Relative efficiency of porcine and human cytotoxic T‐lymphocyte antigen 4 immunoglobulin in inhibiting human CD4 + T‐cell responses co‐stimulated by porcine and human B7 molecules

Summary α1,3‐Galactosyltransferase gene‐knockout pigs transgenic for porcine cytotoxic T‐lymphocyte antigen 4 immunoglobulin (pCTLA4‐Ig) have been produced to reduce T‐cell‐mediated rejection following xenotransplantation. The level of soluble pCTLA4‐Ig in their blood was greatly in excess of the therapeutic level in patients, rendering the pigs immune‐incompetent. Soluble pCTLA4‐Ig produced by these transgenic pigs was evaluated for binding to porcine and human (h) B7 molecules, and for its inhibitory effect on allogeneic and xenogeneic human T‐cell responses. Porcine CTLA4‐Ig‐expressing peripheral blood mononuclear cells (PBMCs) and aortic endothelial cells (AECs) were evaluated for their direct inhibitory effect on hCD4 + T‐cell responses. Soluble pCTLA4‐Ig and purified hCTLA4‐Ig showed similar binding to pB7 molecules, but pCTLA4‐Ig showed significantly less binding to hB7 molecules. The pCTLA4‐Ig and hCTLA4‐Ig inhibited the response of hCD4 + T cells to pAECs equally, but pCTLA4‐Ig was less successful in inhibiting the human allogeneic response. The hCD4 + T‐cell response to PBMCs from pCTLA4‐Ig pigs was significantly lower than that of non‐pCTLA4‐Ig pigs. Although pCTLA4‐Ig was detected in the cytoplasm of pCTLA4‐Ig‐expressing pAECs, only a minimal level of soluble pCTLA4‐Ig was detected in the supernatant during culture, and pCTLA4‐Ig‐expressing pAECs did not inhibit the xenogeneic direct human T‐cell response. High‐level tissue‐specific production of pCTLA4‐Ig may be required for sufficient immunosuppression for organ or cell (e.g. islets) transplantation.