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
Warren, E H; Deeg, H J (2013) Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies. Tissue Antigens 81:183-93
Hansen, John A; Hanash, Samir M; Tabellini, Laura et al. (2013) A novel soluble form of Tim-3 associated with severe graft-versus-host disease. Biol Blood Marrow Transplant 19:1323-30
Warren, Edus H; Matsen 4th, Frederick A; Chou, Jeffrey (2013) High-throughput sequencing of B- and T-lymphocyte antigen receptors in hematology. Blood 122:19-22
Chien, Jason W; Zhang, Xinyi Cindy; Fan, Wenhong et al. (2012) Evaluation of published single nucleotide polymorphisms associated with acute GVHD. Blood 119:5311-9
Marcondes, A Mario; Li, Xiang; Tabellini, Laura et al. (2011) Inhibition of IL-32 activation by ?-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model. Blood 118:5031-9
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
Turtle, Cameron J; Delrow, Jeff; Joslyn, Rochelle C et al. (2011) Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161(hi) CD8?? semi-invariant T cells. Blood 118:2752-62
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
Abbasi, Nissa; Vadnais, Barbara; Knutson, Jennifer A et al. (2011) Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients. J Clin Pharmacol 51:1429-38
Bhatia, Smita; Davies, Stella M; Scott Baker, K et al. (2011) NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges. Biol Blood Marrow Transplant 17:1428-35

Showing the most recent 10 out of 126 publications