0934: The Use Of Preclinical Models To Understand Drivers Of Lupus Pathogenesis

Background/Purpose: Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease with a prevalence of 1.4-15.13/100,000 adults globally. SLE is highly heterogenous and can involve dysregulation of the adaptive and innate arms of the immune system, leading to aberrant lymphocyte activation, autoantibodies, immune complex formation, and/or organ damage. Notably, clinical benefit has been demonstrated in subsets of lupus patients. Thus, it is critical to appropriately model disease and differentiate disease drivers in relevant preclinical models, allowing better stratification of patient subsets for the development of effective therapeutics and opening the door for new target discovery.

Methods: Two mouse models of lupus-like disease were evaluated: NZB/W lupus prone mice and C9orf72-deficient mice, which display a lupus-like phenotype previously described to include elevated autoantibodies and circulating cytokines, glomerulonephropathy, splenomegaly and lymphadenopathy. Profiling of immune populations and serological readouts was performed over time using age matched female WT, NZB/W, and C9orf72 KO animals. Overexpression of IFNα via hydrodynamic DNA delivery (HDD) was used to evaluate the role of IFNα in these strains, while TACI-Ig-mediated B cell depletion was performed to determine the contribution of B cells to pathogenesis.

Results: The respective contributions of IFNa and BAFF, representing pathways with approved targeted therapeutics in SLE, were evaluated and analyzed between these strains. Systemic low dose IFNα synchronizes and significantly accelerates disease progression across NZB/W animals, while disease progression in C9orf72^-/- mice is unaltered by overexpression of IFNα. These data suggest that lupus-like disease in NZB/W mice can be exacerbated by IFNα and thus may model patients for whom Type I IFN is a key driver of disease. Although disease in C9orf72^-/- is unchanged by IFNα, overexpressing TACI-Ig to bind and sequester BAFF and APRIL in the C9orf72-deficient lupus model reversed lupus-associated phenotypes. TACI-Ig-mediated depletion of BAFF/APRIL in C9orf72^-/- resulted in a decrease in B cells and a rapid reduction in anti-dsDNA antibodies. These data indicate that the C9orf72^-/- model captures the dysregulated B cell tolerance pathways that can drive disease in some subsets of lupus patients.

Conclusion: Here we describe two models of SLE-like disease that respond differently to manipulation of key pathways targeted by existing approved therapeutics. Taken together, these data suggest that NZB/W and C9orf72^-/- mice recapitulate distinct disease mechanisms relevant to human patients and can be used in preclinical efforts to validate therapeutic strategies for a heterogeneous SLE patient population.