title: CTLA-4 up-regulation plays a role in tolerance mediated by CD45.
abstract: Cytolytic T lymphocyte-associated antigen 4 (CTLA-4) is a critical down-regulatory molecule in T cells that plays a major role in peripheral tolerance. Although the CD45 protein tyrosine phosphatase is a potent immunomodulatory target, the mechanisms by which antibody against CD45RB isoforms (anti-CD45RB) induces allograft tolerance remain unclear. We show here that anti-CD45RB treatment alters CD45 isoform expression on T cells, which is associated with rapid up-regulation of CTLA-4 expression. These effects appear specific and occur without up-regulation of other activation markers. Administration of a blocking monoclonal antibody to CTLA-4 at the time of transplantation prevents anti-CD45RB therapy from prolonging islet allograft survival. In addition, treatment with cyclosporin A blocks anti-CD45RB-induced CTLA-4 expression and promotes acute rejection. These data suggest that anti-CD45RB acts through mechanisms that include CTLA-4 up-regulation and demonstrate a link between CD45 and CTLA-4 that depends on calcineurin-mediated signaling. They demonstrate also that CTLA-4 expression may be specifically targeted to enhance allograft acceptance.
authors.affiliation: Department of Surgery, Yale Medical School, New Haven, CT 06520, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fecteau
authors.forename: G P
authors.initials: GP
authors.lastname: Basadonna
authors.forename: A
authors.initials: A
authors.lastname: Freitas
authors.forename: C
authors.initials: C
authors.lastname: Ariyan
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: D M
authors.initials: DM
authors.lastname: Rothstein
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D060908:CTLA-4 Antigen; D019703:Calcineurin / Q000378:metabolism; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance; D018796:Immunoconjugates; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept; D019703:Calcineurin; D017493:Leukocyte Common Antigens