshaw HS, Crittenden RB, Dooner M, Peters SO, Rao SS, Quesenberry PJ et al. High levels of engraftment with a single infusion of bone marrow cells into normal unprepared mice. Biol Blood Marrow Transplant 1995; 1: 74–80.

    CAS  PubMed  Google Scholar 

  14. Sykes M, Szot GL, Swenson K, Pearson DA, Wekerle T . Separate regulation of hematopietic and thymic engraftment. Exp Hematol 1997; 26: 457–465.

    Google Scholar 

  15. Bachar-Lustig E, Rachamin N, Li H-W, Lan F, Reisner Y . Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1995; 1: 1268–1273.

    Article  CAS  PubMed  Google Scholar 

  16. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F et al. Treatment of high-risk acute leukemia with T cell-depleted stem cells from related donors with one fully mismatched haplotype. New Engl J Med 1998; 339: 1186–1193.

    Article  CAS  PubMed  Google Scholar 

  17. Bachar-Lustig E, Li HW, Gur H, Krauthgamer R, Marcus H, Reisner Y et al. Induction of donor-type chimerism and transplantation tolerance across major histocompatibility barriers in sublethally irradiated mice by Sca-1+Lin- bone marrow progenitor cells: Synergism with non-alloreactive (host x donor)F1 T cells. Blood 1999; 94: 3212–3221.

    CAS  PubMed  Google Scholar 

  18. Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G et al. Allogeneic bone marrow translantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000; 6: 464–469.

    Article  CAS  PubMed  Google Scholar 

  19. Pilat N, Baranyi U, Klaus C, Jaeckel E, Mpofu N, Wrba F et al. Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning. Am J Transplant 2010; 10: 751–762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sharabi Y, Sachs DH . Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen. J Exp Med 1989; 169: 493–502.

    Article  CAS  PubMed  Google Scholar 

  21. Guo Z, Wang J, Dong Y, Adams AB, Shirasugi N, Kim O et al. Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion. Am J Transplant 2003; 3: 1091–1098.

    Article  CAS  PubMed  Google Scholar 

  22. Shirasugi N, Adams AB, Durham MM, Lukacher AE, Xu H, Rees P et al. Prevention of chronic rejection in murine cardiac allografts: a comparison of chimerism- and nonchimerism-inducing costimulation blockade-based tolerance induction regimens. J Immunol 2002; 169: 2677–2684.

    Article  CAS  PubMed  Google Scholar 

  23. Slavin S . Total lymphoid irradiation. Immunol Today 1987; 3: 88–92.

    Article  Google Scholar 

  24. Pierce GE . Allogeneic versus semiallogeneic F1 bone marrow transplantation into sublethally irradiated MHC-disparate hosts. Effects on mixed lymphoid chimerism, skin graft tolerance, host survival, and alloreactivity. Transplantation 1990; 49: 138–144.

    Article  CAS  PubMed  Google Scholar 

  25. Eto M, Mayumi H, Tomita Y, Y Y, Nomoto K . 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.

    Article  CAS  PubMed  Google Scholar 

  26. Cobbold SP, Qin S, Waldmann H . Reprogramming the immune system for tolerance with monoclonal antibodies. Sem Immunol 1990; 2: 377–387.

    CAS  Google Scholar 

  27. Wekerle T, Sayegh MH, Hill J, Zhao Y, Chandraker A, Swenson KG 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Durham MM, Bingaman AW, Adams AB, Ha J, Waitze SY, Pearson TC 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.

    Article  CAS  PubMed  Google Scholar 

  29. Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP . The role of the thymus in immune reconstiutution in aging, bone marrow transplantion, and HIV-1 infection. Annu Rev Immunol 2000; 18: 529–560.

    Article  CAS  PubMed  Google Scholar 

  30. Ito H, Kurtz J, Shaffer J, Sykes M . CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40L interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway. J Immunol 2001; 166: 2970–2981.

    Article  CAS  PubMed  Google Scholar 

  31. Fehr T, Takeuchi Y, Kurtz J, Sykes M . Early regulation of CD8 T cell alloreactivity by CD4+CD25- T cells in recipients of anti-CD154 antibody and allogeneic BMT is followed by rapid peripheral deletion of donor-reactive CD8+ T cells, precluding a role for sustained regulation. Eur J Immunol 2005; 35: 2679–2690.

