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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI087586-04
Application #
8470536
Study Section
Special Emphasis Panel (ZAI1-PTM-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$334,816
Indirect Cost
$116,297
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Gorbacheva, Victoria; Fan, Ran; Wang, Xi et al. (2015) IFN-? production by memory helper T cells is required for CD40-independent alloantibody responses. J Immunol 194:1347-56
Ishii, Daisuke; Rosenblum, Joshua M; Nozaki, Taiji et al. (2014) Novel CD8 T cell alloreactivities in CCR5-deficient recipients of class II MHC disparate kidney grafts. J Immunol 193:3816-24
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Gaughan, A; Wang, J; Pelletier, R P et al. (2014) Key role for CD4 T cells during mixed antibody-mediated rejection of renal allografts. Am J Transplant 14:284-94
Su, C A; Iida, S; Abe, T et al. (2014) Endogenous memory CD8 T cells directly mediate cardiac allograft rejection. Am J Transplant 14:568-79
Baldwin 3rd, William M; Su, Charles A; Shroka, Thomas M et al. (2014) Experimental models of cardiac transplantation: design determines relevance. Curr Opin Organ Transplant 19:525-30
Basu, Abhijit; Poddar, Darshana; Robinet, Peggy et al. (2014) Ribosomal protein L13a deficiency in macrophages promotes atherosclerosis by limiting translation control-dependent retardation of inflammation. Arterioscler Thromb Vasc Biol 34:533-42
Liu, Qiang; Nassar, Ahmed; Farias, Kevin et al. (2014) Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers. Liver Transpl 20:987-99
Su, Charles A; Fairchild, Robert L (2014) Memory T Cells in Transplantation. Curr Transplant Rep 1:137-146

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