Therapeutic potential of interleukin-17 neutralization in a novel humanized mouse model of Sjögren's disease

Abstract

Sjögren's disease (SjD) is a chronic autoimmune disease, in which the immune system targets exocrine glands and leads to dryness symptoms. There is an increasing need to develop novel therapeutic approach as the treatment plan has not been changed in the past decade. However, findings in mouse model may not be directly applied in patients, given the substantial differences of immune system between human and mice. In the present study, using antigens derived from human salivary A-253 cells, we established experimental Sjögren's syndrome (ESS) in mice with human immune system (HIS). HIS-ESS mice exhibited key features of human disease, including salivary hypofunction, increased serum levels of autoantibodies and tissue destruction in the salivary glands. Phenotypic analysis revealed enhanced effector B and T cell subsets, including Th1, Th17 and T follicular helper (Tfh) cells in HIS-ESS mice, while multiplex imaging analysis suggested enlarged B cell follicles and expanded memory B cells. IL-17 neutralization therapy significantly ameliorated disease pathology at both acute and chronic stages, in which B cells were mainly affected, to the less extent Th1 and Tfh cells in HIS-ESS mice. Together, HIS-ESS mouse model highly recapitulated SjD features and immunopathogenesis, which may serve as a useful tool in drug screening and pre-clinical studies.

Keywords: Humanized; Immunization; Interleukin-17; Mouse model; Neutralization; Sjögren’s disease.