The initiation of organ graft rejection in human transplantation differs from that in rodent transplantation in two important ways: (a) humans, but not rodents, have alloreactive memory T cells in large numbers that correlate with rejection and (b) human but not rodent endothelial cells (EC) are able to activate alloreactive memory T cells. This project will explore two novel features of human EC presentation of alloantigens to human memory T cells. First, the investigators will characterize the process by which graft EC may present alloantigens to effector memory T cells in a manner that triggers both transendothelial migration and in situ activation and then compare this process to transendothelial migration of effector memory T cells initiated by inflammatory chemokines. The effects of the second population of cells in the walls of microvessels, namely pericytes (PC), will also be examined as preliminary data suggest that these cells, like EC, may present alloantigen to memory T cells but tolerize after they activate T cells. These experiments will be performed both in vitro using cultured cells and in vivo using immunodeficient mice engrafted with human skin and receiving adoptively transferred allogeneic T cells. The assays used to characterize transendothelial migration and T cell activation are well established in the investigators' laboratory. The recovery of T cells post transmigration for such analyses involve the application of new technologies to this problem. Second, the investigators will characterize signals that cause cultured human EC release membrane-bound vesicles, such as exosomes or plasma membrane-derived microparticles, determine the composition of such particles, and determine if these particles are capable of activating central memory T cells, initiating rejection at a distance. The systemic release of such particles by human EC within grafted skin on immunodeficient mice will also be examined. The initial characterization of EC-derived exosomes was made by the investigators and the tools for such analyses are well established. This characterization of EC presentation of alloantigen can lead to new strategies to reduce organ rejection in the clinic which remains as a major cause of allograft failure.
Organ transplantation is a life saving therapy for end stage heart, kidney, liver, and lung failure, but success is still limited by immune-mediated rejection. Rodent models have had only limited success in leading to further improvements in large part because the interactions of host memory T cells with graft endothelial cells is very different in humans. This project will further characterize such interactions between human cells and, if successful, will suggest new approaches to reduce organ graft rejection.
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