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.
Bluestone
J A
JA
Ben May Institute, University of Chicago, IL 60637-1470, USA.
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000502:physiology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016377:Organ Transplantation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014181:Transplantation Immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept