Development of an improved preclinical humanized mouse platform representing the diverse clinical phenotypes of Sjögren's syndrome.

BACKGROUND

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, leading to impaired glandular secretion. To elucidate the pathogenic mechanisms underlying SS, suitable preclinical animal models are essential. In this study, we developed a humanized murine model that captures key immunopathological features of SS patients, and assessed its therapeutic utility.

METHODS

PBMCs obtained from SS patients were stimulated with anti-CD3 and anti-CD28 antibodies for 15 hours, and 1 × 106 or 2 × 106 of these cells were intraperitoneally injected into NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ (NSG) mice. At 5 weeks after cell injection, pathological analysis and immunophenotypic characterization of infiltrating immune cells within the salivary gland tissues were performed. To evaluate the efficacy of metformin, NSG mice transplanted with PBMCs were orally administered metformin daily for 5 weeks.

RESULTS

Mice injected with PBMCs from SS patients exhibited a significant increase in the frequency of human IL-17-producing T cells in the spleen, accompanied by enhanced infiltration of these pro-inflammatory cells into the salivary glands. Histopathological analysis of salivary glands revealed marked immune cell infiltration and a significant reduction in Aquaporin-5 expression in SS-derived PBMC-injected mice. Notably, these pathological changes were associated with the local recruitment of CXCR3+ Th17 cells. Metformin treatment significantly attenuated salivary gland inflammation, reduced the infiltration of pathogenic T cells, and mitigated molecular-level tissue damage in this humanized SS model.

CONCLUSIONS

The humanized murine model developed in this study effectively reproduced key cellular and molecular features of SS and provided a useful preclinical platform for investigating early-stage disease mechanisms and evaluating novel therapeutic strategies for SS.