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Porcine Endothelial Cells, Unlike Human Endothelial Cells, Can Be Killed by Human CTL Via Fas Ligand and Cannot Be Protected by Bcl-2¹

Lian Zheng^*, Li-Hong Ben^*, Jordan S. Pober^*, and Alfred L. M. Bothwell^2,*

^* Section of Immunobiology and Interdepartmental Program in Vascular Biology and Transplantation, and Departments of Pathology and Dermatology, Yale University School of Medicine, New Haven, CT 06520

In clinical transplantation host CTL are major effectors of acute rejection, and graft endothelial cells (EC) are major targets of the CTL response. It is unclear what roles CTL will play in pig-into-human xenotransplantation. We compared the mechanisms of killing used by human CTL (huCTL) vs allogeneic and pig xenogeneic EC targets. Both responses show MHC class I restriction of target cell recognition. A granzyme B inhibitor peptide completely blocks anti-human and partially blocks anti-pig responses, while inhibitory Fas ligand Ab only blocks killing of porcine cells despite similar levels of Fas expression in both target cell types. Transduction of Bcl-2 completely protects human EC from huCTL, but has no effect on huCTL-mediated killing of porcine EC despite its efficacy vs drug-induced apoptosis. Bcl-2 effectively protects human EC rendered sensitive to Fas ligand by overexpressing Fas from huCTL, yet fails to protect porcine aortic endothelial cells from huCTL in the presence of anti-Fas ligand Ab. These data reveal differences in the susceptibility of human and porcine targets to huCTL.

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