Current immune suppression protocols have greatly prolonged the life span of the average transplant and transplant recipient, alloantibody mediated rejection remains a limiting factor in long-term transplant survival. Animal models have shown platelet interactions with an inflamed endothelium amplify the immune response, increase leukocyte adhesion, and exacerbate atherosclerosis. However, the role of platelets in transplant rejection is not well understood. The long-term objective of our proposal is to define mechanisms of platelet mediated transplant rejection.
Specific Aim #1 : To demonstrate that platelets promote leukocyte trafficking and endothelial cell inflammation in immune responses to transplants. Leukocyte and endothelial cell interactions are pivotal for both the innate and acquired immune responses. We will demonstrate the role of platelet derived adhesion molecules in promoting leukocyte localization and trafficking in alloimmune responses to transplants.
Specific Aim #2 : To demonstrate that platelet derived chemokines promote an innate immune response in transplantation. Platelets also secrete molecules, including chemokines, that have immuno-regulatory functions and promote leukocyte trafficking. We will demonstrate that platelet derived chemokines increase neutrophil (PMN) and monocyte activation and trafficking as part of innate alloimmune responses.
Specific Aim #3 : To demonstrate that platelet derived chemokines promote an acquired immune response in transplant rejection.

Public Health Relevance

To further explore the important role of platelet derived chemokines in transplant rejection we will demonstrate that platelets also increase transplant directed T-cell activation and recruitment. In 2005 alone almost 27,000 Americans received an organ transplant. Antibody mediated transplant rejection remains a difficult to control cause of transplant loss and its mechanisms are poorly understood.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093179-03
Application #
7904222
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Schwartz, Lisa
Project Start
2008-08-03
Project End
2013-07-31
Budget Start
2010-08-03
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$382,813
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Modjeski, K L; Levy, S C; Ture, S K et al. (2016) Glutamate Receptor Interacting Protein 1 Regulates CD4(+) CTLA-4 Expression and Transplant Rejection. Am J Transplant 16:1383-93
Shi, Guanfang; Field, David J; Ko, Kyung-ae et al. (2014) Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection. J Clin Invest 124:543-52
Le, Nhat-Tu; Takei, Yuichiro; Izawa-Ishizawa, Yuki et al. (2014) Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. J Immunol 193:3803-15
Shi, Guanfang; Field, David J; Long, Xiaochun et al. (2013) Platelet factor 4 mediates vascular smooth muscle cell injury responses. Blood 121:4417-27
Heo, Kyung-Sun; Chang, Eugene; Takei, Yuichiro et al. (2013) Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity. Arterioscler Thromb Vasc Biol 33:321-9
Aggrey, Angela A; Srivastava, Kalyan; Ture, Sara et al. (2013) Platelet induction of the acute-phase response is protective in murine experimental cerebral malaria. J Immunol 190:4685-91
Kuo, Hsiao-Hsuan; Morrell, Craig N; Baldwin 3rd, William M (2012) Alloantibody induced platelet responses in transplants: potent mediators in small packages. Hum Immunol 73:1233-8
Chapman, Lesley M; Aggrey, Angela A; Field, David J et al. (2012) Platelets present antigen in the context of MHC class I. J Immunol 189:916-23
Shi, Guanfang; Morrell, Craig N (2011) Platelets as initiators and mediators of inflammation at the vessel wall. Thromb Res 127:387-90

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