Costimulation and its role in organ transplantation

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Abstract
Antigen‐specific T‐cell activation depends initially on the interaction of the T‐cell receptor with peptide/major histocompatibility complex (MHC). In addition, a costimulatory signal, mediated by distinct cell surface accessory molecules such as CD28, is required for complete T‐cell activation. One essential element of the CD28 costimulatory system that makes it an attractive target for immunotherapy is the selective effect of CD28 antagonists on activated T cells. Only cells encountering antigen presenting cells (APCs) without the appropriate CD28 ligand will be rendered functionally inactive as desired for any next‐generation immunosuppressive drug. This brief review will focus on the role of CD28/B7 interactions in regulating organ graft rejection. In vitro and in vivo studies will describe the use of a soluble fusion protein antagonist of CD28/B7 (CTLA‐41g), anti‐B7 MAbs, and genetically altered CD28 “knockout” mice to study immune responses. The studies suggest that: 1) CTLA‐41g induces long‐term, antigen‐specific unresponsiveness in vivo; 2) two distinct ligands for CD28, B7‐1 and B7‐2, are differentially regulated during immune responses; and 3) both B7‐1 and B7‐2 costimulatory molecules are active, in vivo, although B7‐2 plays a clearly dominant role in murine. allograft rejection.