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 #
5R01CA169116-03
Application #
8628807
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2013-03-05
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$304,946
Indirect Cost
$89,105
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
Schutt, Steven D; Wu, Yongxia; Tang, Chih-Hang Anthony et al. (2018) Inhibition of the IRE-1?/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice. Blood Adv 2:414-427
Iamsawat, Supinya; Daenthanasanmak, Anusara; Voss, Jessica Heinrichs et al. (2018) Stabilization of Foxp3 by Targeting JAK2 Enhances Efficacy of CD8 Induced Regulatory T Cells in the Prevention of Graft-versus-Host Disease. J Immunol 201:2812-2823
Wu, Yongxia; Schutt, Steven; Paz, Katelyn et al. (2018) MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood 131:1974-1986
Nguyen, Hung D; Kuril, Sandeepkumar; Bastian, David et al. (2018) T-Cell Metabolism in Hematopoietic Cell Transplantation. Front Immunol 9:176
Betts, Brian C; Bastian, David; Iamsawat, Supinya et al. (2018) Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc Natl Acad Sci U S A 115:1582-1587
Daenthanasanmak, Anusara; Wu, Yongxia; Iamsawat, Supinya et al. (2018) PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity. J Clin Invest 128:2787-2801
Zhang, Mengmeng; Wu, Yongxia; Bastian, David et al. (2018) Inducible T-Cell Co-Stimulator Impacts Chronic Graft-Versus-Host Disease by Regulating Both Pathogenic and Regulatory T Cells. Front Immunol 9:1461
Woods, David M; Woan, Karrune V; Cheng, Fengdong et al. (2017) T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 130:146-155
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

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