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

Master of Science, The Ohio State University, 2012, Allied Medical Professions

Maintenance of appropriate nutrition status within hematopoietic stem cell transplantation (HSCT) is of great significance in both improving treatment response and reducing morbidity and mortality (1, 2). There is a particular lack of observational research within HSCT studying the extent to which oral intake is inhibited in transplant recipients. Using data available in the electronic medical records at the study institution, this retrospective chart review calculated patient caloric intake on each inpatient day during transplant for all patients in 2010. Of 213 patients, 190 were eligible for inclusion into the study. The researchers calculated percentage of EER met on each day of transplant with the goal of calculating the percentage of patients, aggregated by preparatory regimen, who went an extended period of time (at least 10 consecutive days) without adequate oral intake (at least 50% EER). 21% of patients met the criteria for extended inadequate intake. When aggregated by preparatory regimen extended inadequate intake ranged from 7.7%-60%. This study had demonstrated the potential to tailor nutrition interventions to the HSCT recipients' preparatory regimen, and further research should investigate the feasibility and effectiveness of proposed interventions such as aggressive oral diet counseling, enteral nutrition interventions and parenteral nutrition support.

Committee: Marcia Nahikian-Nelms PhD, RD (Advisor); Christopher Taylor PhD, RD (Committee Member); Kimberlee Orben MS, RD (Committee Member) Subjects: Nutrition