Solid organ transplantation is currently the only effective treatment for end stage heart, lung, kidney, or liver failure. When the donor and host are not genetically identical, the survival of transplanted organs is limited by alloimmunity, i.e. the recognition and attack of the donor graft by the host immune system. In human transplantation, it is widely believed that donor-derived graft endothelial cells (ECs) initiate rejection by presenting non-self antigens to host lymphocytes. Because donor derived ECs are present for the life of the graft, they represent a therapeutic target for the prevention of allogrft rejection. Yet there are no therapies specifically focused at reducing the ability of ECs to trigge alloimmunity. The mTOR inhibitor, rapamycin, is an immunosuppressant used to prevent rejection in transplant recipients. Although it is thought to directly disrupt lymphocyte proliferation, recent data suggest that rapamycin may have tolerance promoting effects on antigen presenting cells (APCs). Specifically, dendritic cells treated with rapamycin have reduced immunogenicity and induce donor specific hyporesponsiveness. Because graft endothelial cells act as APCs to initiate rejection, rapamycin could also be a potential agent to decrease EC triggered alloimmunity. This study proposes to investigate the effects of rapamycin on EC allo-immunogenicity. Preliminary data show that treatment of cultured human ECs with rapamycin decreases their allostimulatory potential and confers tolerance promoting effects. The hypothesis to be tested is that these effects are due to the upregulation of the inhibitory molecules, PD-L1 and PD-L2 on rapamycin-treated ECs. In the first aim, this study will use in vitro models to determine how rapamycin increases EC expression of PD-L1 and PD-L2, and will characterize how elevated expression of these molecules functionally and phenotypically affects allogeneic memory T cells. In the second aim, the effect of rapamycin on ECs will be tested in vivo using a human chimeric mouse model of vascular rejection, with particular emphasis on the role of PD-L1 and PD-L2. Successful completion of these aims may identify new molecular targets that can be manipulated to reduce EC allo-immunogenicity, facilitating development of new therapeutics to improve outcomes in human transplantation. More immediately, these results may determine if preoperative conditioning of allografts with rapamycin in the organ donor can be introduced as a novel therapeutic intervention for reducing allograft rejection.

Public Health Relevance

Solid organ transplantation is currently the only effective treatment for end stage heart, lung, kidney, or liver failure. However, immune-mediated rejection still represents a significant barrier to the survival of transplanted organs. In humans, graft endothelial cells act as an important initiator of rejection and rapamycin, a drug used to prevent rejection, may partly act by reducing the ability of endothelial cells to do so. This project seeks to identify the beneficial changes in endothelial cells produced by rapamycin, and if successful may suggest new approaches to improve human transplantation outcomes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL114253-02
Application #
8469746
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Carlson, Drew E
Project Start
2012-05-16
Project End
2014-05-15
Budget Start
2013-05-16
Budget End
2014-05-15
Support Year
2
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wang, Chen; Yi, Tai; Qin, Lingfeng et al. (2013) Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. J Clin Invest 123:1677-93