Alloreactive T cells, central mediators of graft rejection, can recognize donor MHC: peptide complexes expressed on donor cells through the direct pathway of allorecognition and can recognize processed donor-derived peptide determinants expressed on recipient APCs in the context of recipient MHC molecules (the indirect pathway. While it is clear that CD4 + T cells responding through the indirect pathway participate in graft rejection, the presence and contribution of indirectly primed CD8 T cells to allograft rejection has not been addressed. We hypothesize that placement of an allogeneic transplant indirectly primes CD8 T cells, that these T cells comprise a significant portion of the indirect alloimmune response and that they migrate to the target organ. We further hypothesize that indirectly primed CD8 T cells contribute to the pathologic destruction of the transplanted organ through local effects at the graft site and by influencing the development of the remainder of the alloimmune T cell repertoire. We will test this hypothesis through the following specific aims.
Aim 1. To compare the induction of the indirect CD8+ T call repertoire with the other components of the alloreactive T cell response to allografts. In these studies we will use complementary approaches to determine the contribution of indirectly primed CD8 T cells to the peripheral and intragraft alloimmune repertoire following skin or heart transplantation.
Aim 2. To define the in vivo effector functions of indirectly primed CD8 T cells. In these studies we will use skin graft and heart transplant models to determine the in vivo effector functions and mechanisms of indirectly primed CD8 T cells and to fully assess their ability to mediate and/or contribute to graft pathology.
Aim 3. To determine the in vivo requirements for indirect priming of CD8 T cells to transplant antigens.
This aim will address the cellular and costimulatory requirements for priming CD8 T cells through the indirect pathway in vivo and will assess how eostimulatory blockade based interventions affect the function of these CD8 cells. The proposed studies will address an issue in transplantation immunology that has been ignored--whether and how indirectly primed CD8 T cells contribute to organ rejection. The design of effective therapies aimed at preventing rejection and improving human allograft survival depend on a complete understanding of the recipient alloimmune response. The findings derived from the work will define the role for indirectly primed CD8 T cells in allograft rejection and have the potential to guide future therapies aimed a prolonging graft survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043578-08
Application #
6986245
Study Section
Special Emphasis Panel (ZRG1-SSS-W (46))
Program Officer
Kehn, Patricia J
Project Start
1998-08-01
Project End
2006-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
8
Fiscal Year
2006
Total Cost
$261,459
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Pathology
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Gavzy, Samuel J; Heeger, Peter S (2015) Effect of Absent Immune Cell Expression of Vitamin D Receptor on Cardiac Allograft Survival in Mice. Transplantation 99:1365-71
Cravedi, Paolo; Manrique, Joaquin; Hanlon, Katherine E et al. (2014) Immunosuppressive effects of erythropoietin on human alloreactive T cells. J Am Soc Nephrol 25:2003-15
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Cravedi, Paolo; Heeger, Peter S (2014) Complement as a multifaceted modulator of kidney transplant injury. J Clin Invest 124:2348-54
Kalache, Safa; Lakhani, Parth; Heeger, Peter S (2014) Effects of preexisting autoimmunity on heart graft prolongation after donor-specific transfusion and anti-CD154. Transplantation 97:12-9
van der Touw, William; Cravedi, Paolo; Kwan, Wing-hong et al. (2013) Cutting edge: Receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 190:5921-5
Cravedi, Paolo; van der Touw, William; Heeger, Peter S (2013) Complement regulation of T-cell alloimmunity. Semin Nephrol 33:565-74
Cravedi, P; Lessman, D A; Heeger, P S (2013) Eosinophils are not required for the induction and maintenance of an alloantibody response. Am J Transplant 13:2696-702
Cravedi, P; Leventhal, J; Lakhani, P et al. (2013) Immune cell-derived C3a and C5a costimulate human T cell alloimmunity. Am J Transplant 13:2530-9

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