INHIBITION OF TRANSPLANT REJECTION FOLLOWING TREATMENT WITH ANTI-B7-2AND ANTI-B7-1 ANTIBODIES

Antigen-specific T cell activation depends initially on the interactio n of the T cell receptor (TCR) with peptide/MHC. In addition, a costim ulatory signal, mediated by distinct cell surface accessory molecules, is required for complete T cell activation leading to lymphokine prod uction and proliferation. CD28 has been implicated as the major recept or on T cells responsible for delivering the costimulatory signal, Alt hough two distinct ligands for CD28, B7-1 and B7-2, have been identifi ed on antigen-presenting cells (APC), the costimulatory role of each m olecule during a physiological immune response remains unresolved. In the present study, the relative roles of B7-1 and B7-2 interactions we re evaluated in an allogeneic pancreatic islet transplant setting, In isolation, anti-B7-2 mAbs and, to a much lesser degree, anti-B7-1 mAbs suppressed T cell proliferative responses to allogeneic islets or spl enic APC in vitro. Maximal inhibition of the allogeneic response was o bserved using a combination of the anti-B7-1 and anti-B7-2 mAbs, Admin istration of anti-B7-2 but not anti-B7-1 mAbs prolonged C3H allograft survival in B6 recipients, with a combination of both mAbs significant ly prolonging rejection beyond either mAb alone, The immunosuppressive effects of the in vivo mAb treatment were not manifested in in vitro analyses as T cells isolated from suppressed mice responded normally t o allogeneic stimuli in terms of both proliferation and lymphokine pro duction, However, combined mAb therapy in vivo selectively delayed CD4 (+) T lymphocyte infiltration into the graft. These data suggest that both B7-1 and B7-2 costimulatory molecules are active in vivo, althoug h B7-2 plays a clearly dominant role in this allograft model. The mech anism of immune suppression in vivo remains unresolved but may occur a t sites distinct from the allograft.