Long-lived memory T cells that recognize donor alloantigens may jeopardize the survival of life-saving organ transplants. We propose here that allospecific memory T cells are an important impediment to achieving allograft acceptance because of their unique abilities to persist in the recipient and to respond to donor antigens under much less stringent conditions than those required for naive T cells. To test this hypothesis, we plan to explore the fundamental mechanisms that govern the long-term maintenance and the recall response of allospecific memory T cells in the mouse and to investigate whether targeting one or more of these mechanisms promotes allograft acceptance.
The specific aims are: (1) To investigate the anatomic requirements for the maintenance and recall of allospecific memory T cells. Specifically, we will study the role of secondary lymphoid organs; (2) To investigate the functional requirements for the maintenance and recall of allospecific memory T cells. Specifically, we will study the roles of IL-15 and T cell costimulation; and (3) To investigate whether suppressing allospecific T cell memory by targeting IL-15 or the common cytokine receptor gamma-chain facilitates allograft acceptance and tolerance induction. Mutant, gene-knockout, and T cell receptor transgenic mouse strains will be used to track memory T cells and study their biology. The vascularized heterotopic heart allograft model will be used to investigate the role of T cell memory in organ transplantation. Understanding the fundamental mechanisms that govern the maintenance and recall of alloreactive memory T cells could provide insights into devising clinical strategies for achieving permanent allograft acceptance and transplantation tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049466-05
Application #
6698860
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
2001-07-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
5
Fiscal Year
2004
Total Cost
$327,000
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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:
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
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
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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