There is a critical need to delineate pathobiological correlates of chronic GVHD (cGVHD) and to develop new strategies to prevent and treat cGVHD. These strategies must control both acute and cGVHD, minimize risk of opportunistic infection, and maintain GVL. To do this our understanding of GVHD pathobiology must be broadened. For instance, recognizing that antibody responses to HY antigens are important in cGVHD physiology underscores the need to develop more tools to identify somatic mHA as a step toward the integration of mHA and genetic determinates of immune reactivity. Thus, a coordinated effort combining 1) clinical trials, 2) the development of a relevant animal model to study pathobiology and in which new therapies can be tested, and 3) further elucidation of the immunologic basis of human cGVHD is essential. Project 1 will develop strategies to prevent cGVHD by targeting B cells and regulatory T cells. The first strategy is a novel anti-CD20 prophylaxis regimen, while the second strategy will allow the expansion of regulatory T cells by eliminating calineurin inhibitors from GVHD prophylaxis.
The second aim i s to prevent hepatic VOD by adjusting the therapy to avoid hepatic injury or by preventing vascular complications using the novel agent, defibrotide. Finally, two complementary approaches to treat steroid-resistant GVHD will be assessed: 1) coordinate inhibition of both B and T cells, and 2) expansion of regulatory T cells with ultra low dose IL-2. Project 2 will expand its studies of a new, clinically relevant mouse model of cGVHD. This will allow the pathobiology of cGVHD to be explored in the first aim, while the second aim models therapeutic approaches that can be clinically assessed in Project 1. Project 3 will continue its work in minor histocompatitbility antigen discovery moving now from sex-chromosome associated proteins to more generalized antigen discovery. This project will also develop GVHD-specific biomarkers that will allow more precise prediction of who will develop cGVHD as well as allow the therapy to be closely monitored to reduce toxicity. Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective.

Public Health Relevance

Hematopoietic stem cell transplantation is the only curative therapy for many patients with blood disorders. Worldwide, >16,000 allogeneic HSCT are performed yearly. Realization of the full potential of HSCT requires elimination of HSCT related complications -particularly acute and cGVHD. Traditional means to control GVHD, particularly cGVHD are only partially effective. This Program Project will focus on increasinng our understanding of cGVHD developing novel, more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA142106-10
Application #
8468127
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Merritt, William D
Project Start
2009-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$1,755,269
Indirect Cost
$602,037
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn et al. (2018) A critical role for donor-derived IL-22 in cutaneous chronic GVHD. Am J Transplant 18:810-820
Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57
Koreth, John; Kim, Haesook T; Lange, Paulina B et al. (2018) Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. Haematologica 103:522-530
Chen, Liying; Alexe, Gabriela; Dharia, Neekesh V et al. (2018) CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2. J Clin Invest 128:446-462
Kolupaev, Oleg V; Dant, Trisha A; Bommiasamy, Hemamalini et al. (2018) Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD. Blood Adv 2:2307-2319
Du, Jing; Flynn, Ryan; Paz, Katelyn et al. (2018) Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients. Blood 131:1743-1754
Zeiser, Robert; Sarantopoulos, Stefanie; Blazar, Bruce R (2018) B-cell targeting in chronic graft-versus-host disease. Blood 131:1399-1405
Blazar, Bruce R; MacDonald, Kelli P A; Hill, Geoffrey R (2018) Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood 131:2651-2660
Lu, Yunjie; Gao, Ji; Zhang, Shaopeng et al. (2018) miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg). Cell Death Dis 9:290

Showing the most recent 10 out of 207 publications