Advertisement

Chimerism pp 135-152 | Cite as

Chimerism: A Clinical Guide to Tolerance Induction

  • Andrea R. Merchak
  • Anita Y. Chhabra
  • Joseph R. Leventhal
  • Suzanne T. Ildstad
Chapter

Abstract

Kidney transplantation is now the preferred approach to treat end-stage renal failure. However, graft survival is dependent upon the lifelong use of immunosuppressive drugs, which unfortunately are associated with harmful side effects ranging from kidney damage to shortened life-span. The desire to achieve better long-term outcomes for solid organ transplants has led to the emergence of chimerism-based tolerance. Hematopoietic stem cells from the organ donor are used to modulate the recipient’s immune system to provide long-term, drug-free tolerance to the transplanted organ. Three centers in the United States have conducted chimerism-based clinical trials in kidney transplant recipients and have proven safety, feasibility, and efficacy of the approach. In this chapter, we discuss the mechanisms underlying the establishment of chimerism-based tolerance and review in detail protocols used in clinical trials. This approach to kidney transplant tolerance will likely have significant impact on other solid organ and cellular transplants.

Keywords

Kidney transplant Hematopoietic stem cells Chimerism Immunosuppression Tolerance Clinical trials 

References

  1. 1.
    Russell JD, Beecroft ML, Ludwin D, Churchill DN. The quality of life in renal transplantation—a prospective study. Transplantation. 1992;54(4):656–60.CrossRefPubMedGoogle Scholar
  2. 2.
    Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4(8):1289–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Lodhi SA, Meier-Kriesche HU. Kidney allograft survival: the long and short of it. Nephrol Dial Transplant. 2011;26(1):15–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Orlando G, Hematti P, Stratta RJ, Burke GW III, Di CP, Pisani F, et al. Clinical operational tolerance after renal transplantation: current status and future challenges. Ann Surg. 2010;252(6):915–28.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chandrasekharan D, Issa F, Wood KJ. Achieving operational tolerance in transplantation: how can lessons from the clinic inform research directions? Transpl Int. 2013;26(6):576–89.CrossRefPubMedGoogle Scholar
  6. 6.
    Gao Z, McAlister VC, Williams GM. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet. 2001;357(9260):932–3.CrossRefPubMedGoogle Scholar
  7. 7.
    Shapiro R, Basu A, Tan H, Gray E, Kahn A, Randhawa P, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath. J Am Coll Surg. 2005;200(4):505–15.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Feng S, Ekong UD, Lobritto SJ, Demetris AJ, Roberts JP, Rosenthal P, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012;307(3):283–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Orlando G, Soker S, Wood K. Operational tolerance after liver transplantation. J Hepatol. 2009;50(6):1247–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Shapiro R, Scantlebury VP, Jordan ML, Corry RJ, Potdar S, Jain AB, et al. Combined bone marrow and solid organ transplantation with alemtuzumab induction. Transplant Rev. 2003;17(4):S18–S9.CrossRefGoogle Scholar
  11. 11.
    Billingham RE, Brent L, Medawar PB. ‘Actively acquired tolerance’ of foreign cells. Nature. 1953;172(4379):603–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Owen RD, Davis HP, Morgan RF. Quintuplet calves and erythrocyte mosaicism. J Hered. 1946;37(10):290–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008;358(4):362–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Markmann JF, Kawai T. The quest for transplantation tolerance: have we finally sipped from the cup? Sci Transl Med. 2012;4(124):124fs5.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Von Boehmer H, Aifantis I, Gounari F, Azogui O, Haughn L, Apostolou I, et al. Thymic selection revisited: how essential is it? Immunol Rev. 2003;191:62–78.CrossRefGoogle Scholar
  16. 16.
    Griesemer AD, Sorenson EC, Hardy MA. The role of the thymus in tolerance. Transplantation. 2010;90(5):465–74.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Egerton M, Scollay R, Shortman K. Kinetics of mature T-cell development in the thymus. Proc Natl Acad Sci U S A. 1990;87(7):2579–82.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol. 2010;11(1):21–7.CrossRefPubMedGoogle Scholar
  19. 19.
    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;153:1087–98.PubMedGoogle Scholar
  20. 20.
    Colson YL, Li H, Boggs SS, Patrene KD, Johnson PC, Ildstad ST. Durable mixed allogeneic chimerism and tolerance by a nonlethal radiation-based cytoreductive approach. J Immunol. 1996;157(7):2820–9.PubMedGoogle Scholar
  21. 21.
    Colson YL, Wren SM, Schuchert MJ, Patrene KD, Johnson PC, Boggs SS, et al. A nonlethal conditioning approach to achieve durable multilineage mixed chimerism and tolerance across major, minor, and hematopoietic histocompatibility barriers. J Immunol. 1995;155(9):4179–88.PubMedGoogle Scholar
  22. 22.
    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(6):1236–47.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Braza F, Dugast E, Panov I, Paul C, Vogt K, Pallier A, et al. Central role of CD45RA- Foxp3hi memory regulatory T cells in clinical kidney transplantation tolerance. J Am Soc Nephrol. 2015;26(8):1795–805.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sprangers B, DeWolf S, Savage TM, Morokata T, Obradovic A, LoCascio SA, et al. Origin of enriched regulatory T cells in patients receiving combined kidney-bone marrow transplantation to induce transplantation tolerance. Am J Transplant. 2017;17(8):2020–32.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yamada Y, Nadazdin O, Boskovic S, Lee S, Zorn E, Smith RN, et al. Repeated injections of IL-2 break renal allograft tolerance induced via mixed hematopoietic chimerism in monkeys. Am J Transplant. 2015;15(12):3055–66.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Perez VL, Van Parijs L, Biuckians A, Zheng XX, Strom TB, Abbas AK. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity. 1997;6(4):411–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–95.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(12):1312–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Zuber J, Sykes M. Mechanisms of mixed chimerism-based transplant tolerance. Trends Immunol. 2017;38(11):829–43.CrossRefPubMedGoogle Scholar
