Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse.

Costimulation blockade is a promising strategy for preventing allograft rejection and inducing tolerance. Using a fully allogeneic mouse model, we tested the effectiveness of the combined blockade of the CD40 ligand and the inducible costimulator (ICOS) on islet allograft survival and in the prevention of autoimmune diabetes in the NOD mouse. Recipients treated with blocking monoclonal antibodies (mAbs) to ICOS and the CD40 ligand had significant prolongation of graft survival, with 26 of 28 functioning for >200 days. Long-term engrafted mice maintained antidonor proliferative and cytotoxic responses, but donor-specific immunization did not induce graft rejection, and challenge with second, same donor but not third-party grafts resulted in long-term acceptance. The immunohistology of tolerant grafts demonstrated the presence of CD4(+)CD25(+) T-cells expressing Foxp3, and islet/kidney composite grafts from tolerant mice, but not from mice lacking lymphocytes, were accepted indefinitely when transplanted into naïve B6 mice, suggesting that recipient T-cells were necessary to generate dominant tolerance. Combined anti-ICOS and anti-CD40 ligand mAb therapy also prevented diabetes in NOD mice, with only 11% of treated recipients developing diabetes compared with 75% of controls. These data demonstrate that the blockade of CD40 ligand and ICOS signaling induces islet allograft tolerance involving a dominant mechanism associated with intragraft regulatory cells and prevents autoimmune diabetes in NOD mice.

[1]  D. Zélénika,et al.  Induction of foxP3+ Regulatory T Cells in the Periphery of T Cell Receptor Transgenic Mice Tolerized to Transplants1 , 2004, The Journal of Immunology.

[2]  A. M. Shapiro,et al.  Multiple Combination Therapies Involving Blockade of ICOS/B7RP‐1 Costimulation Facilitate Long‐Term Islet Allograft Survival , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  A. Shapiro,et al.  Combination therapy with anti-ICOS and cyclosporine enhances cardiac but not islet allograft survival. , 2003, Transplantation proceedings.

[4]  E. Simpson,et al.  Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade , 2003, Nature Medicine.

[5]  Wenda Gao,et al.  Stimulating PD-1–negative signals concurrent with blocking CD154 co-stimulation induces long-term islet allograft survival1 , 2003, Transplantation.

[6]  G. Freeman,et al.  The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. , 2003, The Journal of clinical investigation.

[7]  M. Sayegh,et al.  Interaction Between ICOS‐B7RP1 and B7‐CD28 Costimulatory Pathways in Alloimmune Responses In Vivo , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[9]  中村 嘉一郎 Acceptance of islet allografts in the liver of mice by blockade of an inducible costimulator , 2003 .

[10]  R. Gill,et al.  CD4-Dependent Generation of Dominant Transplantation Tolerance Induced by Simultaneous Perturbation of CD154 and LFA-1 Pathways1 , 2002, The Journal of Immunology.

[11]  H. Waldmann,et al.  Identification of Regulatory T Cells in Tolerated Allografts , 2002, The Journal of experimental medicine.

[12]  M. Makuuchi,et al.  Prolonged survival in rat liver transplantation with mouse monoclonal antibody against an inducible costimulator (ICOS)1 , 2002, Transplantation.

[13]  Mary Collins,et al.  The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. , 2002, Annual review of immunology.

[14]  J. Gutiérrez-Ramos,et al.  Importance of ICOS–B7RP-1 costimulation in acute and chronic allograft rejection , 2001, Nature Immunology.

[15]  J. Gutiérrez-Ramos,et al.  The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE , 2001, Nature Immunology.

[16]  J. Bluestone,et al.  ICOS costimulation: it's not just for TH2 cells anymore , 2001, Nature Immunology.

[17]  H. Waldmann,et al.  Regulating the immune response to transplants. a role for CD4+ regulatory cells? , 2001, Immunity.

[18]  C. Orosz,et al.  Immunobiology of Allograft Rejection in the Absence of IFN-γ: CD8+ Effector Cells Develop Independently of CD4+ Cells and CD40-CD40 Ligand Interactions1 , 2001, The Journal of Immunology.

[19]  R. Colvin,et al.  Costimulatory blockade for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. , 2001, Transplantation proceedings.

[20]  J. Allison,et al.  ICOS co-stimulatory receptor is essential for T-cell activation and function , 2001, Nature.

[21]  C. Ariyan,et al.  Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models1 , 2001, The Journal of Immunology.

[22]  G. Freeman,et al.  Mouse Inducible Costimulatory Molecule (ICOS) Expression Is Enhanced by CD28 Costimulation and Regulates Differentiation of CD4+ T Cells1 , 2000, The Journal of Immunology.

[23]  H. Waldmann,et al.  Cutting Edge: Anti-CD154 Therapeutic Antibodies Induce Infectious Transplantation Tolerance1 , 2000, The Journal of Immunology.

[24]  O. Witzke,et al.  CD40-CD40 Ligand-Independent Activation of CD8+ T Cells Can Trigger Allograft Rejection1 , 2000, The Journal of Immunology.

[25]  C. Anderson,et al.  Danger: the view from the bottom of the cliff. , 2000, Seminars in immunology.

[26]  M. Sykes,et al.  Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment , 2000, Nature Medicine.

[27]  C. Larsen,et al.  Asialo GM1(+) CD8(+) T cells play a critical role in costimulation blockade-resistant allograft rejection. , 1999, The Journal of clinical investigation.

[28]  H. Waldmann,et al.  CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression. , 1999, Journal of immunology.

[29]  T. Strom,et al.  Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance , 1999, Nature Medicine.

[30]  D. Harlan,et al.  Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154. , 1999, Diabetes.

[31]  D. Harlan,et al.  Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates , 1999, Nature Medicine.

[32]  T. Strom,et al.  Induce Allograft Tolerance with Combined CTLA 4 Signals Are Required to Optimally , 1999 .

[33]  R. Noelle,et al.  Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4(+) T cells, interferon-gamma, and CTLA4. , 1998, The Journal of clinical investigation.

[34]  R. Flavell,et al.  CD40 and CD154 in cell-mediated immunity. , 1998, Annual review of immunology.

[35]  R. Tisch,et al.  CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice. , 1997, Journal of immunology.

[36]  J Bajorath,et al.  Immune regulation by CD40 and its ligand GP39. , 1996, Annual review of immunology.

[37]  R. Noelle,et al.  Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Sprent,et al.  Split tolerance in spleen chimeras. , 1995, Journal of immunology.

[39]  C. Schlachta,et al.  Improved techniques for kidney transplantation in mice , 1995, Microsurgery.

[40]  R. Gill,et al.  Tolerance induction to cultured islet allografts. I. Characterization of the tolerant state. , 1994, Transplantation.

[41]  R. Gill,et al.  Tolerance induction to cultured islet allografts. II. The status of antidonor reactivity in tolerant animals. , 1994, Transplantation.

[42]  J. Markmann,et al.  Islet allograft, islet xenograft, and skin allograft survival in CD8+ T lymphocyte-deficient mice. , 1993, Transplantation.

[43]  P. Matzinger The JAM test. A simple assay for DNA fragmentation and cell death. , 1991, Journal of immunological methods.

[44]  A. Monaco,et al.  An improved method for isolation of mouse pancreatic islets. , 1985, Transplantation.

[45]  R. Lechler,et al.  The question as to why major histocompatibility complex (MHC) a antigens are uniquely powerful primary immunogens and in this respect differ from antigens of the minor systems , 2003 .

[46]  P. Lacy,et al.  Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas , 1967, Diabetes.