New diagnostic tools and heightened clinical awareness have increased the recognition of antibodymediated rejecfion (AMR). However, the pathogenesis of AMR is incompletely understood, and not all of the mediators of AMR have been defined. After a review of the literature, we concluded that platelets could be critical links in propagafing antibody inifiated inflammation. Experiments using skin allografts allowed us to visualize the engagement of platelets by alloantibodies. Immunohistology demonstrated that alloantibodies are associated with the release of von Willebrand factor (vWO and P-selectin from endothelial cells. Platelets express receptors for both vWf and P-selectin. Our hypothesis is that antibodies initiate platelet responses that augment leukocyte interactions with endothelial cells in the transplant and that complement activafion products intensify each of these interactions. This project is designed to examine interactions of antibody and complement with endothelial cells, platelets and leukocytes in the following 3 specific aims: 1) Determine the effects of antibodies and complement on the localization and activation of platelets in renal transplants; 2) Determine the effects of platelet and complement activation on localization and activation of neutrophils, macrophages and T cells in transplants;and 3) Determine the effects of platelets and complement activation on alloantibody-induced rejection. To accomplish these specific aims, we will use a combinafion of models developed by the leaders of all 3 projects.
For Specific Aims 1 and 2, we will use our model in which monoclonal anfibodies are passively transferred to SCID recipients of renal allografts. SCID mice permit complete control of the dose, fiming, anfigenic specificity and isotype of the anfibodies under investigafion in the absence of confounding additional responses from T cells or B cells.
For Specific Aim 3, we will take advantage of models based on extensive work of Dr. Rob Fairchild in Project 1 and Dr. Anna Valujskikh in Project 3. In these models mice produce high titers of alloantibodies that cause complete rejection of renal transplants. Using these models, we will test the effects of depleting platelets on acute and chronic rejection. These are clinically relevant models that will provide data of mechanisfic and therapeufic importance.

Public Health Relevance

As a result of incomplete knowledge, the treatment options for antibody-mediated rejection are limited and not always effective. In this project we will study the role of platelets in antibody-mediated rejection. We have extensive data to indicate that platelets can be activated by antibodies binding to blood vessels in transplants, but platelets are not targeted by current immunosuppressive therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-PTM-I)
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Cleveland Clinic Lerner
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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
Gorbacheva, Victoria; Fan, Ran; Fairchild, Robert L et al. (2016) Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts. J Am Soc Nephrol 27:3299-3307
Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari et al. (2016) Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts. Kidney Int 89:1293-306
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
Baldwin 3rd, W M; Morelli, A E (2016) Strategically Altering the Balance of Macrophage Subpopulations to Inhibit Chronic Rejection. Am J Transplant 16:2510-1
Ayasoufi, Katayoun; Fan, Ran; Fairchild, Robert L et al. (2016) CD4 T Cell Help via B Cells Is Required for Lymphopenia-Induced CD8 T Cell Proliferation. J Immunol 196:3180-90
Gorbacheva, V; Ayasoufi, K; Fan, R et al. (2015) B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) mediate CD40-independent help by memory CD4 T cells. Am J Transplant 15:346-57
Kuo, Hsiao-Hsuan; Fan, Ran; Dvorina, Nina et al. (2015) Platelets in early antibody-mediated rejection of renal transplants. J Am Soc Nephrol 26:855-63
Valujskikh, Anna N (2015) B cells regulate antidonor T-cell reactivity in transplantation. Kidney Int 88:444-6
Gorbacheva, Victoria; Fan, Ran; Wang, Xi et al. (2015) IFN-γ production by memory helper T cells is required for CD40-independent alloantibody responses. J Immunol 194:1347-56

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