title: 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.
abstract: 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.
authors: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA. harah@upmc.edu
authors: Tadatsura
authors: T
authors: Koshika
authors: Carol
authors: C
authors: Phelps
authors: Jason
authors: J
authors: Fang
authors: Seung Eun
authors: SE
authors: Lee
authors: Minoru
authors: M
authors: Fujita
authors: David
authors: D
authors: Ayares
authors: David K C
authors: DK
authors: Cooper
authors: Hidetaka
authors: H
authors: Hara
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D060887:B7 Antigens / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007165:Immunosuppression Therapy; D013552:Swine / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D060887:B7 Antigens; D015704:CD4 Antigens; D060908:CTLA-4 Antigen