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
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