Transplantation is the preferred mode of therapy for many forms of end-stage organ disease. Success in transplantation has been built upon therapeutic approaches to control the T cell-dependent process of rejection. Thus, a unifying goal of tolerance induction strategies is to selectively inactivate or delete donor- reactive T cells. Transient blockade of the CD28/B7 and CD154/CD40 pathways has shown great promise in tolerance protocols in na?ve recipients, particularly those that induce mixed hematopoietic chimerism and robust donor-specific tolerance. Unfortunately, the anti-CD154 mAbs that are a cornerstone of this approach cause platelet dysfunction and thromboembolism. In addition, the presence of donor-specific memory T cells as a result of heterologous immunity present a potent barrier to transplantation tolerance. Thus, these two factors present challenges that must be met if costimulation blockade to induce transplantation tolerance is to become a clinical reality. Despite years of interest in these pathways, our knowledge of the mechanisms by which CD28 and CD154 blockade synergize to promote the deletion of na?ve donor-reactive T cells remains very incomplete. By extending our knowledge of this process, we may identify new opportunities to program na?ve donor-specific T cells to execute a death program rather than an expansion and differentiation path that leads to rejection. While there has been considerable progress in defining the multiple mechanisms by which CD40 transduces signals, at present we have little insight into which of the CD40-associated adaptor molecules and signaling pathways must be interrupted to promote deletion of na?ve donor-reactive T cells. Furthermore, it is now well-established that memory T cells are less susceptible to the effects of CD28 and CD40 blockade. Thus, the immune history of a transplant recipient and levels of donor-cross-reactive memory T cells within the various compartments (CD4+ or CD8+ TEM or TCM) may dictate the likelihood of success or failure of attempts at tolerance induction or even immunosuppression. By understanding the functions, costimulatory and signaling requirements for recall responses mediated by the various memory T cell subsets, we may be able to tailor tolerance induction approaches to control the predominant forms of memory for specific donor- recipient combinations. Lay Summary: Transplantation represents a cure for many terminal diseases. However, transplant recipients require lifelong immunosuppression to prevent immunological rejection of the allograft. The goal of this grant proposal is to understand the signals that immune cells (T cells) require to reject transplants. With this knowledge, we will design methods to control these cells to develop methods of inducing long- lasting transplant acceptance without the need for toxic immunosuppressive regimens. ? ? PROJECT NARRATIVE Long-term graft survival rates in clinical transplantation have changed little during the last decade despite dramatic reductions in acute rejection rates, motivating the transplant community to develop tolerance induction strategies that broadly improve long-term net health outcomes. Given the central role of T cells in transplant rejection, a unifying goal of tolerance induction strategies is to selectively inactivate or delete donor-reactive T cells. Mechanistic studies proposed here will delineate the determinants of T cell fate in transplant tolerance. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI073707-01A2
Application #
7526807
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2008-06-25
Project End
2013-05-31
Budget Start
2008-06-25
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$387,188
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Laurie, Sonia J; Liu, Danya; Wagener, Maylene E et al. (2018) 2B4 Mediates Inhibition of CD8+ T Cell Responses via Attenuation of Glycolysis and Cell Division. J Immunol 201:1536-1548
Liu, Danya; Badell, I Raul; Ford, Mandy L (2018) Selective CD28 blockade attenuates CTLA-4-dependent CD8+ memory T cell effector function and prolongs graft survival. JCI Insight 3:
Morris, Anna B; Adams, Layne E; Ford, Mandy L (2018) Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses. Front Immunol 9:1810
Badell, I R; La Muraglia 2nd, G M; Liu, D et al. (2018) Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig. Am J Transplant 18:89-101
Bozeman, Alana M; Laurie, Sonia J; Haridas, Divya et al. (2018) Transplantation preferentially induces a KLRG-1lo CD127hi differentiation program in antigen-specific CD8+ T cells. Transpl Immunol 50:34-42
Kitchens, William H; Dong, Ying; Mathews, David V et al. (2017) Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection. JCI Insight 2:e90317
Laurie, Sonia J; Ford, Mandy L (2017) Epigenetic Remodeling in Exhausted T Cells: Implications for Transplantation Tolerance. Transplantation 101:894-895
Russell Knode, Lisa M; Naradikian, Martin S; Myles, Arpita et al. (2017) Age-Associated B Cells Express a Diverse Repertoire of VH and V? Genes with Somatic Hypermutation. J Immunol 198:1921-1927
Crepeau, Rebecca L; Ford, Mandy L (2017) Challenges and opportunities in targeting the CD28/CTLA-4 pathway in transplantation and autoimmunity. Expert Opin Biol Ther 17:1001-1012
Kim, Steven C; Wang, Jun; Dong, Ying et al. (2017) Alloimmunity But Not Viral Immunity Promotes Allograft Loss in a Mouse Model of Polyomavirus-Associated Allograft Injury. Transplant Direct 3:e161

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