This program project grant, titled """"""""Immunobiology of Tolerance Following Allogeneic Hematopoietic Cell Transplantation"""""""" consists of 2 projects aimed at understanding the cellular immune components andinteractions that contribute to graft-versus-host disease (GVHD) and development of immunological tolerance after allogeneic hematopoietic cell transplants (HCT). The transplantation of immune competent hematopoietic cells from normal donors is invariably associated with the activation and expansion of donor T cells reacting to host histocompatibility antigen. This reaction results in a clinical syndrome known as GVHD. GVHD is a major complications of allo-HCT, and causes significant morbidity and mortality. Project 1 (""""""""Role of H-Y-specific T cell responses in GVHD"""""""") will investigate the role of H-Y specific T cell responses in male patients transplanted from a female donor (F-""""""""M). The incidence of acute and chronic GVHD and the duration of immune suppression therapy necessary for treatment of chronic GVHD (cGVHD) are significantly longer in F-""""""""M HCT recipients compared to other donor/recipient sex combinations. Project 1 will track anti-H-Y T cells in patients, and study the frequency and activity of these cells in different phases of active and resolving cGVHD, and ask if long-term tolerance after F->M HCT is associated with the deletion, inactivation or suppression of these responses. The goal of Project 2 (""""""""Regulatory T Cells in GVHD"""""""") is to identify changes in helper, effector and regulatory T cells that are associated with cGVHD and the development of tolerance. The studies proposed will test the hypothesis that the development of tolerance is an active process that can succeed when the activity of regulatory T cells and molecules exceeds and/or suppresses the activity of host-specific responder and effector T cells. The approach will utilize DMA array technology for the assessment of global gene expression to identify the transcriptional profiles of T lymphocytes and selected subsets from HCT patients that are associated with the active chronic GVHD and those associated with the development of tolerance. Critical clinical resources, blood samples and clinical outcome data, provided to projects 1 and 2 by the Core B shared clinical resource. Collaboration between project 1, project 2 and Core B will provide the essential opportunity and synergy necessary to broadly characterize the activation pathways, cellular components and regulatory factors that are responsible for 1) sustaining alloreactivity in patients with active cGVHD, and 2) the mechanism(s) responsible for the development of immunological tolerance. PROJECT 1: H-Y-Specific T Cell Responses in Chronic GvHD Warren, Edus Houston PROJECT 1 DESCRIPTION (provided by applicant): 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-Y antigens - which are not possible in other donor-recipient combinations. Thus, the excess GVHD burden borne by F-""""""""M HCT 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-""""""""M HCT, and that long-term graft-host tolerance after F-""""""""M HCT 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-""""""""M HCT is associated with deletion, inactivation, or suppression of H-Y-specific T cells.

Public Health Relevance

Insight gained from the study of the cellular changes occurring in active and resolving cGVHD may lead to better methods for disease monitoring and guiding the use of 1ST, and suggest the rationale and innovative strategies for new interventions aimed at facilitating the induction of immunological tolerance. The acceleration of durable immune tolerance in allo-HCT recipients will address an emerging public health problem by improving the quality of life and health of transplant survivors afflicted with GVHD.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-SV-I (J2))
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Nabavi, Nasrin N
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Fred Hutchinson Cancer Research Center
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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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