Neutralizing the th1 effector cytokines, TNFalpha and ifngamma, in experimental autoimmune myeloperoxidase ANCA associated glomerulonephritis (MPO-ANCA GN).

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, TNFalpha and IFNgamma 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. Method(s): 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. Result(s): Administration of anti-TNFalpha 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-IFNgamma 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-TNFalpha therapy during established anti-MPO GN (day 32) markedly attenuated kidney injury [GSN: 27+/-2 vs 50+/-4, P=0.01]. TNFalpha blockade acts locally in the kidney as systemic MPO specific IFNgamma and IL-17 recall responses from lymph nodes draining MPO immunization sites were similar to vehicle treated controls. Neutralizing IFNgamma 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 m