A critical step in the rejection process is the migration of anti-donor effector or memory T cells to the transplanted organ. Interrupting this step should prevent or weaken rejection, but safe clinical strategies to do so are not available. During the previous funding cycle we identified a key pathway by which anti-donor effector and memory T cells migrate to vascularized organ allografts. We demonstrated that donor antigen, presented by either graft endothelial cells or bone marrow-derived antigen presenting cells, is necessary and sufficient for the firm adhesion and trans-endothelial migration of anti-donor T cells. Signaling via G?i-coupled chemokine receptors was not required. In this grant renewal, we propose to investigate two novel aspects of antigen-driven T cell migration: (1) the role of graft antigen presenting cells, and (2) the role of TCR-triggered signaling pathways that cause T cell adhesion and transmigration. To accomplish these aims we will utilize heart and kidney mouse transplantation models, gene knockout mice in which antigen presentation or key signaling pathways are disrupted, and intravital imaging techniques that track migrating T cells in real time. The proposed studies are innovative and significant because they represent a shift from the classical, chemokine-dependent migration paradigm and provide novel opportunities for interrupting activated T cell migration in a specific and safe manner.

Public Health Relevance

Despite significant improvement in short-term survival of organ transplants, rejection of transplanted organs remains a significant clinical problem. Identifying the mechanisms by which harmful immune cells, known as memory or effector T lymphocytes, enter and reject transplanted organs could lead to novel therapies that enhance long-term graft and patient survival after transplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
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University of Pittsburgh
Schools of Medicine
United States
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Hughes, Andrew D; Lakkis, Fadi G; Oberbarnscheidt, Martin H (2018) Four-Dimensional Imaging of T Cells in Kidney Transplant Rejection. J Am Soc Nephrol 29:1596-1600
Dai, Hehua; Friday, Andrew J; Abou-Daya, Khodor I et al. (2017) Donor SIRP? polymorphism modulates the innate immune response to allogeneic grafts. Sci Immunol 2:
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Zhuang, Quan; Liu, Quan; Divito, Sherrie J et al. (2016) Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. Nat Commun 7:12623
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Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843
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Zhuang, Quan; Lakkis, Fadi G (2015) Dendritic cells and innate immunity in kidney transplantation. Kidney Int 87:712-8
Walch, Jeffrey M; Lakkis, Fadi G (2014) T-cell migration to vascularized organ allografts. Curr Opin Organ Transplant 19:28-32
Walch, Jeffrey M; Zeng, Qiang; Li, Qi et al. (2013) Cognate antigen directs CD8+ T cell migration to vascularized transplants. J Clin Invest 123:2663-71

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