This application intends to investigate a novel mechanism, by which a newly discovered dendritic cell (DC) of CD8aa + CD11 + phenotype prevents glomerular autoimmune damage by the induction of apoptosis of selfreactive T cells that are causing glomerular damage. Despite their critical role in many autoimmune diseases, pathogenic T cells alone are not sufficient to cause the disease. For example, in our antiGBM glomerulonephritis (GN) model, the disease is induced in WKY rats by a potent nephritogenic T cell epitope pCol(2840) of collagen 4a3 chain. However, LEW rats, which have identical MHC and mount a similar T cell response to pCol(2840), are resistant to GN induction. To define the mechanism associated with GN susceptibility, we first found a transient T cell mediated inflammation in the glomeruli of LEW rats, coincident with infiltration of a novel type of CD8aa + CD11 + DC into the glomeruli. Further studies showed that this glomerular infiltrating DC actively induced a non FasL mediated apoptosis in self reactive T cells through its antigen presentation. In contrast, infiltration of the DC occurred at a much later stage in GN susceptible WKY rats, when glomerular damage had advanced. Therefore, GN resistance in LEW is due to early infiltration of the novel DC which contains further glomerular damage. Our finding reveals a novel self tolerance mechanism for controlling autoimmune diseases after activated T cells initiate tissue damage. This may aid development of new therapeutic strategies for antiGBM GN after its onset. We hypothesize that the novel CD8aa + CD11 + DC is critical for maintenance of self tolerance through its timely infiltration of target tissue and induction of apoptosis of self reactive T cell. In this application, we will fulfill three specific aims to further define this hypothesis. First, we will determine which apoptosis pathway is induced by the DC and whether manipulation of apoptosis would alter GN susceptibility. Second, we will determine whether the DC in WKY is dysfunctional, and whether this is responsible for GN susceptibility. Third, we will test whether glomerular microenvironment is responsible for timely infiltration of the DC.
Anti-GBM glomerulonephritis is a human autoimmune disease that, as of now, is incurable. Using an animal model, we propose to investigate how a special type of dendritic cells control this disease after the tissue damage has begun. With high hopes, our study may aid the development of therapeutic strategies for the disease after its onset.
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