PhD, University of Cincinnati, 2018, Medicine: Pathobiology and Molecular Medicine

Dendritic cells (DCs) are the most efficient antigen presentation cells and execute a pivotal role in the onset and regulation of innate and adaptive immune responses and the recruitment of a variety of leukocytes to the site of inflammation or injury. To counter the challenge of the non-stop exposure to exogenous pathogens, the lungs developed an intrigue and complex immunology defense orchestra that conducted by DCs. An increasing volume of research on DCs in recent years show that the disruption of DC equilibrium in the lung may result in different diseases. In this study, we used two different disease models to elucidate the importance of DC in disease pathogenesis. Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by focal DC accumulation, bronchiolocentric nodule formation, and cystic remodeling of the lung and occurs predominantly in active smokers. Approximately 50% of PLCH patients harbor somatic BRAF-V600E mutations identified mainly within the DC lineage. However, the rare nature of the disease and lack of animal models impedes the study of the pathogenic mechanisms of PLCH. We have established the first mouse model that recapitulates the hallmark characteristics of PLCH. In addition, we show that the BRAF-V600E mutation is associated with increased DC responsiveness towards multiple stimuli including the DC-chemokine CCL20. We provide evidence that DC accumulation in the lung is due to both increased viability and enhanced recruitment. Further evidence indicates that the accumulation of other inflammatory cells in PLCH is a secondary event driven by CCL7 secreted from DCs in a BRAF-V600E-dependent manner. Moreover, we demonstrate that the PLCH-like phenotype in the mouse model can be attenuated following smoking cessation and removal of BRAF-V600E DCs. Furthermore, we show PBMCs isolated from PLCH patients harboring the BRAF-V600E mutation produce CCL7. Collectively, our studies provide the first mechani (open full item for complete abstract)

Committee: Michael Borchers Ph.D. (Committee Chair); Ian Paul Lewkowich Ph.D. (Committee Member); Francis McCormack M.D. (Committee Member); William Miller Ph.D. (Committee Member); Kathryn Wikenheiser-Brokamp M.D. Ph.D. (Committee Member) Subjects: Surgery

Master of Science, The Ohio State University, 2015, Anatomy

Cancer immunotherapy is a treatment approach aimed towards harnessing and enhancing the immune system's intrinsic ability to eliminate malignant cells. One feature which lends to the attractiveness of cancer immunotherapy is the extensive capacity of the immune system to recognize specific molecular targets expressed on pathogenic or malignant cells. Natural-killer group 2, member D (NKG2D) ligands are “stress-induced” proteins which are not typically expressed in most normal, healthy tissues, but are upregulated in response to conditions of cellular stress, such as those arising from malignant transformation. These ligands have been shown to be widely expressed on a variety of cancer types, and thus, represent auspicious targets for the development of novel immunotherapies. To capitalize upon the tumor-specific expression of NKG2D ligands, a novel NKG2D ligand-targeting fusion protein was created, in which the extracellular domain of NKG2D, the receptor for NKG2D ligands, is fused to the Fc domain of human immunoglobulin G1 (IgG1). For this NKG2D-Fc fusion protein (NKG2D-Fc), the NKG2D region serves as the binding domain, intended to target NKG2D ligands expressed on tumor cells, while the Fc region serves as the effector domain, providing a site for interaction with various immune components which can mediate destruction of tumors. This thesis aims to describe this novel immunotherapeutic fusion protein and to examine its binding ability. NKG2D-Fc was hypothesized to be able to recognize and bind to NKG2D ligands expressed on human cancer cells. Results of flow cytometry analysis and ELISA demonstrated that NKG2D-Fc was able to bind to NKG2D ligands expressed on a human breast cancer cell line and a human melanoma cell line. These results are promising as they demonstrate that this novel construct can effectively bind to NKG2D ligands on cancer cells and warrant further investigation of this fusion protein as a potential cancer immunotherapeutic agent.

Committee: Amanda Agnew (Advisor); Eileen Kalmar (Committee Member) Subjects: Anatomy and Physiology; Medicine; Oncology