Voigt Alexandria, Gupta Shivai, Shen Yiran, Glenton Patricia, Li Danmeng, Ostrov David, Bhattacharyya I, Nguyen Cuong Q
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
Department of Pathology, Immunology & Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States.
Immunohorizons. 2025 Aug 25;9(9). doi: 10.1093/immhor/vlaf030.
Sjögren's disease (SjD) is a chronic autoimmune disorder predominantly affecting females, characterized by exocrine gland dysfunction. This study investigates the therapeutic potential of 2-chloro-1-(4-hydroxy-phenyl)-ethanone (CHPE) and metformin in the C57BL/6.NOD-Aec1Aec2 mouse model, which closely mirrors human SjD. Molecular docking identified CHPE and metformin as high-affinity binders to the MHC class II I-Ab antigen-binding groove, suggesting their ability to inhibit antigen presentation and modulate immune responses. In-vitro assays confirmed their effectiveness in reducing T cell activation. In-vivo studies demonstrated that both preventative and therapeutic regimens of CHPE and metformin significantly reduced lymphocytic infiltration in the lacrimal glands, with metformin showing a more pronounced effect in females. Salivary gland infiltration was less responsive, though some reduction in focal scores was observed in male mice treated preventatively with CHPE. Both drugs altered the composition of lymphocytic infiltrates, particularly by reducing B cell populations, with notable sex-specific differences in response to treatment. CHPE and metformin also reduced anti-nuclear antibody levels, with CHPE showing stronger effects in females. Additionally, both drugs improved saliva and tear secretion, with metformin being more effective in the preventative regimen, especially in females. T cell receptor transductant assays revealed that CHPE and metformin exert their therapeutic effects through antigen-specific pathways, inhibiting T cell responses to SjD-associated autoantigens. Overall, this study provides compelling evidence that CHPE and metformin can modulate immune responses and improve gland function, with effectiveness varying by sex and age. These findings support the potential of these compounds as personalized treatments for SjD tailored to individual patient characteristics.
干燥综合征（SjD）是一种主要影响女性的慢性自身免疫性疾病，其特征为外分泌腺功能障碍。本研究在C57BL/6.NOD-Aec1Aec2小鼠模型中探究了2-氯-1-(4-羟基苯基)乙酮（CHPE）和二甲双胍的治疗潜力，该小鼠模型与人类干燥综合征极为相似。分子对接确定CHPE和二甲双胍是与MHC II类I-Ab抗原结合槽具有高亲和力的结合物，表明它们具有抑制抗原呈递和调节免疫反应的能力。体外试验证实了它们在降低T细胞活化方面的有效性。体内研究表明，CHPE和二甲双胍的预防和治疗方案均显著减少了泪腺中的淋巴细胞浸润，二甲双胍在雌性小鼠中显示出更显著的效果。唾液腺浸润的反应较小，不过在预防性给予CHPE治疗的雄性小鼠中观察到局灶性评分有所降低。两种药物均改变了淋巴细胞浸润的组成，特别是通过减少B细胞群体，在治疗反应上存在显著的性别差异。CHPE和二甲双胍还降低了抗核抗体水平，CHPE在雌性小鼠中显示出更强的效果。此外，两种药物均改善了唾液和泪液分泌，二甲双胍在预防方案中更有效，尤其是在雌性小鼠中。T细胞受体转导试验表明，CHPE和二甲双胍通过抗原特异性途径发挥其治疗作用，抑制T细胞对干燥综合征相关自身抗原的反应。总体而言，本研究提供了令人信服的证据，表明CHPE和二甲双胍可以调节免疫反应并改善腺体功能，其有效性因性别和年龄而异。这些发现支持了这些化合物作为根据个体患者特征量身定制的干燥综合征个性化治疗药物的潜力。
