Gherardi Léa, Aubergeon Lucie, Sayah Mélanie, Fauny Jean-Daniel, Dumortier Hélène, Monneaux Fanny
CNRS UPR3572, Immunology, Immunopathology and Therapeutic Chemistry, Institute of Molecular and Cellular Biology, Strasbourg, 67084, France.
Immunotargets Ther. 2025 Jan 17;14:7-23. doi: 10.2147/ITT.S490573. eCollection 2025.
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.
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.
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.
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.
共抑制受体B和T淋巴细胞衰减器（BTLA）对B细胞和T细胞的激活起负向调节作用。我们之前已经表明，狼疮患者体内调节性T细胞的BTLA表达发生改变，且BTLA抑制CD4 T细胞激活的能力受损。在本研究中，我们分析了NZB/W狼疮小鼠模型中BTLA的表达和功能，并研究了靶向BTLA的治疗潜力。
将年轻（10 - 12周龄）和患病老龄（>35周龄且有蛋白尿）的NZB/W小鼠与年龄匹配的BALB/W对照小鼠进行比较，分析BTLA的表达和功能。给20 - 22周龄的NZB/W小鼠（n = 10）腹腔注射3 mg/kg的抗BTLA抗体6F7或其同型对照，每周两次，共十周。
在患病老龄NZB/W小鼠中，B细胞亚群的BTLA表达略有改变，而CD4 T细胞的BTLA功能受损。与同型对照处理的小鼠相比，给20 - 22周龄的NZB/W小鼠注射6F7抗BTLA抗体可导致蛋白尿发病延迟（p<0.01）、肾脏损伤受限（p<0.05）和存活率提高（p<0.01）。这种有益效果与循环B细胞和脾脏滤泡B细胞数量减少有关。关于其作用方式，我们证明6F7抗体不是耗竭性抗体，也不阻断疱疹病毒侵入介导因子（HVEM）与BTLA的结合，而是诱导BTLA下调并在体内表现出激动剂活性。
总体而言，我们的数据证实了BTLA参与狼疮发病机制，并首次证明BTLA是狼疮治疗的潜在靶点。
