title: Accelerating the induction of Fas-mediated T cell apoptosis: a strategy for transplant tolerance?
abstract: Acute allograft rejection is primarily a consequence of clonal expansion of donor-specific T cells with specificity for donor antigen. Immunosuppression current involves the administration of toxic drugs that limit lymphoproliferation, but this treatment is not antigen-specific and allows opportunistic infection. An ideal strategy would be production of donor-specific T cell tolerance in the presence of an otherwise intact and functional T cell repertoire. Methods to enhance normal apoptotic clearance of activated T cells might contribute to development of this state. This study focuses on manipulation in vitro of Fas-mediated T cell apoptosis and compares two methods to enhance the extent and kinetics for clearance of activated T cells. First, the CD4 coreceptor was cross-linked in the presence and absence of Fas-stimulation. It was found that CD4 cross-linking potently induced apoptosis, even in the absence of Fas stimulation. Resting and activated T cells were susceptible to this treatment, precluding the development of antigen-specific tolerance after T cell activation. In a second system, T cells were treated with two staurosporine analogues, Bisindolylmaleimide (Bis) III and VIII and apoptosis was induced by stimulation of Fas. Resting T cells remained resistant to Fas-mediated apoptosis, but treatment of mitogen or alloantigen-activated cells with either Bis III or VIII caused a synergistic increase in apoptosis. These agents also reduced the period of resistance to Fas-mediated apoptosis after T cell activation, possibly by reducing expression of c-FLIP, allowing early activation of caspase 8 in alloreactive T cells. Development of this strategy might provide a route to the induction of specific tolerance after organ transplantation.
authors.affiliation: Applied Immunobiology Group, Department of Surgery, Medical School, University of Newcastle, Newcastle upon Tyne UK.
authors.forename: H P
authors.initials: HP
authors.lastname: Carroll
authors.forename: S
authors.initials: S
authors.lastname: Ali
authors.forename: J A
authors.initials: JA
authors.lastname: Kirby
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003432:Cross-Linking Reagents; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007108:Immune Tolerance; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008301:Maleimides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D014181:Transplantation Immunology; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D007211:Indoles; D008301:Maleimides; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C088060:bisindolylmaleimide