Anti-IL-7 receptor-α treatment ameliorates newly established Sjogren's-like exocrinopathy in non-obese diabetic mice

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Yu, Qing¹ 

[1] Forsyth Inst, 245 First St, Cambridge, MA 02142 USA

关键词: Sjogren's syndrome;    Salivary gland;    Autoimmune exocrinopathy;    T helper 1 cells;    Interferon-gamma;    Hyposalivation;    Autoimmunity;   

DOI  :  10.1016/j.bbadis.2018.04.010

来源: Elsevier

【 摘 要 】

The levels of interleukin (IL)-7 and its receptor are elevated in the salivary glands of patients with Sjogren's syndrome (SS). Our previous study indicates that IL-7 plays a critical pathogenic role in the development and onset of SS in a mouse model of this disease. The present study aims at determining whether IL-7 also plays a role in sustaining SS pathologies after the disease onset, by using the non-obese diabetic (NOD) model. Intraperitoneal administration of a blocking antibody against the IL-7 receptor alpha chain (IL-7R alpha) to female NOD mice aged 10 weeks, which exhibited newly onset clinical SS, for the duration of 3 weeks significantly ameliorated characteristic SS pathologies including hyposalivation and leukocyte infiltration of the submandibular glands (SMGs). These changes were accompanied by a decrease in IFN-gamma-producing CD4 T- and CD8 T cells, B cells, and lymphocyte chemoattractants CXCL9, -10, -11 and -13 in the SMGs. Anti-IL-7R alpha treatment markedly diminished the amount of TNF-alpha in the SMGs and increased the level of claudin-1 and aquaporin 5, two molecules critical for normal salivary secretion. Furthermore, neutralization of IFN-gamma and TNF-alpha, individually or in combination, considerably improved salivary secretion, reduced leukocyte infiltration and down-regulated CXCL9 and -13 expression in the SMGs. Collectively, the results indicate that endogenous IL-7R signals promote Th1 and Tc1 responses and IFN-gamma- and TNF-alpha production to sustain the persistence of SS-like sialadenitis in NOD mice. These findings suggest that IL-7 and Th1 cytokines could serve as promising therapeutic targets for this prevalent autoimmune disease.

【 授权许可】

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