In the last 4 years of funding we have defined the conditions under which T cells obviate the requirement forcostimulatory signaling during activation, and mediate graft rejection in murine models of transplantationdespite treatment with reagents that profoundly Inhibit costimulatory T cells to T cells. Specifically, ourresearch has shown that the presence of high naive CD4'^ or CDS* T cell precursor frequency or pre-existence of donor-reactive memory T cells render recipients refractory to the salutary effects ofcostlmulatlon blockade. These findings have been based on the use of TCR transgenic models which allowthe use of a fixed, monoclonal T cell population in order to control for the effects of altered TCR affinity forantigen, among other variables present In endogenous, polyclonal, polyantigen-speclfic populations.However, during the course of our studies we have begun to Investigate the role of TCR affinity for pMHCcomplexes during graft rejection, and how this parameter fundamentally impacts the magnitude andcharacter ofthe donor-reactive T cell response during graft rejection or survival. After establishing a noveltransgenic system In which graft specific T cells are primed by ligands of increasing affinity for the TCR, wehave demonstrated In preliminary studies that graft-specific TCR affinity profoundly impacts the effectorphenotype of responding T cells, and more Importantly, critically influences their suscepfibility tocosfimulatlon blockade- Induced prolongafion in graft survival. Therefore, experiments outlined In thisproposal will endeavor to elucidate the role of TCR affinity in preclpltafing graft rejection, and to assess themechanisms underlying the ability of cells stimulated with ligands of varying potencies to be tolerized usingcostlmulatlon blockade. These studies are of great significance because they will allow us to begin to unravelthe nature of the alloreactive T cell response, and define a threshold for TCR cross-reactivity above whichclinical manifestations of T cell alio- crossreactlvity will occur.

Public Health Relevance

The proposed research is relevant to public health because fissue and organ transplantafion is a life-savingtreatment opfion for many end-stage organ diseases; however, combating the potent Immune response thatthreatens to destroy transplanted fissue remains an important problem. This grant applicafion seeks tounderstand the factors that allow T cells to mount a vigorous Immune attack against the transplanted tissue.Therefore, the proposed research is relevant to the part of NIH's mission that relates to advancingfundamental knowledge in order to help reduce human morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI040519-16
Application #
8128157
Study Section
Special Emphasis Panel (NSS)
Program Officer
Kehn, Patricia J
Project Start
1996-12-01
Project End
2017-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
16
Fiscal Year
2012
Total Cost
$387,500
Indirect Cost
$137,500
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Krummey, Scott M; Martinez, Ryan J; Andargachew, Rakieb et al. (2016) Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity. J Immunol 196:2838-46
Krummey, Scott M; Chen, Ching-Wen; Guasch, Sara A et al. (2016) Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity. J Immunol 197:2009-15
Badell, I R; Kitchens, W H; Wagener, M E et al. (2015) Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy. Am J Transplant 15:3081-94
Krummey, Scott M; Ford, Mandy L (2015) New insights into T-cell cosignaling in allograft rejection and survival. Curr Opin Organ Transplant 20:43-8
Krummey, S M; Cheeseman, J A; Conger, J A et al. (2014) High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant 14:607-14
Pinelli, D F; Wagener, M E; Liu, D et al. (2013) An anti-CD154 domain antibody prolongs graft survival and induces Foxp3(+) iTreg in the absence and presence of CTLA-4 Ig. Am J Transplant 13:3021-30
Kitchens, W H; Haridas, D; Wagener, M E et al. (2012) Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells. Am J Transplant 12:69-80
Kitchens, William H; Haridas, Divya; Wagener, Maylene E et al. (2012) Combined costimulatory and leukocyte functional antigen-1 blockade prevents transplant rejection mediated by heterologous immune memory alloresponses. Transplantation 93:997-1005
Ferrer, Ivana R; Wagener, Maylene E; Song, Minqing et al. (2011) Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade. Proc Natl Acad Sci U S A 108:20701-6
Ford, Mandy L; Larsen, Christian P (2011) Transplantation tolerance: memories that haunt us. Sci Transl Med 3:86ps22

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