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Combined kidney and hematopoeitic cell transplantation to induce mixed chimerism and tolerance

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Abstract

Based on preclinical studies, combined kidney and hematopoietic cell transplantation was performed on fully HLA matched and haplotype matched patients at the Stanford University Medical Center. The object of the studies was to induce mixed chimerism, immune tolerance, and complete immunosuppressive drug withdrawal. Tolerance, persistent mixed chimerism, and complete withdrawal was achieved in the majority of fully matched patients. Persistent mixed chimerism and partial withdrawal has been achieved in the haplotype matched patients at present.

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References

  1. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. US Renal Data System 2013 Annual Data Report. Am J Kidney Dis. 2014;63(Suppl 1):A7.

  2. Suthanthiran M, Strom TB. Renal transplantation. New Engl J Med. 1994;331:365–76.

    Article  CAS  Google Scholar 

  3. Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009;69:2227–43.

    Article  CAS  Google Scholar 

  4. Srinivas TR, Schold JD, Guerra G, Eagan A, Bucci CM, Meier-Kriesche HU. Mycophenolate mofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation. Am J Transplant. 2007;7:586–94.

    Article  CAS  Google Scholar 

  5. Cecka JM. The UNOS Scientific Renal Transplant Registry–ten years of kidney transplants. Clin Transplant, 1997;1–14.

  6. Yang H. Maintenance immunosuppression regimens: conversion, minimization, withdrawal, and avoidance. Am J Kidney Dis. 2006;47:S37–51.

    Article  CAS  Google Scholar 

  7. Slavin S, Strober S, Fuks Z, Kaplan HS. Long-term survival of skin allografts in mice treated with fractionated total lymphoid irradiation. Science. 1976;193:1252–4.

    Article  CAS  Google Scholar 

  8. Strober S, Slavin S, Gottlieb M, Zan-Bar I, King DP, Hoppe RT, et al. Allograft tolerance after total lymphoid irradiation (TLI). Immunol Rev. 1979;46:87–112.

    Article  CAS  Google Scholar 

  9. Liu YP, Li Z, Nador RG, Strober S. Simultaneous protection against allograft rejection and graft-versus-host disease after total lymphoid irradiation: role of natural killer T cells. Transplantation. 2008;85:607–14.

    Article  Google Scholar 

  10. Slavin S, Reitz B, Bieber CP, Kaplan HS, Strober S. Transplantation tolerance in adult rats using total lymphoid irradiation: permanent survival of skin, heart, and marrow allografts. J Exp Med. 1978;147:700–7.

    Article  CAS  Google Scholar 

  11. Slavin S, Strober S. Induction of allograft tolerance after total lymphoid irradiation (TLI): development of suppressor cells of the mixed leukocyte reaction (MLR). J Immunol. 1979;123:942–6.

    CAS  PubMed  Google Scholar 

  12. Coleman C, Burke J, Varghese A, Rosenberg S, Kaplan H. Malignant lymphomas: etiology, immunology, pathology, treatment (ed H’S Kids Rosenberg 5). Academic Press; New York City, 1982. p. 259–76.

  13. Kaplan H. Hodgkin’s disease. Harvard University Press; Cambridge, MA, 1980.

  14. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172:603–6.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. Sykes M. Mixed chimerism and transplant tolerance. Immunity. 2001;14:417–24.

    Article  CAS  Google Scholar 

  19. Kawai T, Cosimi AB, Colvin RB, Powelson J, Eason J, Kozlowski T, et al. Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation. 1995;59:256–62.

    Article  CAS  Google Scholar 

  20. Hayamizu K, Lan F, Huie P, Sibley RK, Strober S. Comparison of chimeric acid and non-chimeric tolerance using posttransplant total lymphoid irradiation: cytokine expression and chronic rejection. Transplantation. 1999;68:1036–44.

    Article  CAS  Google Scholar 

  21. Woodley SL, Gurley KE, Hoffmann SL, Nicolls MR, Hagberg R, Clayberger C, et al. Induction of tolerance to heart allografts in rats using posttransplant total lymphoid irradiation and anti-T cell antibodies. Transplantation. 1993;56:1443–7.

    Article  CAS  Google Scholar 

  22. Zeng D, Ready A, Huie P, Hayamizu K, Holm B, Yin D, et al. Mechanisms of tolerance to rat heart allografts using posttransplant TLI. Changes in cytokine expression. Transplantation. 1996;62:510–7.

