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Presenter: Tadatsura, Koshika, Tsukuba, Japan
Authors: Tadatsura Koshika1, Carol Phelps2, Jason Fang1, Seung Lee1, Minoru Fujita1, David Ayares2, David K.C. Cooper1, Hidetaka Hara1
Relative efficiency of porcine and human CTLA4-Ig in inhibiting human CD4+Tcell responses costimulated by porcine and human B7 molecules
Tadatsura Koshika1, Carol Phelps2, Jason Fang1, Seung Lee1, Minoru Fujita1, David Ayares2, David K.C. Cooper1, Hidetaka Hara1
1Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA; 2Revivicor, Blacksburg, VA; United States
Purpose: GTKO pigs transgenic for porcine (p) CTLA4-Ig have been produced to reduce T cell-mediated rejection following xenotransplantation. The serum level of soluble pCTLA4-Ig greatly exceeded the clinical therapeutic level, rendering the pigs immune-incompetent. Our aim was (i) toevaluate whether soluble pCTLA4-Ig from pCTLA4-Ig transgenic pigs could bind to p and human (h) B7 molecules (CD80/CD86), (ii) inhibit the xenogeneic direct responses of hCD4+T cells to pAECs, and (iii) to determine the efficacy of pCTLA4-Ig transgenic cells to inhibit host T cell-mediated xenogeneic immune responses.
Methods: Soluble pCTLA4-Ig produced by transgenic pigs was evaluated for binding to p and h B7 molecules on p aortic endothelial cells (pAECs) and hPBMCs, and for its inhibitory effect on allogeneic/xenogeneic hT cell responses to these cells. Both pCTLA4-Ig-expressing PBMCs and pAECs were evaluated for their direct inhibitory effect on hCD4+T cell responses.
Results: Soluble pCTLA4-Ig and purified hCTLA4-Ig showed similar binding to pB7 molecules, but pCTLA4-Ig showed significantly less binding to hB7 molecules. In mixed lymphocyte reaction, pCTLA4-Ig and hCTLA4-Ig equally inhibited the response of hCD4+T cells to pAECs, but pCTLA4-Ig was less effective in inhibiting the h 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, no soluble pCTLA4-Ig was detected in the supernatant during culture, and pCTLA4-Ig-expressing pAECs did not inhibit the xenogeneic direct hT cell response.
Conclusions: (i) Soluble pCTLA4-Ig only inhibits the h direct T cell xenogeneic response. (ii) High-level tissue-specific production of pCTLA4-Ig will be required to suppress the direct T cell response. (iii) hCTLA4-Ig will need to be administered to suppress the indirect response. (iv) The discrepancy between the high levels of soluble CTLA4-Ig in the pigs and its absence in the cell supernatant requires study.
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