Costimulation and its role in organ transplantation

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 immuno-suppressive 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-4Ig), anti-B7 MAbs, and genetically altered CD28 "knockout" mice to study immune responses. The studies suggest that: 1) CTLA-4Ig 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.