title: Significant enhancement by anti-ICOS antibody of suboptimal tacrolimus immunosuppression in rat liver transplantation.
abstract: A member of the costimulatory molecule family, inducible costimulator (ICOS), is expressed on activated T cells and plays a critical role in their primary activation and cytokine production. ICOS is involved in different immune phenomena, such as Th1-mediated autoimmune disease and graft rejection. Although blockade of ICOS costimulation theoretically may protect grafts from rejection, a single dose of anti-ICOS antibody did not result in the prolongation of rat liver allograft survival. However, in this article, we report that anti-rat ICOS antibody markedly enhanced the immunosuppressive activity of a suboptimal dose of tacrolimus (FK506). After fully allogenic DA to LEW liver transplantation, recipients received a single injection of tacrolimus (1 mg/kg, intramuscularly) with or without anti-ICOS antibody (1 mg/kg, intravenously). Recipient survival was significantly prolonged in rats treated with both the antibody and suboptimal tacrolimus (median survival time 44 days vs. 28 days with tacrolimus alone, P <.01). The extent of cell infiltration into the graft was closely associated with prolongation of recipient survival. Our findings thus demonstrate that anti-ICOS antibody immunotherapy combined with suboptimal tacrolimus has a synergistic effect in preventing hepatic allograft rejection and that it may induce long-term graft acceptance intimately associated with a marked reduction of intragraft T lymphocyte infiltration.
authors.affiliation: Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
authors.forename: Shin
authors.initials: S
authors.lastname: Enosawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Funeshima
authors.forename: Seiichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kimura
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Katsunari
authors.initials: K
authors.lastname: Tezuka
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Makuuchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D060889:Inducible T-Cell Co-Stimulator Protein; D007273:Injections, Intramuscular; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D013194:Staining and Labeling; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C556695:Icos protein, rat; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D016559:Tacrolimus