    Article  CAS  Google Scholar 

  23. Higuchi M, Zeng D, Shizuru J, Gworek J, Dejbakhsh-Jones S, Taniguchi M, et al. Immune tolerance to combined organ and bone marrow transplants after fractionated lymphoid irradiation involves regulatory NK T cells and clonal deletion. J Immunol. 2002;169:5564–70. 

    Article  CAS  Google Scholar 

  24. Lan F, Hayamizu K, Strober S. Cyclosporine facilitates chimeric and inhibits nonchimeric tolerance after posttransplant total lymphoid irradiation. Transplantation. 2000;69:649–55.

    Article  CAS  Google Scholar 

  25. Nador RG, Hongo D, Baker J, Yao Z, Strober S. The changed balance of regulatory and naive T cells promotes tolerance after TLI and anti-T-cell antibody conditioning. Am J Transplant. 2010;10:262–72.

    Article  CAS  Google Scholar 

  26. Hongo D, Tang X, Baker J, Engleman EG, Strober S. Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. Am J Transplant. 2014;14:2467–77.

    Article  CAS  Google Scholar 

  27. Hongo D, Tang X, Dutt S, Nador RG, Strober S. Interactions between NKT cells and Tregs are required for tolerance to combined bone marrow and organ transplants. Blood. 2012;119:1581–9.

    Article  CAS  Google Scholar 

  28. Lan F, Zeng D, Higuchi M, Higgins JP, Strober S. Host conditioning with total lymphoid irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-reactive natural killer T cells. Biol Blood Marrow Transplant. 2003;9:355–63.

    Article  Google Scholar 

  29. Lan F, Zeng D, Higuchi M, Huie P, Higgins JP, Strober S. Predominance of NK1.1 + TCR alpha beta + or DX5 + TCR alpha beta + T cells in mice conditioned with fractionated lymphoid irradiation protects against graft-versus-host disease: “natural suppressor” cells. J Immunol. 2001;167:2087–96.

    Article  CAS  Google Scholar 

  30. Pillai AB, George TI, Dutt S, Strober S. Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4 + CD25 + Foxp3 + T regulatory cells that protects against graft-versus-host disease. Blood. 2009;113:4458–67. https://doi.org/10.1182/blood-2008-06-165506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Scandling JD, Busque S, Shizuru JA, 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;15:695–704.

    Article  CAS  Google Scholar 

  32. Kawai T, Leventhal J, Wood K, Strober S. Summary of the third international workshop on clinical tolerance. Am J Transplant. 2018. https://doi.org/10.1111/ajt.15086.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Scandling JD, Busque S, Lowsky R, Shizuru J, Shori A, Engleman E, et al. Macrochimerism and clinical transplant tolerance. Hum Immunol. 2018;79:266–71.

    Article  CAS  Google Scholar 

  34. Cao TM, Shizuru JA, Wong RM, Sheehan K, Laport GG, Stockerl-Goldstein KE, et al. Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8 + T-cell dose. Blood. 2005;105:2300–6.

    Article  CAS  Google Scholar 

  35. Urbano-Ispizua A, Rozman C, Pimentel P, Solano C, de la Rubia J, Brunet S, et al. The number of donor CD3(+) cells is the most important factor for graft failure after allogeneic transplantation of CD34(+) selected cells from peripheral blood from HLA-identical siblings. Blood. 2001;97:383–7.

    Article  CAS  Google Scholar 

  36. Tiong HY, Goldfarb DA, Kattan MW, Alster JM, Thuita L, Yu C, et al. Nomograms for predicting graft function and survival in living donor kidney transplantation based on the UNOS Registry. J Urol. 2009;181:1248–55.

    Article  CAS  Google Scholar 

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Funding

The research was supported by grants from their National Institutes of Health (P01HL075462 and R01 AI 1085024), and a grant from the California Institute of Regenerative Medicine (CLIN2–09439). Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.

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  1. Divisions of Blood and Marrow Transplantation and Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Robert Lowsky & Samuel Strober

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  1. Robert Lowsky
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  2. Samuel Strober
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Correspondence to Samuel Strober.

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SS and RL receive consulting fees and owns equity in Medeor Therapeutics Inc., and receive royalties payments on patents held by their employer.

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Lowsky, R., Strober, S. Combined kidney and hematopoeitic cell transplantation to induce mixed chimerism and tolerance. Bone Marrow Transplant 54 (Suppl 2), 793–797 (2019). https://doi.org/10.1038/s41409-019-0603-4

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