    Article  CAS  PubMed  Google Scholar 

  32. Kurtz J, Ito H, Wekerle T, Shaffer J, Sykes M . Mechanisms involved in the establishment of tolerance through costimulatory blockade and BMT: Lack of requirement for CD40L-mediated signaling for tolerance or deletion of donor-reactive CD4+ cells. Am J Transplant 2001; 1: 339–349.

    Article  CAS  PubMed  Google Scholar 

  33. Kurtz J, Shaffer J, Anosova N, Benichou G, Sykes M . Mechanisms of early peripheral CD4 T cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion, but not regulatory cells. Blood 2004; 103: 4336–4343.

    Article  CAS  PubMed  Google Scholar 

  34. Wekerle T, Sayegh MH, Chandraker A, Swenson KG, Zhao Y, Sykes M et al. Role of peripheral clonal deletion in tolerance induction with bone marrow transplantation and costimulatory blockade. Transplant Proc 1999; 31: 680.

    Article  CAS  PubMed  Google Scholar 

  35. Bigenzahn S, Blaha P, Koporc Z, Pree I, Selzer E, Bergmeister H et al. The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade. Am J Transplant 2005; 5: 1237–1247.

    Article  CAS  PubMed  Google Scholar 

  36. Domenig C, Sanchez-Fueyo A, Kurtz J, Alexopoulos SP, Mariat C, Sykes M et al. Roles of deletion and regulation in creating mixed chimerism and allograft tolerance using a nonlymphoablative irradiation-free protocol. J Immunol 2005; 175: 51–60.

    Article  CAS  PubMed  Google Scholar 

  37. Kawai T, Cosimi AB, C RB, Powelson J, Eason J, Kozlowski T et al. Mixed allogeneic chimerism and renal allograft tolerance in cynomologous monkeys. Transplantation 1995; 59: 256–262.

    Article  CAS  PubMed  Google Scholar 

  38. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic marrow grafts. New Engl J Med 1979; 300: 1068–1073.

    Article  CAS  PubMed  Google Scholar 

  39. Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, Zhao G et al. An inflammatory checkpoint regulates recruitment of graft-versus-host-reactive T cells to peripheral tissues. J Exp Med 2006; 203: 2021–2031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sykes M, Sheard MA, Sachs DH . Graft-versus-host-related immunosuppression is induced in mixed chimeras by alloresponses against either host or donor lymphohematopoietic cells. J Exp Med 1988; 168: 2391–2396.

    Article  CAS  PubMed  Google Scholar 

  41. Mapara MY, Kim Y-M, Wang S-P, Bronson R, Sachs DH, Sykes M et al. Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood 2002; 100: 1903–1909.

    Article  CAS  PubMed  Google Scholar 

  42. Pelot MR, Pearson DA, Swenson K, Zhao G, Sachs J, Yang Y-G et al. Lymphohematopoietic graft-vs-host reactions can be induced without graft-vs-host disease in murine mixed chimeras established with a cyclophosphamide-based non-myeloablative conditioning regimen. Biol Blood Marrow Transplant 1999; 5: 133–143.

    Article  CAS  PubMed  Google Scholar 

  43. Chakraverty R, Eom HS, Sachs J, Buchli J, Cotter P, Hsu R et al. Host MHC Class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood 2006; 108: 2106–2113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mapara MY, Leng C, Kim YM, Bronson R, Lokshin A, Luster A et al. Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biol Blood Marrow Transplant 2006; 12: 623–634.

    Article  CAS  PubMed  Google Scholar 

  45. Spitzer TR, MCafee S, Dey BR, Colby C, Hope J, Grossberg H et al. Non-myeloablative haploidentical stem cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation 2003; 75: 1748–1751.

    Article  CAS  PubMed  Google Scholar 

  46. Shaffer J, Villard J, Means TK, Alexander S, Dombkowski D, Dey BR et al. Regulatory T-cell recovery in recipients of haploidentical nonmyeloablative hematopoietic cell transplantation with a humanized anti-CD2 mAb, MEDI-507, with or without fludarabine. Exp Hematol 2007; 35: 1140–1152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li HW, Sachs J, Pichardo C, Bronson R, Zhao G, Sykes M et al. Nonalloreactive T cells prevent donor lymphocyte infusion-induced graft-versus-host disease by controlling microbial stimuli. J Immunol 2012; 189: 5572–5581.

