Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains the primary case of transplant-related morbidity, disability and mortality, thereby limiting the use of HCT. A dominant mechanism of tolerance mediated by regulatory T cells (Tregs) has obvious therapeutic implications in preventing GVHD, as they can control GVHD and may spare GVL effects depending on their TCR specificity. In an attempt to apply Tregs in clinical HCT, current approaches are focused on adoptive transfer of polyclonal, ex vivo expanded, naturally derived Tregs (nTregs) into transplant recipients before or after HCT. However, these polyclonal nTregs are expected to have a low potency in controlling GVHD and produce non-selective immune suppression without discriminating for GVHD and GVL reactions. The current proposal is aimed at increasing the potency and specificity of Treg therapy by using alloreactive Tregs. Our long-term goal is to using alloantigen-reactive Tregs to prevent GVHD while preserving the GVL effect after HCT in humans. The objective of this proposal is to achieve this goal in pre-clinical bone marrow transplantation (BMT) models in mice. Our central hypothesis is that allo-specific Tregs are highly efficient in the prevention of GVHD, and that Tregs specific for mHAgs expressed by epithelial tissues but not by malignant cells may control GVHD while preserving GVL activity. We plan to test our hypothesis and accomplish the objective by pursuing 3 specific aims: 1) To evaluate the potency of alloantigen-specific Tregs in the prevention of GVHD;2) To determine the effect of cognized antigen-distribution in the recipient on Treg-mediated GVHD;and 3) To define the effect of allo-specific Tregs in GVHD and GVL activity. The information obtained from this proposal is expected to establish a new strategy to prevent GVHD while sparing GVL effect by conferring Tregs with certain antigen specificities and applying them to protect GVHD target tissues but not tumor from attack by donor T cells.

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. On the other hand, there is a subset of T cells, termed regulatory T cells or Tregs, which can suppress the function of other T cells. In this research project, we will confer Tregs to recognize certain antigens and apply those specialized Tregs to protect GVHD target tissues but not hematological cancers from attack by transferred donor T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118116-07
Application #
8717592
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2006-08-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29403
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Nguyen, Hung D; Chatterjee, Shilpak; Haarberg, Kelley M K et al. (2016) Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation. J Clin Invest 126:1337-52
Wu, Yongxia; Heinrichs, Jessica; Bastian, David et al. (2015) MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice. Blood 126:1314-23
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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

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