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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-J (04))
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Eu, Jerry Pc
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Washington University
Schools of Medicine
Saint Louis
United States
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Li, Wenjun; Luehmann, Hannah P; Hsiao, Hsi-Min et al. (2018) Visualization of Monocytic Cells in Regressing Atherosclerotic Plaques by Intravital 2-Photon and Positron Emission Tomography-Based Imaging-Brief Report. Arterioscler Thromb Vasc Biol 38:1030-1036
Takahashi, T; Hsiao, H M; Tanaka, S et al. (2018) PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction. Am J Transplant 18:216-225
Hsiao, Hsi-Min; Scozzi, Davide; Gauthier, Jason M et al. (2017) Mechanisms of graft rejection after lung transplantation. Curr Opin Organ Transplant 22:29-35
Gauthier, Jason M; Li, Wenjun; Hsiao, Hsi-Min et al. (2017) Mechanisms of Graft Rejection and Immune Regulation after Lung Transplant. Ann Am Thorac Soc 14:S216-S219
Onyema, Oscar Okwudiri; Guo, Yizhan; Wang, Qing et al. (2017) Eosinophils promote inducible NOS-mediated lung allograft acceptance. JCI Insight 2:
Gauthier, Jason M; Hachem, Ramsey R; Kreisel, Daniel (2016) Update on Chronic Lung Allograft Dysfunction. Curr Transplant Rep 3:185-191
Hsiao, H-M; Li, W; Gelman, A E et al. (2016) The Role of Lymphoid Neogenesis in Allografts. Am J Transplant 16:1079-85
Li, Wenjun; Hsiao, Hsi-Min; Higashikubo, Ryuji et al. (2016) Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling. JCI Insight 1:
Liu, Y; Li, W; Luehmann, H P et al. (2016) Noninvasive Imaging of CCR2+ Cells in Ischemia-Reperfusion Injury After Lung Transplantation. Am J Transplant 16:3016-3023
Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C et al. (2015) DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 194:4039-48

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