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Abstract: SA-OR039

Neutralizing the Th1 Effector Cytokines, TNFα and IFNγ, in Experimental Autoimmune Myeloperoxidase ANCA Associated Glomerulonephritis (MPO-ANCA GN)

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Nagai, Kei, University of Tsukuba, Tsukuba-city, IBARAKI, Japan
  • Kitching, A. Richard, Monash University, Monash Medical Centre, Melbourne, Victoria, Australia
  • Holdsworth, Stephen R., Monash University, Monash Medical Centre, Melbourne, Victoria, Australia
  • Gan, Poh-Yi, Monash University, Monash Medical Centre, Melbourne, Victoria, Australia
Background

Anti-cytokine monoclonal antibody (mAb) therapies have been effective in many autoimmune diseases but have not been successfully trialled in MPO-ANCA associated vasculitis. This study assessed the efficacy of blocking key CD4+ Th1 subset signature effector cytokines, TNFα and IFNγ in MPO-ANCA GN. Assessing therapeutic efficacy of these anti-cytokine mAbs is now complicated by our recent discovery that Th subset dominance during the development of MPO autoimmunity is biphasic with initial transient Th17 dominance followed by persistent Th1 responses.

Methods

Anti-MPO autoimmunity was induced in C57BL/6 mice by MPO immunization and GN triggered using anti-GBM Ig during early and late development of anti-MPO autoimmunity, and GN assessed 4 days later (days 20 and 32, respectively). mAb treatment began 4hrs post GN triggering.

Results

Administration of anti-TNFα mAb early in anti-MPO development (day 20) had no effect on kidney injury compared with vehicle treated controls: albuminuria [5.7±1.7 vs 5.5±1.7 mg/24hr, P=0.9]; glomerular segmental necrosis [GSN: 50±4 vs 43±3%, P=0.1]. Similarly, anti-IFNγ mAb was ineffective in attenuating GN at this timepoint [GSN: 48±6 vs 45±3%, P=0.53]. Failure of these treatments is concordant with our observation that early developing anti-MPO autoimmunity is Th17 dominant. In contrast, anti-TNFα therapy during established anti-MPO GN (day 32) markedly attenuated kidney injury [GSN: 27±2 vs 50±4%, P=0.01]. TNFα blockade acts locally in the kidney as systemic MPO specific IFNγ and IL-17 recall responses from lymph nodes draining MPO immunization sites were similar to vehicle treated controls. Neutralizing IFNγ at this late timepoint induced a phenotypic switch from Th1 responses to a protective Th2 with increased in serum MPO-ANCA [1.19±0.25 vs 0.48±0.13 OD450nm, P=0.02], increased IL-4 production from MPO challenged LN cells and increased the proportion of activated M2 macrophages [F4/80+CD206+: 29.3±3.2 vs 16.0±0.9%, P=0.01]. However, 4 days of anti-IFNγ treatment was insufficient to improve GN.

Conclusion

In conclusion, Th1 anti-MPO effector responses direct established anti-MPO nephritogenic autoimmunity and glomerular injury (day 32).Therapeutic TNFα neutralizing mAb initiated after triggering GN effectively attenuates kidney injury.

Funding

  • Government Support - Non-U.S.