It is well established that various organ allografts differ in their immunogenicity and susceptibility to immunosuppression-mediated acceptance. Lungs are among the most immunogenic organs with particularly high rates of graft rejection leading to poor long-term outcomes. Immunologic requirements for lung allograft rejection and acceptance remain poorly understood. Our laboratory has made the surprising observation that, in stark contrast to other organs, the presence of CD8+ (specifically CD8+PD-1+) rather than CD4+ T cells, is critical for co-stimulatory blockade-mediated acceptance of lung allografts. The overall goal of this application is to perform mechanistic studies in the mouse vascularized orthotopic lung transplantation model to investigate the role of CD8+ T cells in down-regulating alloimmune responses deleterious to graft survival. In the first aim we will define mechanisms of regulatory CD8+ T cell generation. In the second aim we will investigate the role of antigen presenting cells in CD8+ T cell-mediated lung allograft acceptance. In the third aim we will characterize how clinically relevant innate immune stimulation through Toll-like receptor 2 (TLR2) prevents CD8+ T cell-mediated lung allograft acceptance.

Public Health Relevance

Patients that receive a lung transplant have worse long-term survival than other organ recipients. This grant application explores the immunologic basis for lung transplant acceptance. Results from this application could improve the long-term survival of lung transplant recipients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL113931-01A1
Application #
8372581
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (04))
Program Officer
Eu, Jerry Pc
Project Start
2012-08-15
Project End
2016-05-31
Budget Start
2012-08-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$380,000
Indirect Cost
$130,000
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Krupnick, Alexander Sasha; Lin, Xue; Li, Wenjun et al. (2014) Central memory CD8+ T lymphocytes mediate lung allograft acceptance. J Clin Invest 124:1130-43
Spahn, Jessica H; Kreisel, Daniel (2014) Monocytes in sterile inflammation: recruitment and functional consequences. Arch Immunol Ther Exp (Warsz) 62:187-94
Spahn, Jessica H; Li, Wenjun; Kreisel, Daniel (2014) Innate immune cells in transplantation. Curr Opin Organ Transplant 19:14-9
Chen, D L; Wang, X; Yamamoto, S et al. (2013) Increased T cell glucose uptake reflects acute rejection in lung grafts. Am J Transplant 13:2540-9
Shen, Hua; Kreisel, Daniel; Goldstein, Daniel Robert (2013) Processes of sterile inflammation. J Immunol 191:2857-63