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DNA Vaccination Against Specific Pathogenic TCRs Reduces Proteinuria in Active Heymann Nephritis by Inducing Specific Autoantibodies

Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia

We have previously identified potential pathogenic T cells within glomeruli that use TCR encoding V5, V7, and V13 in combination with J2.6 in Heymann nephritis (HN), a rat autoimmune disease model of human membranous nephritis. Vaccination of Lewis rats with naked DNA encoding these pathogenic TCRs significantly protected against HN. Proteinuria was reduced at 6, 8, 10, and 12 wk after immunization with Fx1A (p < 0.001). Glomerular infiltrates of macrophages and CD8⁺ T cells (p < 0.005) and glomerular IFN- mRNA expression (p < 0.01) were also significantly decreased. DNA vaccination (DV) causes a loss of clonality of T cells in the HN glomeruli. T lymphocytes with surface binding of Abs were found in DNA vaccinated rats. These CD3⁺/IgG⁺ T cells expressed V5 and V13 that the DV encoded. Furthermore, FACS shows that these CD3⁺/IgG⁺ cells were CD8⁺ T cells. Analysis of cytokine mRNA expression showed that IL-10 and IFN- mRNA were not detected in these CD3⁺/IgG⁺ T cells. These results suggest that TCR DNA vaccination produces specific autoantibodies bound to the TCRs encoded by the vaccine, resulting in blocking activation of the specific T cells. In this study, we have shown that treatment with TCR-based DV, targeting previously identified pathogenic V families, protects against HN, and that the mechanism may involve the production of specific anti-TCR Abs.

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