Targeting B and T Lymphocyte Attenuator Regulates Lupus Disease Development in NZB/W Mice.

Abstract

Purpose: The co-inhibitory receptor B and T Lymphocyte Attenuator (BTLA) negatively regulates B and T cell activation. We have previously shown an altered BTLA expression by regulatory T cells and an impaired capacity of BTLA to inhibit CD4⁺ T cell activation in lupus patients. In this study, we analyzed BTLA expression and function in the NZB/W lupus-mouse model and examined the therapeutic potential of BTLA targeting.

Methods: BTLA expression and function were analyzed in young (10-12-week-old) and old-diseased NZB/W mice (>35-week-old with proteinuria) in comparison to age-related BALB/W control mice. 20-22 weeks old NZB/W mice (n=10) were injected i.p with 3 mg/kg, twice a week for ten weeks, with the anti-BTLA antibody 6F7 or its isotype control.

Results: In old-diseased NZB/W mice, BTLA expression is slightly modified in B cell subsets whereas CD4⁺ T cells display impaired BTLA functionality. Administration of the 6F7 anti-BTLA antibody into 20-22 week-old NZB/W mice resulted in a delayed onset of proteinuria (p<0.01), limited kidney damages (p<0.05) and an increased survival rate (p<0.01) compared to isotype-treated mice. This beneficial effect was associated with a decrease in circulating B cell and spleen follicular B cell numbers. Regarding its mode of action, we demonstrated that the 6F7 antibody is not a depleting antibody and does not block HVEM binding to BTLA, but instead induces BTLA down modulation and exhibits in vivo agonist activity.

Conclusion: Overall, our data confirm the involvement of BTLA in lupus pathogenesis and provide the first evidence that BTLA is a potential therapeutic target for the treatment of lupus.