Graft-Versus-Host Disease

Enhancement of cyclosporin A-induced autologous graft-versus-host disease after peripheral blood stem cell transplantation by utilizing selected CD34+ cells


Although autologous graft-versus-host disease (GVHD) can be induced by administration of cyclosporin A (CsA) after peripheral blood stem cell transplantation (PBSCT), the incidence appears to be remarkably lower compared to the incidence after bone marrow transplantation. The reduced incidence of autologous GVHD after PBSCT may be attributed to peripheral regulatory cells that are transferred with the stem cell inoculum. To determine whether transplantation of CD34-selected peripheral blood stem cells (PBSCs) leads to potentiation of autologous GVHD, five patients with malignant lymphoma were transplanted with CD34-selected PBSCs, followed by administration of CsA and interferon (IFN)-γ. Inducibility of autologous GVHD and autocytotoxic activities of peripheral blood mononuclear cells (PBMCs) after transplantation were assessed. All patients demonstrated prompt hematologic recovery. Cytotoxic activity of PBMCs against autologous lymphocytes was detectable in four of four patients analyzed during a limited period from days 14 to 34 post-transplant. An erythematous rash compatible with GVHD, confirmed by skin biopsy, developed in three of five patients. One of the three patients developed not only skin, but also gut and liver GVHD. Transplantation of the CD34-selected stem cell graft that does not accompany transfusion of regulatory cells may potentiate the inducibility of autologous GVHD by the administration of CsA and IFN-γ.

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  1. 1

    Glazier A, Tutschika PJ, Farmer ER, Santos GW . Graft-versus-host disease in cyclosporine treated rats after syngeneic autologous bone marrow reconstitution. J Exp Med 1983; 158: 1–8.

  2. 2

    Hess AD, Horwitz L, Beschorner WE, Santos GW . Development of graft-vs-host disease-like syndrome in cyclosporine-treated rats after syngeneic bone marrow transplantation. I. Development of cytotoxic T lymphocytes with apparent polyclonal anti-Ia specificity, including autoreactivity. J Exp Med 1985; 161: 718–730.

  3. 3

    Jones RJ, Vogelsang GB, Hess AD et al. Induction of graft-versus-host disease after autologous bone marrow transplantation. Lancet 1989; 333: 754–756.

  4. 4

    Fischer AC, Beschorner WE, Hess AD . Requirements for the induction and adoptive transfer of cyclosporine-induced syngeneic graft-versus-host disease. J Exp Med 1989; 169: 1031–1041.

  5. 5

    Vogelsang GB, Hess AD . Graft-versus-host disease: new directions for a persistent problem. Blood 1994; 84: 2061–2067.

  6. 6

    Miura Y, Thoburn CJ, Bright EC et al. Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin-10 and interferon-gamma may be critical mediators for the development of autologous GVHD. Blood 2002; 100: 2650–2658.

  7. 7

    Geller RB, Esa AH, Beschorner WE et al. Successful in vitro graft-versus-tumor effect against an Ia-bearing tumor using cyclosporine-induced syngeneic graft-versus-host disease in the rat. Blood 1989; 74: 1165–1171.

  8. 8

    Hess AD, Bright EC, Thoburn CJ et al. Specificity of effector T lymphocytes in autologous graft-versus-host disease: role of the major histocompatibility complex class II invariant chain peptide. Blood 1997; 89: 2203–2209.

  9. 9

    Hess AD, Thoburn CJ . Immunobiology and immunotherapeutic implications of syngeneic/autologous graft-versus-host disease. Immunol Rev 1997; 157: 111–123.

  10. 10

    Dolei A, Capobianchi MR, Ameglio F . Human interferon-gamma enhances the expression of class I and class II major histocompatibility complex products in neoplastic cells more effectively than interferon-alpha and interferon-beta. Infect Immunol 1983; 40: 172–176.

  11. 11

    Noga SJ, Horwitz L, Kim H et al. Interferon-gamma potentiates the antitumor effect of cyclosporine-induced autoimmunity. J Hematother 1992; 1: 75–84.

  12. 12

    Yeager AM, Vogelsang GB, Jones RJ et al. Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing autologous bone marrow transplantation for acute myeloid leukemia. Blood 1992; 79: 3031–3035.

  13. 13

    Vogelsang G, Bitton R, Piantadosi S et al. Immune modulation in autologous bone marrow transplantation: cyclosporine and gamma-interferon trial. Bone Marrow Transplant 1999; 24: 637–640.

  14. 14

    Marin GH, Porto A, Prates V et al. Graft versus host disease in autologous stem cell transplantation. J Exp Clin Cancer Res 1999; 18: 201–208.

  15. 15

    Miura Y, Ueda M, Zeng W et al. Induction of autologous graft-versus-host disease with cyclosporine A after peripheral blood stem cell transplantation: analysis of factors affecting induction. J Allergy Clin Immunol 2000; 106: 51–57.

  16. 16

    van der Wall E, Horn T, Bright E et al. Autologous graft-versus-host disease induction in advanced breast cancer: role of peripheral blood progenitor cells. Br J Cancer 2000; 83: 1405–1411.

