Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Immune complex mediated autoimmune glomerulonephritis (AGN) is an often-fatal clinical manifestation of systemic lupus erythematosus. In recent years, pro-inflammatory cytokines in the nephritic kidney appear to contribute to the pathogenesis of AGN. The inflammatory cytokine network that drives renal pathology is poorly understood. IL-17, the signature cytokine of T-helper 17 (Th17) cells, which promotes autoimmune pathology in a variety of settings, is beginning to be identified in kidney diseases as well. However, the role of IL-17 and the consequence of blocking IL-17 in the pathogenesis of AGN have not been elucidated.
Methods: We took advantage of a prototypic mouse model of AGN, where glomerular injury is induced by generating an autoimmune response against rabbit anti-mouse glomerular basement membrane serum. In this model, development of AGN is an inevitable consequence of glomerular injury induced by immune-complex deposition, recapitulating many features of lupus nephritis. Accordingly, wild type (WT) and IL-17 receptorA-/- (IL-17RA-/-) mice were subjected to AGN and evaluated for the development of kidney pathology over a period of 14 days. We also test the therapeutic efficacy of neutralizing IL-17 in AGN induced WT mice.
Results: We showed that IL-17RA signaling is critical for the development of renal pathology. Despite normal systemic autoantibody response and glomerular immune-complex deposition, IL-17RA-/-mice exhibit diminished influx of inflammatory cells and kidney specific expression of IL-17 target genes correlating with disease resistance in AGN. IL-17 enhanced the production of pro-inflammatory cytokines and chemokines from tubular epithelial cells. Finally, we were able to show that neutralization of IL-17 ameliorated renal pathology in wild type mice following AGN.
Conclusion: These results clearly demonstrated that IL-17RA signaling significantly contributes to renal tissue injury in experimental AGN. Additionally, it also suggested that blocking IL-17-IL-17R signaling may be a promising therapeutic strategy for the treatment of AGN associated with SLE, which may have ramifications in other autoinflammatory kidney disorders.
Disclosure:
P. Biswas,
None;
K. Ramani,
None;
K. Maers,
None;
A. Huppler,
None;
S. L. Gaffen,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutralization-of-il-17-ameliorated-kidney-pathology-associated-with-immune-complex-mediated-autoimmune-glomerulonephritis/