Memory T cells specific for donor antigens present a unique challenge in transplantation. While memory T cells augment host protection upon re-infection, donor-reactive memory T cells lead to robust immune responses to a transplanted organ translating into increased risk of poor allograft outcome in humans. Furthermore, memory T cells appear to be resistant to the effects of currently used graft-prolonging therapies including immunosuppressive drugs, depletional strategies and conventional costimulatory blockade. The existence of two populations of memory CD4 T cells has been proposed based on distinct migratory properties. While central memory CD4 T cells reside in secondary lymphoid organs, effector memory CD4 T cells preferentially circulate through non-lymphoid peripheral tissues and perform pathogen surveillance. The functions of these memory CD4 T cells subsets, their contribution to allograft rejection and susceptibility to the currently used immunotherapies remain unknown and need to be tested. The goal of the proposed studies is to determine how the anatomical location of lymphoid and peripheral alloreactive memory CD4 T cells affects their activation, function and susceptibility to lymphoid sequestration and to costimulatory blockade. We hypothesize that lymphoid but not peripheral memory CD4 T cells contribute to cardiac allograft rejection by providing help for the induction of donor-reactive CD8 T cells and alloantibody while peripheral memory CD4 T cells migrate into the graft and express functions mediating tissue damage. We further hypothesize that costimulatory ICOS/B7RP-1 interactions are required for helper functions of memory CD4 T cells and for the migration of both memory and newly generated effector T cells into the graft. To test this hypothesis, we propose to compare the migratory properties and functions of lymphoid versus peripheral memory CD4 T cells, to test the effect of lymphoid sequestration on the function of lymphoid versus peripheral alloreactive memory CD4 T cells, and to determine the role of costimulation through ICOS/B7RP- 1 in the re-activation, trafficking and functions of lymphoid and peripheral memory CD4 T cells. The results of the proposed experiments will provide mechanistic insights into the immunobiology of alloreactive memory CD4 T cells in allograft rejection. This information should contribute to the development of combinatorial therapies to improve allograft function and survival in sensitized patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058088-02
Application #
7209761
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$300,039
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Gorbacheva, Victoria; Fan, Ran; Wang, Xi et al. (2015) IFN-? production by memory helper T cells is required for CD40-independent alloantibody responses. J Immunol 194:1347-56
Ayasoufi, K; Yu, H; Fan, R et al. (2013) Pretransplant antithymocyte globulin has increased efficacy in controlling donor-reactive memory T cells in mice. Am J Transplant 13:589-99
Rabant, Marion; Gorbacheva, Victoria; Fan, Ran et al. (2013) CD40-independent help by memory CD4 T cells induces pathogenic alloantibody but does not lead to long-lasting humoral immunity. Am J Transplant 13:2831-2841
Gorbacheva, Victoria; Fan, Ran; Li, Xiaoxia et al. (2010) Interleukin-17 promotes early allograft inflammation. Am J Pathol 177:1265-73
Schenk, A D; Gorbacheva, V; Rabant, M et al. (2009) Effector functions of donor-reactive CD8 memory T cells are dependent on ICOS induced during division in cardiac grafts. Am J Transplant 9:64-73
Valujskikh, Anna (2008) Targeting T-cell memory: where do we stand? Curr Opin Organ Transplant 13:344-9
Schenk, A D; Nozaki, T; Rabant, M et al. (2008) Donor-reactive CD8 memory T cells infiltrate cardiac allografts within 24-h posttransplant in naive recipients. Am J Transplant 8:1652-61
Zhang, Q-W; Rabant, M; Schenk, A et al. (2008) ICOS-Dependent and -independent functions of memory CD4 T cells in allograft rejection. Am J Transplant 8:497-506