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
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
| 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 |
| 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 |
| 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; Özbek, 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 |
| Renteria, Anne S; Levine, John E; Ferrara, James L M (2016) Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease. Expert Opin Orphan Drugs 4:469-484 |
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