The interaction of CD8+ CTL with epithelial layers is an important but poorly defined aspects of renal allograft rejection. Recent studies demonstrating that the epithelial cell-specific integrin, CD103, defines a subset of CD8+ CTL potentially provides new insight into such interactions. The central hypothesis to be tested is that TGFbeta activity present at the site of rejecting allografts exerts local control over CD103 expression by a specific subset of graft infiltrating CD8+ CTL, thereby promoting the capacity of such cells for homing to, and subsequent destruction of, the graft epithelium. Mouse mixed leukocyte cultures will be utilized to elucidate mechanisms that regulate CD103 expression by peripheral CD8 cells, and a vascularized mouse kidney transplant model will be utilized to elucidate mechanisms that regulate CD103 expression. by peripheral CD8 cells, and a vascularized mouse kidney transplant model will be utilized to identify the in vivo compartment in which CD103+CTL originate during the allograft response. The stability and extended phenotyping and functional properties of CD103+CTL will be compared with those of conventional (CD103-) CTL, and the capacity of CD103 to function as tissue-restricted adhesion/co-stimulatory molecule that promotes interaction of CD103+ CTL with the graft epithelium will be defined. Transplant conditions that promote accumulation of CD103+CTL at the graft site will also be determined; specific variables to be examined include graft cell-type, type of rejection (acute, chronic, delayed), and CsA immunosuppression. Finally, to test the central hypothesis that CD103+ CTL possess a unique capacity to infiltrate and destroy the graft epithelium, these studies will determine whether: i) the appearance of CD103+CTL within rejecting allografts correlate with destruction of the graft epithelium, ii) targeted disruption of the CD103 gene (i.e., using CD103 knockout mice) prevents rejection of vascularized renal allografts, and iii) adoptively transferred CD103+ CTL home to the renal epithelium and elicit destructive lesions characteristic of rejection pathology. Together, these studies will fulfill a form of Kock's postulates to document the role of CD103+ CTL as an effector mechanism in renal allograft rejection. Human MLC cultures and clinical transplant nephrectomy specimens will be utilized to confirm relevance to the human system. These studies will provide new insight into the immunologic basis of renal allograft rejection and have the potential to identify novel targets for therapeutic intervention in rejection events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036532-10
Application #
6740244
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
1994-08-01
Project End
2005-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
10
Fiscal Year
2004
Total Cost
$297,000
Indirect Cost
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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