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Megan Sykes, M.D.

Mixed Chimerism to Achieve Transplant Tolerance

Bone marrow transplantation (BMT) from diabetes-resistant strains has already been shown to prevent insulitis and diabetes in experimental mouse models of type I diabetes. However, the routine use of BMT for the treatment of autoimmune diabetes has been prohibited so far, largely because of the unacceptable toxicity associated with the conditioning needed to achieve engraftment, and because of the complications associated with allo-BMT. We have recently described a method of inducing tolerance that uses allo-BMT and costimulatory blockade to induce high levels of allogeneic stem cell engraftment and permanent deletional tolerance, without requiring host T cell depletion or myeloablative conditioning. We have shown that mixed chimerism, induced by a non-myeloablative, non-T cell depleting conditioning regimen is beneficial in pre-diabetic and diabetic NOD mice by 1) reversing the autoimmune T cell response and thus preventing the development and recurrence of disease; and 2) inducing tolerance toward transplanted allogeneic donor islets. We are evaluating the mechanisms by which mixed bone marrow chimerism induced with non-toxic protocols reverses autoimmunity in the nonobese diabetic (NOD) mouse model, which closely resembles human diabetes.

Islet xenotransplantation could overcome the islet shortage. Xenotransplantation of islets would only be acceptable without chronic immunosuppression. We have shown that thymic transplantation from pigs induces immune tolerance to the xenogeneic donor in mice and also works for human T cells in a humanized mouse model. This suggests an approach to islet xenotransplantation that avoids the need for chronic immunosuppression. We are now evaluating the ability of porcine thymic and islet transplantation together to reverse diabetes in autoimmune NOD mice.

We have developed a humanized mouse model that allows the development of a functional human immune system. We are using this humanized mouse model to explore hematopoietic stem cell-intrinsic abnormalities in T cell development in Type 1 diabetic patients.

References:

Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G, Shaffer J, Sayegh MH, Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nature Med. 6:464-469, 2000.
Leykin I, Nikolic B, Sykes M. Mixed bone marrow chimerism as a treatment for autiommune diabetes. Transplant. Proc. 33: 120, 2001.
Ito H, Kurtz J, Shaffer J, Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependant on CD40-CD40 ligand interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway. J. Immunol. 166: 2970-2981, 2001.
Wekerle T, Kurtz J, Sayegh MH, Ito H, Wells A, Bensigner S, Shaffer J, Turka LA, Sykes M. Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activated-induced cell death and passive cell death. J. Immunol. 166: 2311-2316, 2001.
Mapara MY, Kim Y-M, Wang S-P, Bronson R, Sachs DH, Sykes M. Donor lymphocyte infusions (DLI) mediate superior graft-versus-leukemia (GvL) effects in mixed compared to fully allogeneic chimeras: A critical role for host antigen-presenting cells. Blood 100:1903-1909, 2002.
Kim Y-M, Sachs T, Asavaroengchai W, Bronson R, Sykes M. Graft-versus-host disease (GvHD) can be separated from graft-versus-lymphoma effects by controlling lymphocyte trafficking with FTY720. J. Clin. Invest. 111:659-669, 2003.
Kurtz J, Lie A, Griffith M, Eysaman S, Shaffer J, Anosova N, Turka L, Benichou G, Sykes M. Lack of role for CsA-sensitive or Fas pathways in the tolerization of CD4 T cells via BMT and anti-CD40L. Am J Transplant.2003; 3:804-816.
Zhao Y, Ohdan H, Manilay JO, Sykes M. NK cell tolerance in mixed allogeneic chimeras. J. Immunol. 2003; 170:5398-5405.
Takeuchi Y, Ito H, Kurtz J, Wekerle T, Ho L, Sykes M. Earlier low dose TBI or DST overcomes CD8+ T cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L. Am J Transplantation, 2004; 4:31-40.
Nikolic B, Takeuchi Y, Leykin I, Smith RN, Sykes M. Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes, 2004; 53 (2) 376-383.
Kurtz J, Shaffer J, Lie A, Anosova N, Benichou G, Sykes M. Mechanisms of early peripheral CD4 cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: Evidence for anergy and deletion, but not regulatory cells. Blood, In press.
Zhao Y, Swenson K, Sergio JJ, Arn JS, Sachs DH and Sykes M. Skin graft tolerance across a discordant xenogeneic barrier. Nature Med 2: 1211-1216, 1996.
Nikolic B, Gardner JP, Scadden DT, Arn JS, Sachs DH and Sykes M. Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC. J Immunol 162: 3402-3407, 1999.
Tonomura N, Habiro K, Shimizu A, Sykes M and Yang YG. Antigen-specific human T-cell responses and T cell-dependent production of human antibodies in a humanized mouse model. Blood 111: 4293- 4296, 2008.






