The infiltration of CD8+ T effector populations (CD8 effectors) into graft renal tubules has long been recognized as a key lesion in progression of clinical renal allograft rejection. Studies resulting from the previous funding period revealed a pivotal role for the integrin CD103 in promoting destruction of the graft renal tubules by donor-specific CD8 effector populations. Based on these data, we postulate that blockade of the CD103 pathway as an adjunct to conventional immunosuppressive strategies provides a means of promoting long-term survival of renal allografts. The overall objective of this proposal is to test this hypothesis. In order to achieve this goal, we will first elucidate the mechanisms by which CD103+CD8+ effectors destroy the graft renal tubules, and identify the origin of CD103+CD8+ effector populations that infiltrate renal allografts. The information gained from these studies will be used to develop optimal strategies for abrogating the contribution of CD103+CD8+ effector mechanisms to renal allograft destruction. The studies in Aim 1 will use gene expression analyses in combination with mouse renal transplant models to define the mechanisms by which CD103 expression promotes accumulation and subsequent destruction of the graft renal tubules by donor-specific CD8 effectors in the graft renal tubules. The studies in Aim 2 will use mouse renal allograft models to identify the precursors of CD103+CD8+ effectors that infiltrate epithelial allografts, and elucidate the role of local transforming growth factor-beta activity in their generation. The studies in Aim 3 will use rat kidney transplant models to determine the impact of CD103 blockade on development of tubular atrophy and interstitial fibrosis in vascularized renal allografts. Together, the proposed studies will elucidate the mechanisms by which CD8+ T cells destroy renal allografts and identify novel targets for therapeutic intervention in the important clinical problem of late graft loss. Relevance to public health: Current immunosuppressive strategies do not reliably prevent the occurrence of rejection episodes and long-term damage to the graft. Consequently, late graft loss now represents the major rejection problem in clinical renal transplantation. Thus, a better understanding of the pathways by which this occurs is likely to reveal novel targets for therapeutic intervention in this important clinical problem. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI036532-13
Application #
7214640
Study Section
Special Emphasis Panel (ZRG1-IMM-L (04))
Program Officer
Kehn, Patricia J
Project Start
1994-08-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
13
Fiscal Year
2007
Total Cost
$364,125
Indirect Cost
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Barrie, Elizabeth S; Lodder, Mels; Weinreb, Paul H et al. (2015) Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice. J Endocrinol 224:235-43
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
Anthony, Bryan A; Hadley, Gregg A (2012) Induction of graft-versus-host disease and in vivo T cell monitoring using an MHC-matched murine model. J Vis Exp :e3697
Liu, Kechang; Anthony, Bryan A; Yearsly, Martha M et al. (2011) CD103 deficiency prevents graft-versus-host disease but spares graft-versus-tumor effects mediated by alloreactive CD8 T cells. PLoS One 6:e21968
Lee, Young-Tae; Suarez-Ramirez, Jenny E; Wu, Tao et al. (2011) Environmental and antigen receptor-derived signals support sustained surveillance of the lungs by pathogen-specific cytotoxic T lymphocytes. J Virol 85:4085-94
Zhang, Lei; Hadley, Gregg A (2010) Application of anti-CD103 immunotoxin for saving islet allograft in context of transplantation. Chin Med J (Engl) 123:3644-51
Wang, Jiao-Jing; Hockenheimer, Sara; Bickerstaff, Alice A et al. (2009) Murine renal transplantation procedure. J Vis Exp :
Zhang, L; Moffatt-Bruce, S D; Gaughan, A A et al. (2009) An anti-CD103 immunotoxin promotes long-term survival of pancreatic islet allografts. Am J Transplant 9:2012-23