title: Lack of role for CsA-sensitive or Fas pathways in the tolerization of CD4 T cells via BMT and anti-CD40L.
abstract: Anti-CD40L mAb plus bone marrow transplantation (BMT) and recipient CD8 T-cell depletion permits long-term mixed hematopoietic chimerism and systemic donor-specific tolerance to be achieved across full MHC barriers. Initial tolerance is characterized by peripheral deletion of donor-reactive CD4 cells. In regimens using costimulatory blockade without BMT to achieve allograft survival, cyclosporine inhibited graft survival, suggesting that the combination may not be clinically applicable. We assessed the role of cyclosporine-sensitive mechanisms and the mechanisms of T-cell apoptosis involved in the induction of early peripheral CD4+ T-cell tolerance by BMT with anti-CD40L. Neither a short course of cyclosporine (14 days) nor the absence of FAS-mediated activation-induced cell death (AICD) blocked the induction or maintenance of donor-specific tolerance. IL-2 production was not associated with tolerance induction, consistent with the lack of a role for Fas-mediated AICD. Mice in which passive T-cell death was impaired because of constitutive expression of a Bcl-xL transgene did not develop tolerance with this protocol. These data confirm that deletion of donor-reactive T cells is critical for the induction of mixed chimerism and tolerance. However, the mechanisms involved may differ from those involved in costimulatory blockade regimens that do not include BMT.
authors.affiliation: Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Kurtz
authors.forename: Ariadne
authors.initials: A
authors.lastname: Lie
authors.forename: Mathew
authors.initials: M
authors.lastname: Griffith
authors.forename: Shannon
authors.initials: S
authors.lastname: Eysaman
authors.forename: Juanita
authors.initials: J
authors.lastname: Shaffer
authors.forename: Natalie
authors.initials: N
authors.lastname: Anosova
authors.forename: Laurence
authors.initials: L
authors.lastname: Turka
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D016038:Skin Transplantation / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology
chemical_list: D000906:Antibodies; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D019014:fas Receptor; D023201:CD40 Ligand; D016559:Tacrolimus