Therapeutic Efficacy of Targeting HLA-DR3 Using A Spontaneous Humanized Mouse Model of Sjögren’s Disease 3606

Abstract Description Sjögren’s Disease (SjD) is an autoimmune disease characterized by dry mouth and eyes, affecting approximately 4 million Americans. SjD is a complex condition with a multifactorial etiology and a diverse patient population in terms of disease activity, severity, and response to therapy. To better comprehend the etiologies and develop effective treatments, it is crucial to utilize appropriate animal models to unravel the different aspects of the autoimmune process. In this study, we have been examining the Non-Obese Diabetic (NOD)-DR3 mouse model, an NOD-congenic animal with human HLA class II expression, specifically the DR3(DRw17) transgene. The DR3 transgene expresses the HLA-DR3 genotype, comprising HLA-DRA0101 and HLA-DRB10301. Our research revealed that NOD-DR3 mice develop SjD phenotypes characterized by decreased salivary flow rates, elevated levels of anti-nuclear autoantibodies, changes in salivary gland proinflammatory immune cell populations and their cytokines, and increased focal scores. A notable finding is that NOD-DR3 mice exhibit sexually dimorphic disease phenotypes, mirroring patterns observed in human patients. Lastly, employing machine learning algorithms targeting DR3, we have identified and tested novel drug compounds. Some compounds alleviated the clinical signs of SjD in the mouse model. In summary, our research demonstrates the potential of this inaugural humanized mouse model of SjD and identifies DR3 as a target for treating the disease. Funding Sources Supported by the National Institute of Dental and Craniofacial Research (NIDCR) (DE028544, DE028544-02S1) Topic Categories Therapeutic Approaches to Autoimmunity (THER)