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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049466-11
Application #
7860325
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2001-02-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2013-05-31
Support Year
11
Fiscal Year
2010
Total Cost
$329,027
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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:
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
Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843
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
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
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

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