Graft versus host disease (GVHD) remains a major and intractable complication of allogeneic bone marrow transplantation (BMT). Two major effector mechanisms of GVHD are inflammatory cytokines and activated lymphocytes. In this new project, we explore a novel bioenergetic strategy to eliminate lymphocyte effectors in GHVD. Preliminary studies show that during GVHD lymphocytes that are chronically activated by histocompatibility antigens of the host have abnormal bioenergetic profiles. GVHD effector lymphocytes have low levels of glycolysis compared to acutely activated lymphocytes and show signs of mitochondrial stress, including elevated levels of reactive oxygen species (ROS). Effector lymphocytes can be selectively induced to apoptose with a cytotoxic benzodiazepine, Bz-423, that inhibits a mitochondrial ATPase. Administration of Bz-423 beginning seven days after induction of GVHD in two separate mouse models reverses GVHD by all clinical and histologic parameters and significantly improves long term survival. This project will investigate the molecular mechanisms of action of Bz-423 and explore its effects on the bioenergetic profiles of critical cellular subpopulations during hematologic and immunologic reconstitution after BMT in these animal models. This project will also define the bioenergetic profiles of leukocyte subpopulations in clinical samples from human allogeneic BMT recipients.
Our Specific Aims are: 1. To analyze Bz-423 and its analogs in eliminating effector lymphocytes during GVHD 2. To determine the effects of Bz-423 on immunologic reconstitution 3. To analyze the impact of Bz-423 on key myeloid populations following BMT 4. To analyze the bioenergetic profiles of human PBMC populations after allogeneic BMT

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)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
Curry Jr, William T; Gorrepati, Ramana; Piesche, Matthias et al. (2016) Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma. Clin Cancer Res 22:2885-96
Kitko, Carrie L; Braun, Thomas; Couriel, Daniel R et al. (2016) Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial. Biol Blood Marrow Transplant 22:862-8
Harris, Andrew C; Young, Rachel; Devine, Steven et al. (2016) International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 22:4-10
Renteria, Anne S; Levine, John E; Ferrara, James L (2016) Development of a biomarker scoring system for use in graft-versus-host disease. Biomark Med 10:793-5
Abedin, Sameem; Yanik, Gregory A; Braun, Thomas et al. (2015) Predictive value of bronchiolitis obliterans syndrome stage 0p in chronic graft-versus-host disease of the lung. Biol Blood Marrow Transplant 21:1127-31
Chiaranunt, Pailin; Ferrara, James L M; Byersdorfer, Craig A (2015) Rethinking the paradigm: How comparative studies on fatty acid oxidation inform our understanding of T cell metabolism. Mol Immunol 68:564-74
Levine, John E; Braun, Thomas M; Harris, Andrew C et al. (2015) A PROGNOSTIC SCORE FOR ACUTE GRAFT-VERSUS-HOST DISEASE BASED ON BIOMARKERS: A MULTICENTER STUDY. Lancet Haematol 2:e21-e29
Levine, John E; Braun, Thomas M; Harris, Andrew C et al. (2015) A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2:e21-9
Tkachev, Victor; Goodell, Stefanie; Opipari, Anthony W et al. (2015) Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol 194:5789-800
Levine, John E; Hogan, William J; Harris, Andrew C et al. (2014) Improved accuracy of acute graft-versus-host disease staging among multiple centers. Best Pract Res Clin Haematol 27:283-7

Showing the most recent 10 out of 219 publications