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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.<\/jats:p>","DOI":"10.1093\/immhor\/vlaf030","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T23:50:00Z","timestamp":1756165800000},"source":"Crossref","is-referenced-by-count":4,"title":["Exploring MHC class II I-Ab blockade as a potential treatment for Sj\u00f6gren\u2019s disease in the mouse model"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5703-9190","authenticated-orcid":false,"given":"Alexandria","family":"Voigt","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida , Gainesville, FL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivai","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Infectious 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