A great deal of progress has been made in identifying autoantigens for experimental and clinical autoimmunity. Major antigens are known for lupus autoantibodies, and T cell determinants are being elucidated in such diseases as multiple sclerosis and insulin dependent diabetes mellitus [IDDM]. This progress in identifying autoantigens provides a new impetus for developing molecular interventions that slow or silence autoreactivity. Our goal is to develop new strategies that will permit clinicians to intervene and manipulate the immune response. In the afferent limb, we will target antigens to a new receptor, DEC-205, that is abundant on Dendritic and certain Epithelial Cells. DEC-205 was recently cloned. It is a DECalectin, with 10 Calcium-dependent lectin domains arranged in tandem. It is hypothesized that DEC-205 allows dendritic cells and certain epithelia [thymic cortex and intestinal epithelia] to recognize a wide array of glycans. Subprojects 1 and 2 are closely interwoven and entail the biochemical and immunological identification of ligands for DEC-205. Appropriate glycoprotein antigens will then be targeted via DEC-205 in vivo to determine their tolerizing potential. Specific T cell peptides will be coupled to anti-DEC-205 Ig as an alternative targeting approach. It has just been found that a rat monoclonal to DEC-205 is able to target dendritic cells and tolerize the animal to a subsequent T cell response to rat Ig. We will also identify human DEC-205 and its expression on dendritic cells in human tissues, especially those undergoing autoimmune attack. We will collaborate to construct mice that are genetically deficient in DEC-205 in either marrow and/or nonmarrow derived compartments. In the efferent limb, subject 3 will capitalize on new mouse strains. The role of Fcgamma receptors and C3 will be assessed by crossing genetically deficient mice to other lines in which for example an anti-DNA Ig transgene induces nephritis, plus several sublines of lupus prone NZM mice in which several different susceptibility genes are being mapped. Immunological sequelae will be studied together with immunolabeling of tissues, function of APCs, and B cell responses, crossing with DEC-205 deficient lines. Given the complementary expertises of the PI's and their prior and proposed interactions, we are in a position to identify new molecular strategies for manipulating the afferent and efferent limbs of immunity in a way that should be pertinent to lupus, IDDM, and other diseases.
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