Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains a significant source of transplant-related mortality and morbidity. Donor T cells in the stem cell grafts recognize widely distributed mismatched major (MHC) and/or minor histocompatibility antigens (miHAg), undergo robust expansion and functional differentiation within recipients, and can cause severe damage to host tissues. Classically, Th1 cells are believed to play a critical role in the induction of GVHD;although recently we and others showed that Th17 cells can also cause GVHD. By targeting Th1 and Th17 specific transcription factors (T-bet and ROR?t), we demonstrated 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. Targeting transcription factors was used to prove the principle, but essentially lacks translational potential. In our current application, e will extend these findings and evaluate clinically applicable approaches to target T cell differentiation. Specifically, we hypothesize that targeting p40, IL-12R?1 or their downstream signaling events will disrupt Th1/Th17 differentiation and thus control GVHD. p40 is a common subunit that pairs with p35 or p19 to form IL-12 or IL-23;IL-12R?1 is a shared subunit for IL-12 and IL-23 receptors. The rationale to support this hypothesis is that IL-12 signal is essential for Th1 differentiation whereas IL-23 signal is critical for the maintenance of Th17 subset, and either subset can cause acute GVHD. Thus, blocking p40, IL-12R?1 or their downstream signaling events may be sufficient to disrupt Th1 and Th17 differentiation leading to GVHD prevention.
Specific Aims are: 1) To prevent GVHD by targeting p40;2) To control GVHD by targeting IL-12R?1;and 3) To characterize and target downstream signaling events of IL-12R?1. These studies will validate IL-12/23 pathway as a therapeutic target for GVHD prevention at the cytokine, receptor and downstream signaling level. Because clinical grade antibodies for neutralizing p40 or blocking IL-12R?1 subunit and small molecular inhibitor for IL-12/23R signaling are currently available, the information learned from these pre-clinical studies can be readily translated into clinical application.

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. Our recent research demonstrates that each of two T cell subsets is sufficient to cause GVHD, and thus blocking both subsets is necessary to prevent GVHD. Because existing evidence shows that a cytokine p40 plays a critical role in the generation of these 2 T cell subsets. In this research project, we will test the hypothesis that inhibition of p40 effects will interrupt T cells becoming either of these 2 subsets and prevent GVHD development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA169116-01A1
Application #
8446757
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2013-03-05
Project End
2013-05-12
Budget Start
2013-03-05
Budget End
2013-05-12
Support Year
1
Fiscal Year
2013
Total Cost
$133,678
Indirect Cost
$54,344
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Heinrichs, Jessica; Bastian, David; Veerapathran, Anandharaman et al. (2016) Regulatory T-Cell Therapy for Graft-versus-host Disease. J Immunol Res Ther 1:1-14
Fu, Jianing; Wu, Yongxia; Nguyen, Hung et al. (2016) T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice. J Immunol 196:3168-79
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
Li, Jun; Heinrichs, Jessica; Haarberg, Kelley et al. (2015) HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease. J Immunol 195:717-25
Wu, Yongxia; Bastian, David; Schutt, Steven et al. (2015) Essential Role of Interleukin-12/23p40 in the Development of Graft-versus-Host Disease in Mice. Biol Blood Marrow Transplant 21:1195-204
Schutt, Steven D; Fu, Jianing; Nguyen, Hung et al. (2015) Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice. PLoS One 10:e0137641
Fu, Jianing; Wang, Dapeng; Yu, Yu et al. (2015) T-bet is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function. J Immunol 194:388-97
Fu, Jianing; Heinrichs, Jessica; Yu, Xue-Zhong (2014) Helper T-cell differentiation in graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Arch Immunol Ther Exp (Warsz) 62:277-301
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

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