Blockage of co-stimulatory signal

In addition to the production of an intracellular first signal following specific TCR-MHC interaction, full activation of a T cell requires a second co-stimulatory signal, which can be provided by the interaction of CD28 and B7-1 or B7-2 (CD80 or CD86, respectively). Cytotoxic T-lymphocyte antigen 4 (CTLA-4; also called CD152) is an alternative ligand for CD80 and CD86, and is homologous with CD28. CTLA-4 is believed to play a role in the negative regulation of T-cell activation. The blockage of this co-stimulatory signal, for example using a fusion protein, has been shown in many murine and primate studies to inhibit cell-mediated and humoral immune responses in vivo. In one such study that used an adenoviral vector to deliver a CTLA-4Ig gene [a fusion protein comprising CTLA-4 and an immunoglobulin (Ig)] intravenously following cardiac allograft transplantation, the median survival time was increased from 6 days in the control group to 23 days in the group treated with the adenoviral vector expressing the CTLA-4Ig transgene . In another investigation by Chahine and colleagues .., transgene for CTLA-4Ig was transfected to both syngeneic and allogeneic mouse muscle precursor cells (myoblasts) and co-transplanted with allogeneic pancreatic islet cells under the kidney capsule of diabetic mice. Syngeneic myoblasts significantly prolonged the survival of the islets from 11 days to 31.7 days; no beneficial effect was observed for the transfected allogeneic myoblasts. The syngeneic myoblasts actively secreted CTLA-4Ig, to create local immunosuppression in the environment of the allogeneic islets, and thus allow them to function. When the myoblasts were allogeneic themselves, the MHC disparity with the recipient was enough to destroy them, thus preventing any CTLA-4Ig from being produced.