title: Combined coinhibitory and costimulatory modulation with anti-BTLA and CTLA4Ig facilitates tolerance in murine islet allografts.
abstract: Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4Ig alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4Ig led to indefinite (>100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4Ig, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4Ig mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4Ig and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4Ig costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts.
authors.affiliation: The Surgical Medical Research Institute, Department of Surgery, Faculty of Medicine, The University of Alberta, Edmonton, Alberta, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Truong
authors.forename: J C
authors.initials: JC
authors.lastname: Plester
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: S
authors.initials: S
authors.lastname: Merani
authors.forename: T L
authors.initials: TL
authors.lastname: Murphy
authors.forename: K M
authors.initials: KM
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Kaye
authors.forename: C C
authors.initials: CC
authors.lastname: Anderson
authors.forename: A M J
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018796:Immunoconjugates / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; C488868:BTLA protein, mouse; D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018796:Immunoconjugates; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000069594:Abatacept