Background/Purpose: Anti-cytokine monoclonal antibody (mAb) therapies have shown efficacy in numerous autoimmune diseases but have yet to succeed in myeloperoxidase anti-neutrophil cytoplasmic antibody associated vasculitis (MPO-AAV). T helper (Th) cell subset participation in experimental MPO-AAV is biphasic with initial transient Th17 dominance followed by persistent Th1 responses. This study evaluated the effectiveness of blocking key CD4⁺ Th1 subset signature effector cytokines, TNF-α and IFN-γ in established experimental MPO-AAV disease.

Methods: Autoimmune nephritis was induced in C57BL/6 mice via MPO in Freund’s adjuvant immunization, triggering GN using sub nephritogenic dose of anti-glomerular basement membrane antibody during early (day 16) and late (day 28 and 34) stages of anti-MPO autoimmunity, with GN assessment four days later. anti-cytokine mAb treatment commenced at the onset of inducing GN.

Results: Early administration of anti-TNF-α mAb (day 16) did not mitigate kidney injury compared to vehicle controls: albuminuria (5.7±1.7 vs. 5.5±1.7 mg/24hr, P=0.9) and glomerular segmental necrosis (GSN: 50±4 vs. 43±3%, P=0.1). Similarly, anti-IFN-γ mAb was also ineffective at this timepoint (GSN: 48±6% vs. 45±3%, P=0.53). Failure of these cytokine mAb treatments at this timepoint is concordant with early developing anti-MPO autoimmunity is Th17 dominant.

In established MPO-AAV disease (day 28), anti-TNF-α mAb therapy effectively attenuated kidney injury (albuminuria: 4.1±2.0 vs. 0.5±0.2 albuminuria:creatinine, P< 0.05 and GSN: 26.5±1.6 vs. 49.8±3.8%, P< 0.01). Late neutralization of IFN-γ induced a phenotypic switch from Th1 to protective Th2 responses, increasing MPO-ANCA Ig levels (1.2±0.3 vs. 0.48±0.13 OD 450nm, P< 0.02), IL-4 production from MPO-challenged lymph node cells, and activated M2 macrophages (F4/80+CD206+: 29.3±3.2% vs. 16.0±0.9%, P< 0.01). Despite the restoration of immune homeostasis, anti-IFN-γ treatment at day 28 was insufficient to improve GN.

To further explore the protective effects of M2 macrophages and Th2 cells to attenuate GN, we  triggered GN on day 34 to induce severe MPO-AAV. At this timepoint, compared to controls, anti-IFN-γ treatment significantly attenuated kidney injury (proteinuria: 6.3±1 vs.3.4±1 protein:creatinine, P< 0.05 and GSN: 72±7 vs 35±6%, P< 0.001) and reduced glomerular effector leukocytes (T cells, macrophages and neutrophils).

Conclusion: Th1 effector responses governs severe, established MPO-AAV, and initiating therapeutic TNF-α and IFN-γ neutralization at this specific timepoint effectively mitigates kidney injury, underscoring the importance of timing in treatment strategies for MPO-ANCA associated vasculitis.

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-th1-effector-cytokines-tnf-%ce%b1-and-ifn-%ce%b3-attenuates-experimental-autoimmune-myeloperoxidase-anca-associated-vasculitis/