Hematopoietic cell transplantation (HCT) offers great promise for the treatment of a variety of malignant and non-malignant hematopoietic diseases, but graft-versus-host disease (GVHD) remains the major obstacle for success of HCT as it leads to high incidence of morbidity and mortality. Donor T cells that are included in the stem cell inoculum and recognize recipient alloantigens are the major cause of GVHD. When used as immunotherapy for hematopoietic malignances (e.g. leukemia), the therapeutic potential of allogeneic HCT relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. T cell is a multi-potential precursor with defined antigen recognition specificity but substantial plasticity for differentiation into distinct lineages according to the signals encountered. Naive T helper cells (Th) can differentiate into four different subsets: Th1, Th2, Th17 and T regulatory cells, but the contributions of these activated T cell subsets to GVHD development and GVL effect remains unclear. Lacking the knowledge precludes us from selectively targeting the pathogenic subset or its associated cytokines for controlling GVHD while maintaining GVL effect. The goal of this project is to understand the contribution of Th1/Th17 differentiation, the cytokines that induce T-cell differentiation, and the cytokines produced by Th1/Th17 cells to GVHD development and GVL activity. The central hypothesis is that both the Th1 and Th17 subsets contribute to GVHD development but either lineage alone is sufficient to induce GVHD, and thus both lineages must to be blocked in order to control GVHD. This proposal will systematically and stringently addresses the contribution of Th1 and Th17 differentiation in GVHD by targeting lineage-specific transcription factor(s) for proof-of-concept (Aim 1). In parallel, more translational studies will be conducted to understand the role of Th17 priming and effector cytokine in GVHD and the reciprocal regulation of Th1/Th17 lineages in alloresponse in vivo (Aim 2). Because allogeneic HCT is primarily utilized to treat hematopoietic malignances, it is critically important to evaluate the contribution of different subset of T cells to GVL effect. We will evaluate the role of Th1/Th17 subsets in GVL effect along with GVHD development by using MHC-mismatched and -matched BMT models with leukemia or lymphoma. Furthermore, clinically applicable interventions will be used to block Th1/Th17 differentiation in these studies (Aim 3). The information learned from this research project will provide the rationale and means to regulate T-cell differentiation toward our ultimate goal of preventing GVHD while sparing GVL activity.

Public Health Relevance

Hematopoietic cell transplantation (HCT) offers great promise for the treatment of a variety of diseases, including cancer. However, this therapeutic procedure has a major complication, termed graft-versus-host disease (GVHD), which is induced by donor T cells that recognize disparate antigens and cause tissue injuries in the recipient. Donor T cells, on the other hand, can also bring beneficial effects to the patient, including anti- tumor and anti-infection. In the current research, we will study how donor T cells respond to antigens in recipient normal tissues and in tumor cells. Results may provide the rationale and means to regulate T-cell activation toward our ultimate goal of preventing GVHD while sparing those beneficial effects mediated by donor T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA143812-04
Application #
8458597
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2010-06-01
Project End
2014-04-30
Budget Start
2013-06-14
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$293,729
Indirect Cost
$97,145
Name
Medical University of South Carolina
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Betts, Brian C; Veerapathran, Anandharaman; Pidala, Joseph et al. (2014) STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity. J Leukoc Biol 95:205-13
Wang, Dapeng; Yu, Yu; Haarberg, Kelley et al. (2013) Dynamic change and impact of myeloid-derived suppressor cells in allogeneic bone marrow transplantation in mice. Biol Blood Marrow Transplant 19:692-702
Li, Jun; Heinrichs, Jessica; Leconte, Julien et al. (2013) Phosphatidylinositol 3-kinase-independent signaling pathways contribute to ICOS-mediated T cell costimulation in acute graft-versus-host disease in mice. J Immunol 191:200-7
Yu, Yu; Cho, Hyun-Ii; Wang, Dapeng et al. (2013) Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms. J Immunol 190:1873-81
Haarberg, Kelley M K; Li, Jun; Heinrichs, Jessica et al. (2013) Pharmacologic inhibition of PKC? and PKC? prevents GVHD while preserving GVL activity in mice. Blood 122:2500-11
Yu, Yu; Wang, Dapeng; Kaosaard, Kane et al. (2013) c-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice. Eur J Immunol 43:2327-37
Yu, Yu; Wang, Dapeng; Liu, Chen et al. (2011) Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and ROR?t in mice. Blood 118:5011-20
Semple, Kenrick; Yu, Yu; Wang, Dapeng et al. (2011) Efficient and selective prevention of GVHD by antigen-specific induced Tregs via linked-suppression in mice. Biol Blood Marrow Transplant 17:309-18
Semple, Kenrick; Nguyen, Antony; Yu, Yu et al. (2011) Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling. Blood 117:3096-103

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