The Research Plan comprises the basic research experience component of Phase I of the NIDR Physician Scientist Award Program for Dentists. This activity, intergrated with an intensive didactic component will prepare the candidate to do basic research into the immunophathology of periodontal disease in Phase II. Our broad purpose during Phase I will be to define the roles played by vascular endothelial cells (EC) in immunity, both as initiators of cell-mediated immunity (e.g., by functioning as antigen-presenting accessory cells), and as specific and non-specific targets of humoral or cell-mediated cytotoxicity. Because both the physiology and the immunologic function of vascular endothelium may vary according to vessel type or size, or anatomic location, we will also investigate the issue of EC heterogeneity. We will determine the immune function of EC in the initiation of immune responses by examining their abilities to synthesize and express cell-surface Ia antigens, and to replace macrophages as antigen-presenting accessory cells. We will analyze the mechanisms of immunologically induced EC injury by testing the capacity of various leukocyte populations to injure EC in vitro, and define the circumstances under which such cytotoxic leukocytes appear in vivo. We will examine the heterogenity of EC populations in vitro, using cloned and uncloned EC derived from various vessels and tissue sources from strain 2 and strain 13 guinea pigs, by analyzing their immune functions, expression of factor VIII-related antigen, levels of angiotensin converting enzyme activity, and their ultrastructure, including their synthesis of Weibel-Palade bodies. These studies will be conducted entirely with guinea pigs and guinea pig cells maintained in vitro. The guinea pig represents an ideal model for the proposed studies as we will use inbred strain 2 and 13 animals as sources of various leukocyte populations as well as EC, providing a completely syngeneic model system. Further, our use of cloned EC populations (derived from a single precursor cell and maintained under strictly isologous conditions in vitro), devoid of any contaminating cells whatsoever, provides a unique opportunity to examine the immune function of EC.
