A cardinal feature of the adaptive immune response is its ability to generate long-lived populations of memory T lymphocytes. Memory T cells that recognize donor allo-antigens jeopardize the survival of life- saving organ transplants. Therefore, exploring the biology of memory T cells is essential for developing better anti-rejection therapies. In the previous funding cycle (2001 - 2006), we investigated the mechanisms that govern the maintenance and recall of memory T cells in mouse models of heart, skin, and islet transplantation. A principal finding was that memory T cells generated in response to allo-stimulation migrate widely to non-lymphoid tissues where they are maintained long-term and are activated upon encountering donor antigens. Unlike naive T cells, whose migration and activation were largely restricted to secondary lymphoid tissues, allo-reactive memory T cells homed directly to the graft and mediated its rejection. Therefore, the goal of this application is to investigate the mechanisms that govern the migration of memory T cells to a transplanted organ.
The specific aims are: (1) To investigate the mechanisms which govern the migration of allo-reactive memory T cells to vascularized cardiac allografts during acute inflammation - we will examine the roles of the chemokine receptor CXCR3 and the adhesion molecule a4|31 integrin (VLA-4) expressed on memory T cells. (2) To investigate the mechanisms which govern the migration of allo-reactive memory T cells to vascularized cardiac allografts during chronic inflammation - we will examine the roles of the chemokine receptor CCR7 and the adhesion molecule L-selectin (CD62L) expressed on memory T cells. Although both CD4 and CD8 memory T cells mediate allograft rejection, we will concentrate on studying the CD8 memory population. Congenic markers will be used to track adoptively transferred CD8 memory T cells. Gene knockout mice and monoclonal antibodies will be used to examine the roles of chemokine receptors and adhesion molecules. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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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
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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
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

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