title: In vivo function of immune inhibitory molecule B7-H4 in alloimmune responses.
abstract: B7 ligands deliver both costimulatory and coinhibitory signals to the CD28 family of receptors on T lymphocytes, the balance between which determines the ultimate immune response. Although B7-H4, a recently discovered member of the B7 family, is known to negatively regulate T cell immunity in autoimmunity and cancer, its role in solid organ allograft rejection and tolerance has not been established. Targeting the B7-H4 molecule by a blocking antibody or use of B7-H4(-/-) mice as recipients of fully MHC-mismatched cardiac allografts did not affect graft survival. However, B7-H4 blockade resulted in accelerated allograft rejection in CD28-deficient recipients. B7-1/B7-2-double-deficient recipients are truly independent of CD28/CTLA-4:B7 signals and usually accept MHC-mismatched heart allografts. Blockade of B7-H4 in these mice also precipitated rejection, demonstrating regulatory function of this molecule independent of an intact CD28/CTLA-4:B7 costimulatory pathway. Accelerated allograft rejection was always accompanied by increased frequencies of alloreactive IFN-γ-, IL-4- and Granzyme B-producing splenocytes. Finally, intact recipient, but not donor, B7-H4 is essential for prolongation of allograft survival by blocking CD28/CTLA4:B7 pathway using CTLA4-Ig. These data are the first to provide evidence of the regulatory effects of B7-H4 in alloimmune responses in a murine model of solid organ transplantation.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yamaura
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: O
authors.initials: O
authors.lastname: Boenisch
authors.forename: M
authors.initials: M
authors.lastname: Yeung
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.forename: C N
authors.initials: CN
authors.lastname: Magee
authors.forename: R
authors.initials: R
authors.lastname: Padera
authors.forename: S
authors.initials: S
authors.lastname: Datta
authors.forename: T
authors.initials: T
authors.lastname: Schatton
authors.forename: Y
authors.initials: Y
authors.lastname: Kamimura
authors.forename: M
authors.initials: M
authors.lastname: Azuma
authors.forename: N
authors.initials: N
authors.lastname: Najafian
mesh_terms: D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
chemical_list: D019138:Antibodies, Blocking; D018122:B7-1 Antigen; D018796:Immunoconjugates; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D000069594:Abatacept