Background/Purpose: Application of B cell depletion therapy (BCDT) for treatment of SLE has shown promise in some patients, but some patients exhibit disease relapses. Anti-type I interferon (IFN) receptor therapy has recently been shown to be effective in SLE. We previously showed that type I IFN plays an important role in promoting autoimmune disease in the BXD2 mouse model of lupus. Here, we address the question of whether type I IFN blockade can prevent the relapse and return of autoreactive B cells after anti-CD20 depletion therapy using the BXD2 mouse model of lupus.

Methods: Groups of BXD2 mice (4 weeks old) were either untreated or treated with anti-CD20 and followed by treatment with control antibody, neutralizing antibody against IFNβ, or neutralizing antibody against IFNαR beginning at the time of B cell repopulation. FACS analysis was carried out using validated antibodies. Confocal imaging was carried out to determine areas of repopulation in the spleen. Sera antibody levels of anti-DNA, anti-La, and rheumatoid factor were determined by ELISA analysis.

Results: Compared to normal B6 mice, there was rapid repopulation of transitional and mature B cells in the spleens of BXD2 mice at weeks 2 and 3, after BCDT. Interestingly, treatment with anti-IFNαR normalized the kinetics of repopulation in BXD2 mice and decreased the rapid development from transitional B cells to more mature B cells, suggesting a “window of opportunity” to normalize B cell repopulation after BCDT. To determine superiority of anti-IFNαR during this “window”, groups of mice were treated with either anti-IFNβ or anti-IFNαR, during from 2 to 4 week (MOD, ip) and short and longterm effects of interferon inhibition were determined at week 4 and 12, after BCDT. Early repopulation, determined by confocal imaging at week 4 after BCDT showed a significant inhibition of class-switched (IgM, IgD⁺) transitional B cells in the MZ zone and outer follicles of anti-IFNβ-treated mice compared to IFNαR-treated mice. Decreased development of early-stage transitional (CD93⁺) La_13-23 tetramer⁺ autoreactive B cells accompanied by decreased Ki67+ proliferation was observed in both anti-IFNβ-treated and anti-IFNαR-treated mice with no significant difference between treatment groups. At week 12 after BCDT, there was a significant decrease in the percent of Fas⁺ GL7 GC-B cells after short-term treatment with anti-IFNAR and anti-IFN-β. Sera levels of anti-DNA, La and rheumatoid factor were reduced in anti-IFN-β and anti-IFNαR blockade treated mice compared to anti-CD20 therapy alone.

Conclusion: Type I interferons exert a prominent effect on the development of autoreactive B cells during a critical “window of opportunity” where transitional B cells are repopulating the periphery following B cell depletion therapy. Importantly, transient blockade of type I IFN during B cell repopulation was sufficient to prevent development of autoreactive B cells and antibodies long-term. These results suggest that blockade of type I IFN may be an effective therapeutic option to enhance and prolong the effects of B cell depletion therapy in lupus. Also, specific inhibition of IFN-β may be sufficient as blockade of all type I IFN signaling in B cells using anti-IFNαR did not offer additional benefit.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-ifn-blockade-restores-normal-transitional-b-cell-development-post-anti-cd20-depletion/