Objective To examine the role of CD40–CD154 costimulation and effects of therapeutic pathway blockade in the non-obese diabetic (NOD/ShiLtJ) model of Sjögren’s syndrome (SS).
Methods We assessed leucocyte infiltration in salivary glands (SGs) from NOD/ShiLtJ mice by immunohistochemistry and examined transcriptomics data of SG tissue from these animals for evidence of a CD40 pathway gene signature. Additionally, we dosed MR1 (anti-CD154 antibody) in NOD mice after the onset of SS-like disease and examined the effects of MR1 treatment on sialadenitis, autoantibody production, SG leucocyte infiltration, gene expression downstream of CD40 and acquaporin 5 (AQP5) expression.
Results We could detect evidence of CD40 expression and pathway activation in SG tissue from NOD mice. Additionally, therapeutic treatment with MR1 suppressed CD40 pathway genes and sialadenitis, inhibited ectopic lymphoid structure formation and autoantibody production, as well as decreased the frequency of antibody-secreting cells in SGs but had minimal effects on AQP5 expression in NOD/ShiLtJ SGs.
Conclusion CD40–CD154 interactions play an important role in key pathological processes in a mouse model of SS, suggesting that blockade of this costimulatory pathway in the clinic may have beneficial therapeutic effects in patients suffering from this autoimmune exocrinopathy.
- autoimmune diseases
- B cells
- Sjøgren's syndrome
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Handling editor Josef S Smolen
Contributors GW, MB and JSR planned and reported the study, SB conduted the bioinformatics analysis, KM, CA, MH, CT, MH, CC, ME, NM and MC conducted and analysed the study. GW and JSR wrote the paper.
Funding Study sponsored by Novartis Pharma AG.
Competing interests All authors on the paper are employees of Novartis Pharma AG.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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