			Megan Sykes, M.D. Mixed Chimerism to Achieve Transplant Tolerance Bone marrow transplantation (BMT) from diabetes-resistant strains has already been shown to prevent insulitis and diabetes in experimental mouse models of type I diabetes. However, the routine use of BMT for the treatment of autoimmune diabetes has been prohibited so far, largely because of the unacceptable toxicity associated with the conditioning needed to achieve engraftment, and because of the complications associated with allo-BMT. We have recently described a method of inducing tolerance that uses allo-BMT and costimulatory blockade to induce high levels of allogeneic stem cell engraftment and permanent deletional tolerance, without requiring host T cell depletion or myeloablative conditioning. We have shown that mixed chimerism, induced by a non-myeloablative, non-T cell depleting conditioning regimen is beneficial in pre-diabetic and diabetic NOD mice by 1) reversing the autoimmune T cell response and thus preventing the development and recurrence of disease; and 2) inducing tolerance toward transplanted allogeneic donor islets. We are evaluating the mechanisms by which mixed bone marrow chimerism induced with non-toxic protocols reverses autoimmunity in the nonobese diabetic (NOD) mouse model, which closely resembles human diabetes. Islet xenotransplantation could overcome the islet shortage. Xenotransplantation of islets would only be acceptable without chronic immunosuppression. We have shown that thymic transplantation from pigs induces immune tolerance to the xenogeneic donor in mice and also works for human T cells in a humanized mouse model. This suggests an approach to islet xenotransplantation that avoids the need for chronic immunosuppression. We are now evaluating the ability of porcine thymic and islet transplantation together to reverse diabetes in autoimmune NOD mice. We have developed a humanized mouse model that allows the development of a functional human immune system. We are using this humanized mouse model to explore hematopoietic stem cell-intrinsic abnormalities in T cell development in Type 1 diabetic patients. References: Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G, Shaffer J, Sayegh MH, Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nature Med. 6:464-469, 2000. Leykin I, Nikolic B, Sykes M. Mixed bone marrow chimerism as a treatment for autiommune diabetes. Transplant. Proc. 33: 120, 2001. Ito H, Kurtz J, Shaffer J, Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependant on CD40-CD40 ligand interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway. J. Immunol. 166: 2970-2981, 2001. Wekerle T, Kurtz J, Sayegh MH, Ito H, Wells A, Bensigner S, Shaffer J, Turka LA, Sykes M. Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activated-induced cell death and passive cell death. J. Immunol. 166: 2311-2316, 2001. Mapara MY, Kim Y-M, Wang S-P, Bronson R, Sachs DH, Sykes M. Donor lymphocyte infusions (DLI) mediate superior graft-versus-leukemia (GvL) effects in mixed compared to fully allogeneic chimeras: A critical role for host antigen-presenting cells. Blood 100:1903-1909, 2002. Kim Y-M, Sachs T, Asavaroengchai W, Bronson R, Sykes M. Graft-versus-host disease (GvHD) can be separated from graft-versus-lymphoma effects by controlling lymphocyte trafficking with FTY720. J. Clin. Invest. 111:659-669, 2003. Kurtz J, Lie A, Griffith M, Eysaman S, Shaffer J, Anosova N, Turka L, Benichou G, Sykes M. Lack of role for CsA-sensitive or Fas pathways in the tolerization of CD4 T cells via BMT and anti-CD40L. Am J Transplant.2003; 3:804-816. Zhao Y, Ohdan H, Manilay JO, Sykes M. NK cell tolerance in mixed allogeneic chimeras. J. Immunol. 2003; 170:5398-5405. Takeuchi Y, Ito H, Kurtz J, Wekerle T, Ho L, Sykes M. Earlier low dose TBI or DST overcomes CD8+ T cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L. Am J Transplantation, 2004; 4:31-40. Nikolic B, Takeuchi Y, Leykin I, Smith RN, Sykes M. Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes, 2004; 53 (2) 376-383. Kurtz J, Shaffer J, Lie A, Anosova N, Benichou G, Sykes M. Mechanisms of early peripheral CD4 cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: Evidence for anergy and deletion, but not regulatory cells. Blood, In press. Zhao Y, Swenson K, Sergio JJ, Arn JS, Sachs DH and Sykes M. Skin graft tolerance across a discordant xenogeneic barrier. Nature Med 2: 1211-1216, 1996. Nikolic B, Gardner JP, Scadden DT, Arn JS, Sachs DH and Sykes M. Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC. J Immunol 162: 3402-3407, 1999. Tonomura N, Habiro K, Shimizu A, Sykes M and Yang YG. Antigen-specific human T-cell responses and T cell-dependent production of human antibodies in a humanized mouse model. Blood 111: 4293- 4296, 2008.