  17. 17

    Pati AR, Godder KT, Abhyankar SH et al. Cyclosporine-induced autologous graft-versus-host disease following autologous blood stem cell transplantation for lymphoma. Bone Marrow Transplant 1996; 17: 1081–1083.

  18. 18

    Hess AD, Fischer AC, Horwitz L et al. Characterization of peripheral autoregulatory mechanisms that prevent development cyclosporine-induced syngeneic graft-versus-host disease. J Immunol 1994; 153: 400–411.

  19. 19

    Kappler JW, Roehm N, Marrack P . T cell tolerance by clonal elimination in the thymus. Cell 1987; 49: 273–280.

  20. 20

    Aguilar LK, Aguilar-Cordova E, Cartwright Jr J, Belmont JW . Thymic nurse cells are sites of thymocyte apoptosis. J Immunol 1994; 152: 2645–2651.

  21. 21

    Jenkins MK, Schwartz RH, Pardoll DM . Effects of cyclosporine A on T cell development and clonal deletion. Science 1988; 241: 1655–1658.

  22. 22

    Gao EK, Lo D, Cheney R et al. Abnormal differentiation of thymocytes in mice treated with cyclosporin A. Nature 1988; 336: 176–179.

  23. 23

    Hess AD, Fischer AC, Horwitz L et al. Characterization of peripheral autoregulatory mechanisms that prevent development cyclosporine-induced syngeneic graft-versus-host disease. J Immunol 1994; 53: 400–411.

  24. 24

    Berenson RJ, Bensinger WI, Hill RS et al. Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma. Blood 1991; 77: 1717–1722.

  25. 25

    Gorin NC, Lopez M, Laporte JP et al. Preparation and successful engraftment of purified CD34+ bone marrow progenitor cells in patients with non-Hodgkin's lymphoma. Blood 1995; 85: 1647–1654.

  26. 26

    Foucar K, McKenna RW, Frizzera G et al. Incidence and patterns of bone marrow and blood involvement by lymphoma in relationship to the Lukes–Collins classification. Blood 1979; 54: 1417–1422.

  27. 27

    McQuaker IG, Haynes AP, Anderson S et al. Engraftment and molecular monitoring of CD34+ peripheral-blood stem-cell transplants for follicular lymphoma: a pilot study. J Clin Oncol 1997; 15: 2288–2295.

  28. 28

    Takahashi T, Kanda Y, Mori M et al. B cell lymphoma-associated hemophagocytic syndrome after PBSCT. Bone Marrow Transplant 1998; 21: 623–625.

  29. 29

    Fischer AC, Hess AD . Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes. J Exp Med 1990; 172: 85–94.

  30. 30

    Fischer AC, Laulis MK, Horwitz L et al. Host resistance to cyclosporine induced syngeneic graft-versus-host disease. Requirement for two distinct lymphocyte subsets. J Immunol 1989; 143: 827–832.

  31. 31

    Wu DY, Goldschneider I . Cyclosporin A-induced autologous graft-versus-host disease: a prototypical model of autoimmunity and active (dominant) tolerance coordinately induced by recent thymic emigrants. J Immunol 1999; 162: 6926–6933.

  32. 32

    Mielcarek M, Graf L, Johnson G, Torok-Storb B . Production of interleukin-10 by granulocyte colony-stimulating factor-mobilized blood products: a mechanism for monocyte-mediated suppression of T-cell proliferation. Blood 1998; 92: 215–222.

  33. 33

    Kusnierz-Glaz CR, Still BJ, Amano M et al. Granulocyte colony-stimulating factor induced comobilization of CD4CD8 T cells and hematopoietic progenitor cells (CD34+) in the blood of normal donors. Blood 1997; 89: 2586–2595.

  34. 34

    Sica S, Chiusolo P, Salutari P et al. Autologous graft-versus-host disease after CD34+-purified autologous peripheral blood progenitor cell transplantation. J Hematother Stem Cell Res 2000; 9: 375–379.

  35. 35

    Bastion Y, Brice P, Haioun C et al. Intensive therapy with peripheral-blood progenitor-cell transplantation in 60 patients with poor prognosis follicular lymphoma. Blood 1995; 86: 3257–3262.

  36. 36

    Schultze JL, Seamon MJ, Michalak S et al. Autologous tumor infiltrating T cells cytotoxic for follicular lymphoma cells can be expanded in vitro. Blood 1997; 89: 3806–3816.

  37. 37

    Dorfman DM, Schultze JL, Shahsafaei A et al. In vivo expression of B7-1 and B7-2 by follicular lymphoma cells can prevent induction of T-cell anergy but is insufficient to induce significant T-cell proliferation. Blood 1997; 90: 4297–4306.

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We thank Dr Christopher J Thoburn (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center) for providing helpful discussion and critically reading the manuscript.

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Correspondence to Y Miura.

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Miura, Y., Ueda, M., Takami, A. et al. Enhancement of cyclosporin A-induced autologous graft-versus-host disease after peripheral blood stem cell transplantation by utilizing selected CD34+ cells. Bone Marrow Transplant 32, 785–790 (2003) doi:10.1038/sj.bmt.1704208

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  • autologous graft-versus-host disease
  • cyclosporin A
  • CD34-selected peripheral blood stem cell transplantation

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