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Abstract Number: 1032

Neutralization of IL-17 Ameliorated Kidney Pathology Associated with Immune-Complex Mediated Autoimmune Glomerulonephritis

Partha Biswas1, Kritika Ramani2, Kelly Maers3, Anna Huppler4 and Sarah L. Gaffen5, 1Medicine/Rheumatology, University of Pittsburgh, Pittsburgh, PA, 2Dept of Medicine, University of Pittsburgh, Pittsburgh, PA, 3Medicine, University of Pittsburgh, Pittsburgh, PA, 4Medicine, University of Pittsburgh, Pittsurgh, PA, 5Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Autoimmunity, cytokines and glomerulonephritis, Kidney

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Session Information

Session Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis

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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