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Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2438-2447. doi: 10.1016/j.bbadis.2018.04.010. Epub 2018 Apr 19.

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

Author information

1
The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115.
2
The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115.. Electronic address: qyu@forsyth.org.

Abstract

The levels of interleukin (IL)-7 and its receptor are elevated in the salivary glands of patients with Sjögren'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 α chain (IL-7Rα) 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-γ-producing CD4 T- and CD8 T cells, B cells, and lymphocyte chemoattractants CXCL9, -10, -11 and -13 in the SMGs. Anti-IL-7Rα treatment markedly diminished the amount of TNF-α in the SMGs and increased the level of claudin-1 and aquaporin 5, two molecules critical for normal salivary secretion. Furthermore, neutralization of IFN-γ and TNF-α, 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-γ- and TNF-α 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.

KEYWORDS:

Autoimmune exocrinopathy; Autoimmunity; Hyposalivation; Interferon-γ; Salivary gland; Sjögren's syndrome; T helper 1 cells

PMID:
29680668
PMCID:
PMC5963292
[Available on 2019-07-01]
DOI:
10.1016/j.bbadis.2018.04.010
[Indexed for MEDLINE]

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