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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI049466-12A1
Application #
8773885
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2001-02-01
Project End
2019-05-30
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$383,071
Indirect Cost
$133,071
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Tieu, Roger; Lakkis, Fadi G; Oberbarnscheidt, Martin H (2016) Getting Down and Dirty: Germ-Exposed Laboratory Mice as a Model of the Adult Human Immune System. Transplantation 100:2490-2491
Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843
Zhang, Qianqian; Dai, Hehua; Yatim, Karim M et al. (2016) CD8+ Effector T Cell Migration to Pancreatic Islet Grafts Is Dependent on Cognate Antigen Presentation by Donor Graft Cells. J Immunol 197:1471-6
Yatim, Karim M; Lakkis, Fadi G (2015) A brief journey through the immune system. Clin J Am Soc Nephrol 10:1274-81
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
Macedo, Camila; Walters, John T; Orkis, Elizabeth A et al. (2012) Long-term effects of alemtuzumab on regulatory and memory T-cell subsets in kidney transplantation. Transplantation 93:813-21
Oberbarnscheidt, Martin H; Walch, Jeffrey M; Li, Qi et al. (2011) Memory T cells migrate to and reject vascularized cardiac allografts independent of the chemokine receptor CXCR3. Transplantation 91:827-32

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