New treatments are needed for graft-vs-host disease (GVHD), the most serious complication of allogeneic bone marrow transplantation (BMT). Current pharmacologic agents for GVHD prevention and treatment primarily target one of the essential effectors for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Extensive experimental data developed by this PPG support the conduct of translational clinical trials to test agents that act upon this additional GVHD mechanism. We have demonstrated that APC function can be modulated by histone deacetylase inhibitors (HDACi) and in preliminary data we published, that the HDACi, suberoylanalide hydroxamic acid (SAHA), also known as vorinostat, regulates experimental GVHD. In this project will perform a unique clinical trial of this drug for GVHD prevention. A further advance in GVHD, the individualization of treatment, is presently hampered because GVHD can not be predicted precisely, the diagnosis is often hard to establish, and patients whose GVHD is likely to be resistant to standard therapy can not be identified. One of the first GVHD biomarker panels with predictive and diagnostic power was identified in work supported by this projecL We have recently identified multiple additional biomarkers using a large-scale proteomics discovery approach. In this project we will integrate newly discovered biomarkers with those already validated to create informative and clinically useful panels for allogeneic BMT patients.
The Specific Aims are: 1. To conduct a Phase II trial using the HDACi, vorinostat in addition to standard immunosuppression to prevent GVHD in related donor reduced intensity transplantation 2. To develop biomarkers specific to GVHD target organs (skin and Gl tract). 3. To validate eight newly discovered candidate proteins as biomarkers for the diagnosis, prognosis and prediction of systemic acute GVHD. 4. To optimize predictive, diagnostic, and prognostic biomarker panels using validated combinations of target organ specific and systemic biomarkers and to analyze their value in new clinical trials.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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University of Michigan Ann Arbor
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Holtan, Shernan G; DeFor, Todd E; Panoskaltsis-Mortari, Angela et al. (2018) Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. Blood Adv 2:1882-1888
Ortiz-Velez, Laura; Ortiz-Villalobos, Javiera; Schulman, Abby et al. (2018) Genome alterations associated with improved transformation efficiency in Lactobacillus reuteri. Microb Cell Fact 17:138
Ferrara, James L M; Chaudhry, Mohammed S (2018) GVHD: biology matters. Hematology Am Soc Hematol Educ Program 2018:221-227
Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol et al. (2018) MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood 131:2846-2855
Naymagon, Steven; Naymagon, Leonard; Wong, Serre-Yu et al. (2017) Acute graft-versus-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol 14:711-726
Hartwell, Matthew J; Ă–zbek, Umut; Holler, Ernst et al. (2017) An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight 2:e89798
Stickel, N; Hanke, K; Marschner, D et al. (2017) MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31:2732-2741
Ferrara, James Lm; Smith, Christopher M; Sheets, Julia et al. (2017) Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. J Clin Invest 127:2441-2451
Miller, Holly K; Braun, Thomas M; Stillwell, Terri et al. (2017) Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:522-528
Holtan, Shernan G; Khera, Nandita; Levine, John E et al. (2016) Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors. Blood 128:2350-2358

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