A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis.

Yue Shi, Xiao-Yu Jia, Qiu-Hua Gu, Miao Wang, Zhao Cui, Ming-Hui Zhao

Journal of the American Society of Nephrology : JASN 2020 Jan

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In Goodpasture disease, the noncollagenous domain 1 of the α3 chain (α3NC1) of type IV collagen is the main target antigen of antibodies against glomerular basement membrane (GBM). We previously identified a nephritogenic epitope, P14 (α3127-148), that could induce crescentic nephritis in WKY rats, and defined its core motif. Designing a modified peptide, replacing critical pathogenic residues with nonpathogenic ones (on the basis of homologous regions in α1NC1 chain of type IV collagen, known to be nonpathogenic), might provide a therapeutic option for anti-GBM GN. We synthesized a modified peptide, replacing a single amino acid, and injected it into α3-P14-immunized rats from day 0 (the early-treatment group) or a later-treatment group (from days 17 to 21). A scrambled peptide administrated with the same protocol served as a control. The modified peptide, but not the scrambled peptide, attenuated anti-GBM GN in both treatment groups, and halted further crescent formation even after disease onset. Kidneys from the modified peptide-treated rats exhibited reductions in IgG deposits, complement activation, and infiltration by T cells and macrophages. Treatment also resulted in an anti-inflammatory cytokine profile versus a proinflammatory profile for animals not receiving the modified peptide; it also reduced α3-P14-specific T cell activation, modulated T cell differentiation by decreasing Th17 cells and enhancing the ratio of Treg/Th17 cells, and inhibited binding of α3-P14 to antibodies and MHC II molecules. A modified peptide involving alteration of a critical motif in a nephritogenic T cell epitope alleviated anti-GBM GN in a rat model. Our findings may provide insights into an immunotherapeutic approach for autoimmune kidney disorders such as Goodpasture disease. Copyright © 2020 by the American Society of Nephrology.

Citation

Yue Shi, Xiao-Yu Jia, Qiu-Hua Gu, Miao Wang, Zhao Cui, Ming-Hui Zhao. A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis. Journal of the American Society of Nephrology : JASN. 2020 Jan;31(1):40-53