Every year 8,000 allogeneic hematopoietic stem cell transplants (aHSCT) are performed in the United States alone. This procedure is currently the only curative treatment for hematological malignancies. Chronic graft-versus-host disease (cGVHD) is a long-term immune complication following aHSCT and a leading cause of non-relapse mortality. The standard of clinical management of broad immunosuppression by corticosteroids has been largely unchanged in several decades. With many patients exhibiting steroid-resistant or steroid-refractory disease, newer therapies are needed. Murine modeling of cGVHD has allowed for greater understanding of disease pathogenesis and for testing of novel therapeutic agents. Donor T-cells, responsible for the initiation disease, require specific signaling pathways and changes in their metabolic profile to sustain their survival, proliferation and differentiation. In cGVHD, activated donor CD4+ T-cells differentiate into pathogenic, cytokine producing Th17 cells, which contribute to inflammation. They also develop into T follicular helper cells, a specialized cell subset that provide necessary signaling to germinal center B cells to promote their differentiation into antibody-producing plasma cells. Immunoglobulin deposition along with abnormal tissue repair activates pro-fibrotic pathways, leading to collagen buildup in target organs in cGVHD. In this study, we sought to explore therapeutic approaches that would decrease Tfh and Th17 cells, leading to reduction in cGVHD disease burden. First, we demonstrate that targeting pathways necessary for T-cell activation are effective for reduction of cGVHD. PI3Kδ, which is downstream of TCR, co-stimulatory and cytokine signals, is necessary for cGVHD and inhibition can reduce cGHVD in BO and sclerodermatous models. We also show that metabolic pathways for glycolysis, fatty acid synthesis and glutaminolysis are all required by donor T-cells for development of cGVHD. Targeting Glutaminolysis for pharmacologic inhibition in particular was found to be an effective therapeutic for cGVHD. We determined that targeting the germinal center directly via BCL6 inhibition reduces cGVHD in GC-mediated murine models. Finally, we demonstrate the importance of Th17-prone cell subsets in human and murine cGVHD. Take together; these results identify pathways required for development of cGVHD as well as potential novel therapeutic targets.
University of Minnesota Ph.D. dissertation.July 2018. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Bruce Blazar. 1 computer file (PDF); xii, 163 pages.
Signaling pathways and novel therapeutic strategies for the treatment of murine chronic graft versus host disease.
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