THU0245 Individual versus Combined BLYs Or/and april Neutralization Reveals Developmental Plasticity for Plasma Cell Survival Factor Requirements

Background

The role of the TNF family cytokine APRIL (a proliferation inducing ligand) in the etiology and pathogenesis of autoimmunity is incompletely understood. The inhibition of B cell survival factors in the NZBWF1 mouse model of systemic lupus erythematosus (SLE) thus far revealed similar efficacy profiles for compounds that neutralize BLyS (B lymphocyte stimulator, also known as BAFF) only, or both BLyS and APRIL (1, 2). Strategies that exclusively target APRIL are sparse, mostly confined to genetic approaches and do not dissect its temporal requirements in disease progression.

Objectives

Comparison of single versus dual pharmacological inhibition of BLyS and APRIL in a mouse model for the human autoimmune disease SLE.

Methods

Reagents that neutralize either APRIL alone (an anti-APRIL antibody), BLyS alone (BAFFR-Fc), or both BLyS and APRIL (TACI-Fc), were administered to NZBWF1 mice after the onset of autoimmunity, but before nephritis occurred.

Results

The inhibition of APRIL alone was inefficient, in contrast to BLyS single antagonism, which instead delayed lupus symptoms, or to the dual inhibition of BLyS and APRIL, which arrested further disease development, autoantibody production, immune complex deposition in glomeruli and prevented onset of nephritis. While studying the plasma cell compartment over time in a T-dependent hapten/carrier immunization system, developmental plasticity in terms of survival factor requirements was observed. Moreover, a maturation window for plasma cells was identified during which APRIL predominantly mediated survival. The results indicate that plasma cells are flexible in the use of APRIL or BLyS to support their survival in the bone marrow niche.

Conclusions

These results suggest that targeting plasma cells by neutralization of both BLyS and APRIL might be beneficial to prevent autoantibody-mediated damages in SLE.

References

Ramanujam M, et al. J Clin Invest 116: 724–734; Ramanujam M, et al. Arthritis Rheum 62: 1457–1468.

Disclosure of Interest

P. Haselmayer Employee of: Merck KGgA, M. Vigolo: None declared, J. Nys Shareholder of: AstraZeneca, Employee of: Medimmune, P. Schneider Grant/research support from: EMD Serono, a subsidiary of Merck, KGaA, H. Hess Shareholder of: Merck KGaA, Employee of: Merck KGaA