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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051014-21
Application #
8588948
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Schwartz, Lisa
Project Start
1994-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
21
Fiscal Year
2014
Total Cost
$464,036
Indirect Cost
$185,336
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Manes, Thomas D; Pober, Jordan S (2016) Significant Differences in Antigen-Induced Transendothelial Migration of Human CD8 and CD4 T Effector Memory Cells. Arterioscler Thromb Vasc Biol 36:1910-8
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Tellides, George; Pober, Jordan S (2015) Inflammatory and immune responses in the arterial media. Circ Res 116:312-22
Abrahimi, Parwiz; Chang, William G; Kluger, Martin S et al. (2015) Efficient gene disruption in cultured primary human endothelial cells by CRISPR/Cas9. Circ Res 117:121-8
Yao, Yi; Liu, Rebecca; Shin, Min Sun et al. (2014) CyTOF supports efficient detection of immune cell subsets from small samples. J Immunol Methods 415:1-5
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Manes, Thomas D; Pober, Jordan S (2014) Polarized granzyme release is required for antigen-driven transendothelial migration of human effector memory CD4 T cells. J Immunol 193:5809-15
Pober, Jordan S (2014) Is hypertension an autoimmune disease? J Clin Invest 124:4234-6

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