Targeting B and T lymphocyte attenuator regulates lupus disease development in NZB/W mice

ABSTRACT B and T Lymphocyte Attenuator (BTLA) is a co-inhibitory receptor expressed by most immune cells, playing a role in negatively regulating immune responses. Studies in MRL/lpr lupus mice deficient for BTLA, indicate that BTLA has a protective role in lupus. 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 thoroughly analyzed BTLA expression and function in the NZB/W lupus-mouse model. We found that diseased NZB/W mice exhibit a BTLA expression and function pattern similar to that observed in lupus patients, emphasizing the importance of this mouse model in evaluating the therapeutic potential of targeting BTLA. Administration of a monoclonal anti-BTLA antibody (clone 6F7, which displays agonist properties ex vivo ) into pre-diseased NZB/W mice resulted in a delayed onset of proteinuria, limited kidney damages and an increased survival rate compared to isotype-treated mice. This beneficial effect was associated with a decrease in circulating B cell frequency and required continuous exposure to the antibody. 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, leading to a selective reduction of follicular B cell numbers, and exhibits in vivo agonist activity. 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.