title: Anti-CD8 abrogates effect of anti-CD4-mediated islet allograft survival in rat model.
abstract: We studied the effects of anti-CD4 treatment of diabetic ACI rats on the induction of tolerance to allogeneic (Lewis) islet allografts. When given as a 4-day treatment regimen, OX38, a mouse anti-rat CD4 antibody, caused depletion of greater than 80% of CD4+ cells from the peripheral blood of treated rats. After induction of diabetes (a single high-dose bolus of streptozocin) and 3 days after the initiation of anti-CD4 immunotherapy, recipient ACI rats were transplanted with fully allogeneic (Lewis) islets of Langerhans via the portal circulation. These transplanted islets were capable of returning the anti-CD4-treated ACI recipients to normoglycemia, which was maintained indefinitely in the absence of further immunosuppression. In contrast, treatment of recipient rats with OX8, an anti-CD8 monoclonal antibody (MoAb), induced only a slight prolongation of graft survival (less than or equal to 30 days). Further characterization of the cellular requirements for the induction of long-term transplantation survival revealed that successful pretransplantation anti-CD4 therapy could be ablated by the coincident treatment of recipient rats with depleting levels of anti-CD8 MoAb. These data point to the necessity of a regulator CD8+ cell in the induction of anti-CD4-mediated transplantation survival in this rat model of islet transplantation.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, California 94305-5111.
authors.forename: K
authors.initials: K
authors.lastname: Seydel
authors.forename: J
authors.initials: J
authors.lastname: Shizuru
authors.forename: D
authors.initials: D
authors.lastname: Grossman
authors.forename: A
authors.initials: A
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Alters
authors.forename: C G
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery / Q000628:therapy; D004195:Disease Models, Animal; D006085:Graft Survival / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013311:Streptozocin; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D013311:Streptozocin