Autoimmune anti-GBM glomerulonephritis (GN) is currently incurable.
We aim to elucidate pathogenesis of this disease, which may lead to development of a novel therapeutic strategy. In our rat model for anti-GBM GN, LEW rats spontaneously recover from early inflammation. Observations on this naturally occurring recovery mechanism had led to our working hypothesis for the current grant: A novel glomeruli- infiltrating CD8 + DC (GIL CD8 + DC) terminated autoimmune damage in glomeruli by inducing apoptosis in self-reactive T cells through antigen presentation;failure in this mechanism led to uncontrolled glomerular damage as seen in GN-susceptible WKY rats. In the past 3 years, we have verified our hypothesis. First, we demonstrated that GIL CD8 + DC induced apoptosis in T cells by its intracellular Fas-L. Second, timely infiltration of GIL CD8 + DC into glomeruli was decisive for the recovery. Third, we delineated the lineage of GIL CD8 + DCs and identified its precursor in PBL. Most importantly, transfer of PBL precursor of GIL CD8 + DCs of LEW rats cured GN in GN-susceptible WKY rats. Thus, defects in GIL CD8 + DCs are responsible for GN in WKY rats. In addition, our preliminary data suggested that defect in expression of several leukocyte- trafficking related molecules in precursor of GIL CD8 + DCs in WKY rats may be responsible for the delay. Thus, mimicking this natural recovery mechanism in rats may lead to a potential immunotherapy for human autoimmune GN. We hypothesize that timely expression of leukocyte trafficking related molecules in both GIL CD8 + DC and inflamed glomeruli governs timely infiltration. This renewal application will investigate how the CD8 + DCs timely infiltrate glomeruli with emphasis on leukocyte trafficking related molecules in both PBL CD8 + precursor and inflamed glomeruli in Aims 1 and 3. We will further test if enhancing the cell's ability in timely infiltration through genetic manipulation will cure GN in GN-susceptible WKY rats (Aim 2). Accomplishment of those aims will not only reveal a unique immune tolerance mechanism occurring in the target organ, but also provide a working model for development of cell-based immunotherapy for autoimmune GN.
Autoimmune anti-GBM glomerulonephritis is currently incurable. A rat strain shows spontaneous recovery from this disease. We aim to elucidate why a novel CD8 + DC-like cell is critical for the recovery, and further to test if mimicking this natual recovery mechanism can be applied for a cell-based immunotherapy for this disease.
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