Antibodies are a major cause of acute and chronic rejection in renal transplants. Some pathologic manifestations of acute antibody-mediated rejection (AMR) that has progressed to graft dysfunction have been defined. However, it is evident that not all of the mediators of AMR have been identified. The potentially reversible stages that precede graft impairment are difficult to resolve in clinical studies even with protocol biopsies because of uncontrollable variables inherent among patients. We have used in vitro and in vivo models to demonstrate that antibodies stimulate endothelial cells to exocytose von Willebrand factor and P- selectin. We propose that activated platelets have critical functions in early AMR and greatly expand inflammation by interacting with endothelial cells and leukocytes. We reported that platelet factor 4 and serotonin accumulated in renal allografts at 100- to 1000-fold higher concentrations compared with other platelet-transported mediators. The localization of large quantities of platelet factor 4 in the allograft has multiple consequences on macrophage function. These interactions are particularly relevant because macrophage infiltrates in human biopsies are a characteristic of AMR. Release of serotonin from platelets also has potential to recruit leukocytes to renal transplants. In addition, platelets can stimulate monocytes and macrophages indirectly at sites of inflammation where endothelial cells release increased amounts of the extracellular matrix protein hyaluronan. Hyaluronidase 2 expressed by activated platelets cleaves HA into fragments that act as danger signals to stimulate macrophages through toll like receptors. The potential beneficial effects of modulating platelet activation in AMR have not been tested fully. In addition to blocking specific platelet mediators, we have found that clinically relevant complement inhibitors are one approach to decrease platelet localization in allografts. We propose the hypothesis that antibodies initiate platelet and endothelial responses that augment leukocyte interactions with blood vessels in renal transplants during AMR. We will test this hypothesis in 3 specific aims: 1) Test the role of platelet-derived mediators in directly causing injury to renal transplants; 2) Test the multiple effects of C1 inhibitor on recruitment and activation of platelets and macrophages; and 3) Test the role of hyaluronan released by vascular endothelium and cleaved by platelets in augmenting inflammation and contributing to fibrosis in renal transplants. To accomplish these specific aims, we will use mouse models of AMR in renal transplants that have been developed by Drs. Fairchild and Valujskikh in Projects 1 and 3 in the previous funding period as well as the passive transfer models developed in our Project 2. Our goals for each specific aim are to understand mechanisms by which platelets contribute to AMR, identify biomarkers of platelet-induced injury and test potential therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI087586-06
Application #
8932401
Study Section
Special Emphasis Panel (ZAI1-BDP-I (M2))
Project Start
Project End
Budget Start
2015-06-15
Budget End
2016-05-31
Support Year
6
Fiscal Year
2015
Total Cost
$390,172
Indirect Cost
$144,007
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Iida, Shoichi; Miyairi, Satoshi; Su, Charles A et al. (2018) Peritransplant VLA-4 blockade inhibits endogenous memory CD8 T cell infiltration into high-risk cardiac allografts and CTLA-4Ig resistant rejection. Am J Transplant :
Tsuda, Hidetoshi; Su, Charles A; Tanaka, Toshiaki et al. (2018) Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells. JCI Insight 3:
Ayasoufi, Katayoun; Kohei, Naoki; Nicosia, Michael et al. (2018) Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia. Am J Transplant 18:1238-1246
Danturti, Sreedevi; Keslar, Karen S; Steinhoff, Leah R et al. (2017) CD4+ T lymphocytes produce adiponectin in response to transplants. JCI Insight 2:
Purroy, Carolina; Fairchild, Robert L; Tanaka, Toshiaki et al. (2017) Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival. J Am Soc Nephrol 28:2377-2392
Benichou, Gilles; Gonzalez, Bruno; Marino, Jose et al. (2017) Role of Memory T Cells in Allograft Rejection and Tolerance. Front Immunol 8:170
Baldwin 3rd, William M; Valujskikh, Anna; Fairchild, Robert L (2016) Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. Curr Opin Organ Transplant 21:7-14
Poddar, Darshana; Kaur, Ravinder; Baldwin 3rd, William M et al. (2016) L13a-dependent translational control in macrophages limits the pathogenesis of colitis. Cell Mol Immunol 13:816-827
Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki et al. (2016) IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts. J Immunol 196:2827-37

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