The long-term objective of this proposal is to study the role of the vascular endothelium in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). The expression of autoimmune diabetes involves a large number of factors which we view as analogous to the tumblers in a lock. These tumblers include the target beta cell, effector and regulatory immunocytes, humoral factors, the pancreatic endothelium, genetics, and environmental factors. The endothelium is the least well understood tumbler at this time. It potentially plays a pivotal role since 1) cells involved in beta cell destruction must locate and traverse the pancreatic endothelium, and 2) endothelial cells express Ia antigens and present processed foreign antigen. Studies of pancreatic venular endothelium in humans are obviously difficult to carry out and its is therefore reasonable to propose to perform them in an animal model of IDDM. Foremost among such models is the BB rat which strongly resembles its human counterpart in having an autoimmune pathogenesis, and which has been found to have a venular permeability defect limited to the pancreas. We propose to study the pancreatic venular endothelium of the BB rat in the following series of experiments.
Specific Aim No. 1 is to characterize pancreatic venular endothelial leakage in the rat using Monastral blue B pigment and the technique of vascular labeling. The strain specificity, organ specificity, genetics, and dose response profile will be determined.
Specific Aim No. 2 is to determine which factor or factors are responsible for the macrophage toxins silica and carrageenan completely block Monastral blue induced leakage in the BB rat. Macrophages themselves and their secretory products will be evaluated for their effects on venular leakage.
Specific Aim No. 3 is to study rat pancreatic venular endothelial cells in vitro. We will characterize the endothelia in culture and then use the cultured cells to study Ia activation, lymphocyte adherence, and effects on in vitro cytoctoxicity. Our ultimate goal is to understand the importance of the pancreatic venular endothelium as either an initiator or abettor of autoimmune diabetes mellitus. These experiments should allow us to determine if the expression of insulin dependent diabetes mellitus depends in part on factors specific to endothelial cells.
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