title: Tolerance induction of alloreactive T cells via ex vivo blockade of the CD40:CD40L costimulatory pathway results in the generation of a potent immune regulatory cell.
abstract: We previously reported that ex vivo blockade of the CD40:CD40L costimulatory pathway in primary mixed lymphocyte reaction cultures resulted in profound in vitro secondary hyporesponsiveness and 30-fold or greater protection from graft-versus-host-disease (GVHD) lethality. Present studies demonstrate that tolerance induction via costimulatory blockade also results in the generation of a potent immunoregulatory cell that inhibits both naive and primed alloresponses. The immunoregulatory capacity was dependent upon cell-to-cell contact that prevented the full activation of the naive or primed cells. The inhibitory effect of tolerized cells did not preclude the response of naive T cells to nominal protein antigen if antigen was present at high concentration. However, under suboptimal antigen concentration, nonspecific inhibition of responses occurred. The tolerized regulatory cell population maintained a polyclonal T-cell receptor V beta repertoire that was broader than in control primed cultures. These data, the first to demonstrate that tolerance induction via CD40:CD40L costimulatory blockade results in potent regulatory function, are relevant to bone-marrow and solid-organ transplantation. The generation of potent immunoregulatory capacity during tolerization via CD40:CD40L blockade provides a fail-safe mechanism to control alloreactive T cells that may have escaped tolerization. These potent regulatory cells may be clinically exploitable for the treatment and prevention of GVHD or autoimmunity.
authors.affiliation: University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, 55455, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Thea M
authors.initials: TM
authors.lastname: Friedman
authors.forename: Robert
authors.initials: R
authors.lastname: Korngold
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015398:Signal Transduction; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand