title: Aggressive skin allograft rejection in CD28-/- mice independent of the CD40/CD40L costimulatory pathway.
abstract: CD28-/- mice have been utilized to study the role of B7/CD28 and B7-CTLA4 interactions. There is evidence that CTLA4 ligation may be critical for tolerance induction. The aim of the current study is to further investigate rejection responses of CD28-/- mice and to define the role of B7-CTLA4 interactions in the absence of the CD40 and CD28 pathways. Balb/c skin allografts were transplanted onto C57BL/6 (B6) wild type or CD28-/- mice treated with anti-CD40L, CTLA4-Ig, or combination blockade. To investigate the cellular mechanism of rejection in CD28-/- recipients, mice were treated with anti-CD4 or anti-CD8 antibodies prior to treatment with costimulation blockade. The fluoroscein dye CFSE was utilized to study T cell expansion in vivo. Surprisingly, treatment of B6 CD28-/- mice with CTLA4-Ig alone (MST 12d), anti-CD40L alone (MST 13d), or combined blockade (MST 13d) had no effect on allograft survival compared to untreated B6 CD28 mice (MST 11d). CD28-/- recipients depleted of CD4+ cells and treated with CTLA4-Ig, anti-CD40L, or combination blockade also did not have prolonged survival compared with untreated mice (MST 10d). In contrast, CD28-/- recipients depleted of CD8+ cells had markedly prolonged allograft survival when treated with either anti-CD40L alone (MST 49d) or with combination blockade (MST 57d). Studies utilizing CFSE demonstrated that CD28-/- CD8+ T cells are not defective in in vivo proliferation responses compared with wild type CD8 cells. Thus, CD28-/- CD8+ T cells are responsible for aggressive rejection responses of CD28-/- mice independent of the CD40 pathway. In addition, CD40L blockade does not result in CD4+ T cell tolerance in CD28 recipients, despite an intact B7-CTLA4 pathway.
authors.affiliation: The Carlos and Marguerite Mason Transplantation Biology Research Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322 USA.
authors.forename: J
authors.initials: J
authors.lastname: Ha
authors.forename: A W
authors.initials: AW
authors.lastname: Bingaman
authors.forename: M M
authors.initials: MM
authors.lastname: Durham
authors.forename: T C
authors.initials: TC
authors.lastname: Pearson
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D005856:Germ-Free Life; D006084:Graft Rejection / Q000276:immunology*; D018796:Immunoconjugates; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; D019013:CD40 Antigens; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept