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Author ORCID Identifier
Open Access Dissertation
Doctor of Philosophy (PhD)
Animal Biotechnology & Biomedical Sciences
Year Degree Awarded
Month Degree Awarded
Lisa M. Minter
Barbara A. Osborne
Wilmore C. Webley
Immune System Diseases | Immunopathology | Medical Immunology | Other Immunology and Infectious Disease
Aplastic Anemia is a rare immune mediated bone marrow failure disease that is mediated by autoreactive T cells that cause destruction to the stem, progenitor, and stromal cells in the bone marrow. Because little is known about the etiology of the disease, our lab has developed a major MHC mismatch GVHD model to examine cellular pathways in autoreactive T cells that contribute to disease. We examined three pathways that are important in T cell activation and differentiation and asked if they were important in the development of Aplastic Anemia. First, we were able to show that expression of active PKCθ (pPKCθ) is highly expressed in AA mice compared to irradiation controls and active PKCθ is needed for Notch1IC activation and IFNγ production in T cells. Also, pPKCθ is highly expressed in peripheral blood mononuclear cells collected from treatment-naïve AA patients and treating patient samples with the PKCq inhibitor, rottlerin, reduced both NOTCH1IC expression and IFNγ production. Additionally, NF-κB signaling was necessary to drive AA through multiple pathways. For example, we were able to decrease T cell activation, expansion and Th1 cytokine production in our mouse model when we blocked NF- κB signaling. We were also able to show that NF-κB signaling regulates CXCR4 expression, and AA induced mice have higher levels of CXCR4 present on their T cells. Surprisingly, we were further able to reduce CXCR4 expression and motility in response to its chemokine ligand, SDF-1 by blocking NF-κB signaling. Finally, we were able to delineate a role for the microRNA, miR-155 in our mouse model of AA. We found that miR-155 expression was increased in AA induced mice, and its inhibition was able to ameliorate disease symptoms and ablate infiltration of T cells into the bone marrow. We identified a potential target of miR-155 in CD4+ T cells called programmed death ligand 1 (PD-L1) and show that mice induced with miR-155-deficient cells have increased iTregs in the bone marrow and spleen. Taken together, these data illuminate multiple pathways that contribute to AA which could be further investigated for alternative treatments of the disease.
Kuksin, Christina M., "Elucidating Cellular Signaling Pathways that Contribute to the Immunopathogenesis of Aplastic Anemia" (2014). Doctoral Dissertations. 255.