Hormonal Modulation of DCs: Influences on Innate and Adaptive Immunity

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DESCRIPTION (provided by applicant): Dr. Papenfuss, D.V.M., M.S. has demonstrated continued commitment to biomedical research during her clinical training. She completed an M.S. during her D.V.M. training, has completed a residency in Anatomic Pathology and is a candidate for a Ph.D. in veterinary pathobiology with an expected graduation date of Spring 2006. Dr. Papenfuss has gained expertise in comparative pathology, immunology and the immunopathogenesis of disease by investigating the immunomodulatory effects of hormones as they relate to the autoimmune disease model experimental autoimmune encephalomyelitis (EAE). EAE is an animal model for multiple sclerosis (M.S.) and is an important model for understanding not only autoimmune diseases, but serves as a powerful tool to understand fundamental immunological mechanisms underlying numerous diseases. Dendritic cells (DCs) are cells of the immune system that drive inflammation and dramatically influence the character of the resultant immune response. Thus, they are potent therapeutic targets in a broad range of inflammatory or immune- mediated disorders (e.g. autoimmunity, infectious diseases, allergy and oncology). Recent data identifies a novel population of hormonally modulated dendritic cells demonstrating potent immunoregulatory capabilities (i.e., reg-DCs). The overall research goals are to investigate how hormonal environments can produce reg-DCs, how these reg-DCs influence inflammation and helper T cell development and to determine the therapeutic potential of these reg-DCs using the animal model EAE. Aim 1 will evaluate phenotypic and functional characteristics of reg-DCs and determine the capacity of reg-DCs from hormonal environments to influence the adaptive immune response and EAE. Aim 2 determine the relative contributions of costimulatory molecules (PD-L1, PD-L2), soluble factors (i.e. IL-10, indoleamine 2,3-dioxygenase, IL-12 and TNF-ot) on how reg-DCs promote protection in EAE and Aim 3 will determine the role of estrogen receptors in the generation of reg-DCs. Environment: The research will be performed within the laboratory and under the guidance of the sponsor, Dr. Caroline Whitacre, a recognized expert in fundamental immunology, T cell biology and EAE. The work will be conducted within the Departments of Molecular Virology, Immunology and Medical Genetics and Veterinary Biosciences. The combined resources of these two departments, in conjunction with the collaborative environment of the researchers at the Ohio State University, and the extensive collaborations afforded by Dr. Whitacre and OSU colleagues, will afford Dr. Papenfuss numerous collaborative possibilities within the biomedical research community. The SERCA grant will permit Dr. Papenfuss to devote full time to research training, facilitate her development into an independent scientist and fulfill her lifelong career objectives of becoming an academic research pathologist.