Current Immunosuppression has decreased the incidence of acute cellular rejection of renal allografts. However, the incidence of acute humoral rejection (AHR) in renal transplant patients is increasingly observed and is particularly difficult to treat. Antibody mediated mechanisms causing renal graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of animal models to study the development of donor-specific antibody response and subsequent allograft injury. The absence of appropriate models has also hindered the design of strategies to inhibit antibody-mediated graft acute and chronic graft pathology. The long-term goal of this new program is to provide a clearer understanding of inflammatory mechanisms underlying renal allograft injury during AHR. This program comprises three established and interactive investigators who will utilize mouse models of kidney transplantation to address how T cell sensitization impacts allograft reactive antibody production and to identify mechanisms of antibody mediated graft injury leading to either acute rejection or to the development of interstitial fibrosis in the renal allograft. Project 1 will study the impact of graft-reactive antibody induced neutrophil infiltration and activation on acute graft injury and the development of interstitial fibrosis in renal allografts with varying MHC disparities. Project 2 will investigate the role of other innate mediators, platelets and complement, in mediating renal allograft injury in response to antibody binding to the graft endothelium. Project 3 will determine the impact of donor-antigen specific memory T helper cells on the generation of the donor-reactive antibody response, focusing on changes in the specificities and affinities of the antibodies induced. The results of these intertwined projects will provide novel insights into the series of pathogenic events occurring down-stream from antibody binding to the graft endothelium. Importantly, these studies will test novel strategies to prevent generation of donor-reactive antibody and antibody mediated acute injury in renal allografts as well as the development of interstitial fibrosis.

Public Health Relevance

The use of current immunosuppression has decreased the incidence of T lymphocyte mediated rejection of renal transplants but rejection mediated by antibodies that bind to the graft continues to be a problem in causing graft loss. This project will utilize mouse models to investigate mechanisms of kidney graft injury and rejection induced by graft-reactive antibody and will test novel strategies to prevent this injury. PROJECT 1: Title: - Antibody Induced Neutrophil Tissue Pathology in Renal Allografts Project Leader: Fairchild, R PROJECT 1 DESCRIPTION (provided by applicant): Antibody mediated mechanisms leading to graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody response is initiated and increases. For the most part, models studying acute humoral rejection use either transfer of graft-reactive antibodies or sensitization of recipients with donor cells which also primes donor-reactive T cell populations. We have recently reported a novel model of antibody-mediated rejection of renal allografts in CCR5-/- recipients where the titers of donor specific antibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and graft rejection was characteristic of acute humoral rejection observed in clinical transplants. In CCR5- deficient animals, the renal allografts are rejected between days 10 and 20 with heavy deposition of C3d, peritubular edema and neutrophil infiltration. These and our preliminary results have led us to propose the hypothesis that a key mechanisms underlying antibody-mediated rejection of renal allografts is the induced infiltration and activation of neutrophils in the grafts which directly causes graft tissue injury and increases the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims.
In Specific Aim 1 we will directly test the role of neutrophils in the graft tissue pathology inflated by specific antibodies in the rejection of renal allografts of varying MHC disparities in the CCR5-/- recipients.
In Specific Aim 2 we will test the role of this neutrophil mediated tissue damage on the repertoire of antibodies induced to renal allografts of varying MHC disparities. In the final specific aim we will use a B cell depletion strategy to test the effect of limiting donor-specific antibody interaction with the renal allograft on the development of acute tissue injury as well as on the development of interstitial fibrosis, pathologies that impact the immediate function and long-term outcome of renal allograft survival. These studies will provide novel insights into mechanisms underlying the pathologies induced following donor-reactive antibody binding to the allograft endothelium.

Public Health Relevance

Rejection of renal transplants mediated by antibodies that bind to the graft continues to be a problem in causing graft dysfunction and loss. This project will utilize a novel mouse model to investigate graft-reactive antibody induced mechanisms that mediate the acute or chronic kidney graft injury that causes the loss of kidney transplants

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI087586-04
Application #
8470532
Study Section
Special Emphasis Panel (ZAI1-PTM-I (J1))
Program Officer
Kehn, Patricia J
Project Start
2010-06-08
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$1,524,640
Indirect Cost
$548,271
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
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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