Cytolytic T lymphocytes (CTL) have been identified as major effector cells of acute allograft rejection and vascular endothelial cells (EC) are the primary cellular targets of allograft injury. Injury to graft arterial BC (endothelialitis Or type II rejection) is both a harbinger of therapy-resistant acute rejection and a potential precursor lesion for chronic rejection. Rejecting cardiac allografts contain endothelial-specific alloreactive CTL that do not kill donor leukocytes. The investigators hypothesize that the CTL which mediate endotheliaiitis are specific for graft BC and may differ from conventional alloreactive CTL, explaining the prognostic distinction hetween acute parenchymal (type I) and vascular (type II) rejection. The investigators have found that cultured human EC stimulate generation of EC-specific alloreactive CTL in vitro while suppressing the development of conventional CTL. They also have developed novel models, utilizing huPBL-SCID/beige mice, to produce human CTL-mediated injury to human skin microvessel or arterial allografts in vivo. The investigators have optimized conditions for stable retroviral transduction of exogenous genes into human EC and have developed a synthetic microvesse1 system for transplanting transduced EC into SCID/beige mice. Finally, they have discovered that the cytokine IL-11 can make human EC resistant to lysis by CTL.
The specific aims of the proposal are: (1) to identify signals (costimulators and cytokines) provided by EC that cause the development of EC-specific CTL while suppressing conventional CTL and to determine if EC-mediated effects are also observed in vivo in various huPBL/SCID beige mouse models; (2) to determine the basis of EC-specific recognition, evaluating the relative contributions of EC-specific peptides, of EC MHC class Ib molecules, and of EC accessory interactions (e.g., involving selectins, integrins or CD44); and (3) to determine the basis of the IL- 11 cytoprotective effect and to evaluate the protective effects of bcl-2 and survivin overexpression in vitro and in vivo. The results of these studies will advance knowledge about EC-CTL interactions in transplantation and provide a basis for novel immunomodulatory or gene-based therapies to improve graft outcome.
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