The development of imaging technology for autoimmune diseases is crucial to mechanistically dissect these complex, chronic diseases. Without comprehending the process that leads to disease, it is difficult to develop therapies aimed at ameliorating or preventing autoimmunity. Our proposal is focused on development of imaging model for rheumatoid arthritis (RA), but the models are widely applicable. RA is a debilitating disease that afflicts a large number of people in the U.S. and the world, about 1-2 percent of the world's population. In addition, there are several rodent models that mimic RA. We are particularly interested in developing techniques and reagents to study the process of leukocyte migration from the blood through the synovium and into the joint. We reason that inhibiting leukocyte transmigration will prevent the disease. Indeed, preventing leukocytes from invading tissue will inhibit most autoimmune diseases as well as prevent graft rejection. Intravital microscopy provides a technique to image in vivo the microvasculature at high magnifications. Fluorescence labeled cells can be visualized traveling through the microvasculature and the rate of movement assessed by offline analyses. Various treatments can be administered to modulate in vivo cell movement through the tissues. To develop in vivo intravital microscopy for RA, we will develop a series of transgenic mice with selected cell-types expressing fluorescent proteins. These transgenic mice will allow imaging of selected cell-types in vivo by intravital microscopy. To image changes in cell adhesion molecule expression, which are essential for leukocyte transmigration, we will develop mice expressing fluorescent proteins with similar kinetics as the cell adhesion molecules. To bridge the gap between animal studies and human RA, we will develop a system to image in vivo human leukocyte and human synovium interactions by using the humanized SCID model system. Upon completion of these studies, we will have developed a comprehensive imaging system to study leukocyte migration during autoimmune diseases.
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