  30. 30.
    Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342(9):605–12.CrossRefPubMedGoogle Scholar
  31. 31.
    Spitzer TR, Delmonico F, Tolkoff-Rubin N, McAfee S, Sackstein R, Saidman S, et al. Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation. 1999;68(4):480–4.CrossRefPubMedGoogle Scholar
  32. 32.
    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(6):672–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kawai T, Chen Y-B, Sykes M, Benedict C, Tolkoff-Rubin N, Day B, et al. HLA identical or haploidentical combined kidney and bone marrow transplantation for multiple myeloma with end-stage renal failure. Am J Transplant. 2016;16(Suppl 3):270.Google Scholar
  34. 34.
    Chen YB, Kawai T, Spitzer TR. Combined bone marrow and kidney transplantation for the induction of specific tolerance. Adv Hematol. 2016;2016:6471901.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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(9):2121–33.CrossRefPubMedGoogle Scholar
  36. 36.
    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(4):353–61.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kawai T, Sachs DH, Sykes M, Cosimi AB. HLA-mismatched renal transplantation without maintenance immunosuppression. Letter to the editor. N Engl J Med. 2013;368(19):1850–2.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kawai T, Sachs D, Sprangers B, Spitzer T, Saidman S, 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(7):1599–611.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Strober S. Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants. Blood. 2016;127(12):1539–43.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sogawa H, Boskovic S, Nadazdin O, Abrahamian G, Colvin RB, Sachs DH, et al. Limited efficacy and unacceptable toxicity of cyclophosphamide for the induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation. 2008;86(4):615–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Scandling J, Busque S, Shizuru J, Lowsky R, Hoppe R, Dejbakhsh-Jones S, et al. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015;15(3):695–704.CrossRefPubMedGoogle Scholar
  43. 43.
    Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Sarwal M, Millan MT, et al. Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant. 2012;12(5):1133–45.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011;365(14):1359–60.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Busque S, Scandling J, Shizuru J, Lowsky R, Shori A, Kent J, et al. Relationship between mixed chimerism and tolerance in HJLA-matched and-mismatched recipients of kidney and hematopoietic cell transplants. Am J Transplant. 2017;17:276.Google Scholar
  46. 46.
    Leventhal JR, Mathew JM, Salomon DR, Kurian SM, Suthanthiran M, Tambur A, et al. Genomic biomarkers correlate with HLA-identical renal transplant tolerance. J Am Soc Nephrol. 2013;24(9):1376–85.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Chhabra AY, Leventhal J, Merchak AR, Ildstad S. HSCT-based approaches for tolerance induction in renal transplant. Transplantation. 2017;101(11):2682–90.CrossRefPubMedGoogle Scholar
  48. 48.
    Leventhal JR, Mathew J, Ildstad S, Salomon D, Kurian S, Suthanthiran M, et al. HLA identical non-chimeric and HLA disparate chimeric renal transplant tolerance. Clin Transpl. 2013:145–56.Google Scholar
  49. 49.
    Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Brodsky RA, Luznik L, Bolanos-Meade J, Leffell MS, Jones RJ, Fuchs EJ. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008;42(8):523–7.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Leventhal J, Galvin J, Stare D, Gallon L, Miller J, Mathew J, Abecassis M, Ildstad S. Seven year follow-up of a phase 2 clinical trial to induce tolerance in living donor renal transplant recipients. Am J Transplant. 2016;16:269.CrossRefGoogle Scholar
  52. 52.
    Leventhal JR, Abecassis M, Miller J, Gallon L, Herzig R, Tollerud DJ, et al. A phase 2 clinical trial of donor-specific tolerance induction in recipients of HLA disparate living donor kidney allografts by donor stem cell infusion. Am J Transplant. 2012;12(Suppl s3):27.Google Scholar
  53. 53.
    Leventhal JR, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud D, et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med. 2012;4(124):124ra28.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Leventhal J, Galvin J, Stare D, Gallon L, Miller J, Mathew J, Abecassis M, Ildstad S. Eight year follow-up of a phase 2 clinical trial to induce tolerance in living donor renal transplant recipients. Am J Transplant. 2017;17(Suppl 3):276.Google Scholar
  55. 55.
    Leventhal JR, Miller J, Abecassis M, Tollerud DJ, Ildstad ST. Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance. J Clin Pharm Ther. 2013;93(1):36–45.CrossRefGoogle Scholar
  56. 56.
    Orlando G, Wood KJ, Soker S, Stratta RJ. How regenerative medicine may contribute to the achievement of an immunosuppression-free state. Transplantation. 2011;92(8):e36–8; author reply e9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Andrea R. Merchak
    • 1
  • Anita Y. Chhabra
    • 1
  • Joseph R. Leventhal
    • 2
  • Suzanne T. Ildstad
    • 1
    • 3
  1. 1.Institute for Cellular Therapeutics, University of LouisvilleLouisvilleUSA
  2. 2.Northwestern Medical GroupNorthwestern UniversityChicagoUSA
  3. 3.Regenerex, LLCLouisvilleUSA

Personalised recommendations