    Article  CAS  PubMed  Google Scholar 

  48. Sykes M, Preffer F, McAffee S, Saidman SL, Colby C, Sackstein R et al. Mixed lymphohematopoietic chimerism and graft-vs-lymphoma effects are achievable in adult humans following non-myeloablative therapy and HLA-mismatched donor bone marrow transplantation. Lancet 1999; 353: 1755–1759.

    Article  CAS  PubMed  Google Scholar 

  49. Spitzer TR, MCafee S, Sackstein R, Colby C, Toh HC, Multani P et al. The intentional induction of mixed chimerism and achievement of anti-tumor responses following non-myeloablative conditioning therapy and HLA-matched and mismatched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 2000; 6: 309–320.

    Article  CAS  PubMed  Google Scholar 

  50. Fudaba Y, Spitzer TR, Shaffer J, Kawai T, Fehr T, Delmonico F et al. Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses. Am J Transplant 2006; 6: 2121–2133.

    Article  CAS  PubMed  Google Scholar 

  51. Spitzer TR, Sykes M, Tolkoff-Rubin N, Kawai T, McAfee SL, Dey BR et al. Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease. Transplantation 2011; 91: 672–676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rubio MT, Kim YM, Sachs T, Mapara M, Zhao G, Sykes M et al. Anti-tumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-{gamma}. Blood 2003; 102: 2300–2307.

    Article  CAS  PubMed  Google Scholar 

  53. Rubio MT, Saito TI, Kattelman K, Zhao G, Buchli J, Sykes M et al. Mechanisms of the anti-tumor responses and host-versus graft reactions induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: a critical role for recipient CD4+ T cells and recipient leukocyte infusion-derived IFN-gamma-producing CD8+ T cells. J Immunol 2005; 175: 665–676.

    Article  CAS  PubMed  Google Scholar 

  54. Rubio MT, Zhao G, Buchli J, Chittenden M, Sykes M . Role of indirect allo- and autoreactivity in anti-tumor responses induced by recipient leukocyte infusions (RLI) in mixed chimeras prepared with nonmyeloablative conditioning. Clin Immunol 2006; 120: 33–44.

    Article  CAS  PubMed  Google Scholar 

  55. Saito TI, Rubio MT, Sykes M . Clinical relevance of recipient leukocyte infusion as antitumor therapy following nonmyeloablative allogeneic hematopoietic cell transplantation. Exp Hematol 2006; 34: 1271–1277.

    Article  CAS  PubMed  Google Scholar 

  56. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2008; 358: 353–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kawai T, Sachs DH, Sykes M, Cosimi AB Immune Tolerance Network. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2013; 368: 1850–1852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Andreola G, Chittenden M, Shaffer J, Cosimi AB, Kawai T, Cotter P et al. Mechanisms of donor-specific tolerance in recipients of haploidentical combined bone marrow/kidney transplantation. Am J Transplant 2011; 11: 1236–1247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kawai T, Sachs DH, Sprangers B, Spitzer TR, Saidman SL, Zorn E et al. Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am J Transplant 2014; 14: 1599–1611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Locascio SA, Morokata T, Chittenden M, Preffer FI, Dombkowski DM, Andreola G et al. Mixed chimerism, lymphocyte recovery, and evidence for early donor-specific unresponsiveness in patients receiving combined kidney and bone marrow transplantation to induce tolerance. Transplantation 2010; 90: 1607–1615.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Morris H, De Wolf S, Robins H, Sprangers B, Locascio S, Shonts B et al. Tracking donor-reactive T cells: evidence for clonal deletion in tolerant kidney transplant patients. Sci Transl Med 2015; 7: 272ra10.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work described here was supported by the NCI, NIAID, NHLBI and The Immune Tolerance Network. Research reported in this publication was performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under awards S10RR027050 and S10OD020056. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA

    M Sykes

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This article was published as part of a supplement, supported by WIS-CSP Foundation, in collaboration with Gilead, Milteny Biotec, Gamida Cell, Adienne Pharma and Biotech, Medac Hematology, Kiadis Pharma, Almog Diagnostic.

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Sykes, M. Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. Bone Marrow Transplant 50 (Suppl 2), S82–S86 (2015). https://doi.org/10.1038/bmt.2015.102

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