Antibody mediated mechanisms leading to graft injury and loss remain pooriy understood. Investigafion into these mechanisms is hampared 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-meidated rejection of renal allografts in CCR5-/- recipients where the titers of donorspecific anfibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and graft rejection was characterisfic of acute humoral rejecfion 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 infiltrafion. These and our preliminary results have led us to propose the hypothesis that a key mechanims 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 fissue pathology inflated by specifc antibodies in the rejecfion of renal allografts of varying MHC disparities in the CCR5-/- recipients.
In Specific Aim 2 we will test the role of this neutrophil mediated fissue damage on the repertoire of anfibodies 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 interstitital fibrosis, pathologies that impact the immediate function and longterm outcome of renal allograft survival. These studies will provide novel insights into mechanisms underlying the pathologies induced following donor-reactive anfibody 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)
Type
Research Program Projects (P01)
Project #
5P01AI087586-05
Application #
8664781
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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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