Graft-versus-host disease (GVHD) is the most serious and common long-term complication of allogeneic hematopoietic cell transplantation, and is mediated by recognition of recipient minor or major histocompatibility antigens by donor T cells. Male recipients of hematopoietic cell grafts from MHC-matched female donors (F->M HCT) provide a unique opportunity to study the contribution of specific donor T cell responses to the development and persistence of graft-versus-host disease (GVHD). F-?M HCT is characterized clinically by a higher incidence of both acute and historically defined chronic GVHD, as well as a longer mean duration of treatment for GVHD, than that seen in any other donor-recipient sex combination. At the cellular level, F-?M transplants are characterized by the occurrence of donor (female) T cell responses against protein products of the Y chromosome - termed H-Yantigens - which are not possible in other donor-recipient combinations. Thus, the excess GVHD burden borne by F-?MHCT recipients may in part be attributable to female T cell responses against H-Y antigens. The studies in this project will test the hypothesis that donor T cell responses against H-Y antigens contribute to GVHD among day +100 survivors after F-?MHCT, and that long-term graft-host tolerance after F-?MHCT will be associated with deletion, inactivation, or suppression of these responses. The results of these studies should provide insight into the mechanisms responsible for the development and persistence of GVHD, and will thereby provide the rationale and direction for future interventions aimed at overcoming alloreactivity and facilitating donor-host tolerance.
The specific aims of this project are: (1) To define the specificity of the CD8+ and CD4+ effector T cell response to H-Y antigens in male recipients of hematopoietic cell grafts from MHC-matched female donors. (2) To determine whether the presence of H-Y-specific effector T cells in recipients of F-?M HCT correlates with the presence of GVHD beyond day +100 after allogeneic HCT. (3) To determine whether the development of graft-host tolerance after F-?MHCTis associated with deletion, inactivation, or suppression of H-Y-specific T cells.

Public Health Relevance

The effectiveness of allogeneic hematopoietic cell transplantation for the treatment of blood diseases is significantly limited by a complication called graft-versus-host disease (GVHD). The studies described in this Project will investigate whether donor immune responses specifically recognizing the recipient are associated with the development of GVHD. These studies could potentially lead to improved strategies for preventing or treating GVHD in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI033484-18
Application #
8508158
Study Section
Special Emphasis Panel (ZAI1-SV-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
18
Fiscal Year
2013
Total Cost
$453,346
Indirect Cost
$195,763
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Nakasone, Hideki; Tian, Lu; Sahaf, Bita et al. (2015) Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans. Blood 125:3193-201
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Warren, Edus H; Zhang, Xinyi Cindy; Li, Shuying et al. (2012) Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT. Blood 120:2796-806
Grogan, Bryan M; Tabellini, Laura; Storer, Barry et al. (2011) Activation and expansion of CD8(+) T effector cells in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant 17:1121-32
Chronic GVHD Consortium (2011) Rationale and design of the chronic GVHD cohort study: improving outcomes assessment in chronic GVHD. Biol Blood Marrow Transplant 17:1114-20

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