Mechanism of T cell-mediated endothelial apoptosis

Alexander S. Krupnick, Daniel Kreisel, Sicco H. Popma, Keki R. Balsara, Wilson Y. Szeto, Alyssa M. Krasinskas, Markus Riha, Andrew D. Wells, Laurence A. Turka, Bruce R. Rosengard

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Background. Cytotoxic T lymphocyte (CTL)-mediated destruction of allogeneic vascular endothelium is important in the pathogenesis of both acute and chronic allograft rejection. Despite the importance of this phenomenon, the effector mechanisms responsible for endothelial cell killing are not well defined, and conflicting conclusions have been reached based on variation in experimental methodology. Methods. We used a recently described method for isolating mouse vascular endothelium to evaluate endothelial cell lysis by CTLs. Endothelial cell destruction was assessed in vitro both by 51Cr release and DNA fragmentation using wild-type and lpr (Fas deficient) endothelium of C3H/HeJ (H2k) mice by MHC alloantigen-specific T cells of wild-type, gld (Fas ligand deficient), and perforin-deficient mice on a C57BL/6 (H2b) background. Results. Although maximal lysis of 56.6±0.8% was seen when using wild-type targets and effectors, only a moderate decrease in apoptosis to 37.6±4.0% was detected when the Fas/Fas ligand death receptor pathway was eliminated. This decrease in cytotoxicity occurred despite the preserved functional capacity of this pathway. Alternatively, a significant decrease in cytotoxicity to 17.4±4.7% was seen when the perforin/granzyme exocytosis pathway was eliminated. Conclusions. These data indicate that CTLs destroy vascular endothelium primarily by the perforin/granzyme exocytosis pathway with only a minor contribution to apoptosis by the Fas/Fas ligand death receptor pathway. These data are critical for the proper interpretation of studies evaluating acute and chronic allograft rejection and for the design of rational strategies to ameliorate vascular injury concomitant to the rejection process.

Original languageEnglish
Pages (from-to)871-876
Number of pages6
JournalTransplantation
Volume74
Issue number6
DOIs
StatePublished - Sep 27 2002
Externally publishedYes

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