Two major obstacles to successful prevention of transplant rejection using costimulation blockade-based therapy are 1) the presence of donor-reactive memory T cells prior to transplantation that precipitate acute rejection, and 2) PTLD resulting from compromised EBV-specific immunity in the setting of CD28 blockade. Thus, the identification of strategies to overcome these obstacles is of critical importance in order to optimize the use of belatacept in the clinic. Our preliminary studies revealed that CTLA-4 Ig-resistant CD8+ breakthrough responses are inhibited by selective CD28 blockade using novel CD28 domain antibody (dAb) technology. Using powerful transgenic murine systems in which we can specifically identify, track, and characterize both CD4+ and CD8+ donor-reactive T cells following transplantation, we have identified a coinhibitory molecule (2B4, SLAMf4) that is specifically expressed following selective CD28 blockade. Interrogating the role of 2B4 in CD28 dAb-mediated prolongation of graft survival is innovative in that 2B4 has been shown to play an important role in autoimmunity and in chronic viral infections in both mice and humans, yet has never before been studied in transplantation. Interestingly, 2B4 is expressed at increased levels on secondary CD8+ effectors relative to primary effectors, and a recent study demonstrated that the expression of 2B4 plays a functional role in inhibiting CD8+ secondary effectors during recall responses. These intriguing data raise the possibility that this inhibitory pathway could be harnessed to inhibit donor-specific memory T cell recall responses during transplantation. Finally, we propose to directly compare the effects of selective CD28 blockade vs. CTLA-4 Ig on protective immune responses to a murine homolog of EBV (MHV). A recent study revealed that while CD80/86-/- animals exhibited a profound inability to control MHV replication and reactivation from latency, CD28-/- animals exhibited undetectable viral loads equivalent to wild-type mice. These important data suggest that selective CD28 blockade may better preserve EBV-specific protective immune responses following transplantation. Thus, many questions remain unanswered with regard to the impact of selective CD28 blockade during transplantation. How does selective CD28 blockade in the presence of CTLA-4 coinhibitory signals impact the expression of other costimulatory and coinhibitory molecules to alter T cell programming? How does CD28 blockade differentially impact secondary recall responses, given the fact that memory T cells may be CTLA-4hi and therefore more reliant on this pathway for control of the response? What is the impact of selective CD28 blockade on protective immunity to EBV? Answers to these questions will provide fundamental insights into the biology of costimuatory and coinhibitory receptors in transplantation, and will provide a mechanistic foundation for the further development of novel selective CD28 blockers for use in clinical transplantation.

Public Health Relevance

The proposed research is relevant to public health because it investigates the coinhibitory receptor 2B4 as a novel therapeutic target to attenuate both primary and secondary alloreactive T cell responses in transplantation. Expression of 2B4 can be modified using third-generation costimulation blockers that selectively target CD28 costimulatory signals while leaving CTLA-4 coinhibitory signals intact. Understanding the mechanisms by which coinhibitory receptors including 2B4 are modulated following selective CD28 blockade on both donor-reactive and virus-specific CD8+ T cells is critical for optimization of clinical use of these agents. This contribution is relevant to NIH's mission in that it has the potential to decrease rates of acute rejection and reduce infectious complications in transplant recipients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI104699-02S1
Application #
8827578
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Kehn, Patricia J
Project Start
2014-05-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ford, Mandy L (2016) Micromanaging alloimmunity. J Clin Invest 126:2422-4
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
Ford, Mandy L (2016) T Cell Cosignaling Molecules in Transplantation. Immunity 44:1020-33
Liu, Danya; Burd, Eileen M; Coopersmith, Craig M et al. (2016) Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses. J Immunol 196:1000-12
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 Raul; Ford, Mandy L (2016) T follicular helper cells in the generation of alloantibody and graft rejection. Curr Opin Organ Transplant 21:1-6
Pinelli, D F; Wakeman, B S; Wagener, M E et al. (2015) Rapamycin ameliorates the CTLA4-Ig-mediated defect in CD8(+) T cell immunity during gammaherpesvirus infection. Am J Transplant 15:2576-87
Mittal, Rohit; Chen, Ching-Wen; Lyons, John D et al. (2015) Murine lung cancer induces generalized T-cell exhaustion. J Surg Res 195:541-9
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

Showing the most recent 10 out of 18 publications