Doctor of Philosophy, The Ohio State University, 2018, Comparative and Veterinary Medicine

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving therapy both for malignant and non-malignant diseases. The success of allo-HSCTs, however, is limited by acute graft-versus-host disease (aGVHD), a frequent complication that remains a leading causes of non-relapse mortality following allo-HSCT. The pathogenesis of aGVHD involves donor T cells which target human leukocyte antigen mismatched host tissues, causing tissue injury through pro-inflammatory cytokine secretion and direct cytotoxicity. The morbidity and mortality associated with aGVHD pose a major barrier against the wider application of allo-HSCT as a curative modality. Thus, better understanding of aGVHD pathogenesis and novel therapeutics are needed. Modulation of T cell function, broadly, depends on control of gene expression. Two well-studied modes of modulating gene expression are noncoding RNAs and epigenetic modifications. Using unbiased approaches, we identified multiple microRNAs that are upregulated during aGVHD. We validated two of these, T-cell intrinsic miR-155 and serum miR-29a, due to their pivotal role in regulating the adaptive immune system. First, we investigate the molecular mechanisms by which miR-155 modulates T cell function in aGVHD. We identify that miR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Furthermore, we show that miR-155 strongly impacts alloreactive T cell expansion through proliferation and exhaustion as well as function by promoting a pro-inflammatory Th1 phenotype. Finally, we demonstrate that miR-155 expression in donor T cells regulates chemokine-dependent migration and infiltration into target organs. These findings provide novel insight into the role of miR-155 in regulating T cell function post-transplant and are convincing biological rationale to justify investigation of novel antagomiR-155 therapeutics to prevent or minimize aGVHD. Next, we strive to identify s (open full item for complete abstract)

Committee: Ramiro Garzon MD (Advisor); Michael Caligiuri MD (Committee Member); Renukaradhya Gourapura DVM, MS, PhD (Committee Member); M. Judith Radin DVM, PhD (Committee Member) Subjects: Immunology; Molecular Biology; Oncology