title: Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells.
abstract: Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interactions, which may have opposing effects. We have examined the roles of CD28:B7 and CTLA-4:B7 on in vivo alloresponses. A critical role of B7:CD28 was demonstrated by markedly compromised expansion of CD28-deficient T cells and diminished graft-versus-host disease lethality of limited numbers of purified CD4+ or CD8+ T cells. When high numbers of T cells were infused, the requirement for CD28:B7 interaction was lessened. In lethally irradiated recipients, anti-CTLA-4 mAb enhanced in vivo donor T cell expansion, but did not affect, on a per cell basis, anti-host proliferative or CTL responses of donor T cells. Graft-versus-host lethality was accelerated by anti-CTLA-4 mAb infusion given early post-bone marrow transplantation (BMT), mostly in a CD28-dependent fashion. Donor T cells obtained from anti-CTLA-4 mAb-treated recipients were skewed toward a Th2 phenotype. Enhanced T cell expansion in mAb-treated recipients was strikingly advantageous in the graft-versus-leukemia effects of delayed donor lymphocyte infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of allogeneic T cell-depleted marrow infused into sublethally irradiated recipients. We conclude that blockade of the selective CD28-B7 interactions early post-BMT, which preserve CTLA-4:B7 interactions, would be preferable to blocking both pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions provides a potent and previously unidentified means for augmenting the GVL effect of delayed donor lymphocyte infusion.
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis 55455, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: P A
authors.initials: PA
authors.lastname: Taylor
authors.forename: A
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: A H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: D A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000401:mortality; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality; D020350:Graft vs Tumor Effect / Q000276:immunology; D006649:Histocompatibility Antigens / Q000008:administration & dosage / Q000276:immunology*; D018796:Immunoconjugates; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011184:Postoperative Period; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D006649:Histocompatibility Antigens; D018796:Immunoconjugates; D000069594:Abatacept