Gene therapy using IL-27 ameliorates Sjögren's syndrome-like autoimmune exocrinopathy
1 Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
2 Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
3 Molecular Physiology and Therapeutics Branch, National Institutes of Dental and Cranial Research, National Institutes of Health, Bethesda, MD 20892, USA
4 Center for Orphan Autoimmune Disorders, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
5 Department of Pathology, Immunology & Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
6 Department of Infectious Disease and Pathology, College of Veterinary Medicine, Gainesville, FL 32608, USA
Arthritis Research & Therapy 2012, 14:R172 doi:10.1186/ar3925Published: 24 July 2012
Sjögren's syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that TH17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. In the present study, we examined whether IL-27, a natural inhibitor of TH17 activity, could down-regulate or reverse SjS in C57BL/6.NOD-Aec1Aec2 mice, a model of primary-SjS.
Recombinant serotype 2 adeno-associated viral (AAV2) vectors expressing either IL-27 (rAAV2-IL27) or LacZ (rAAV2-LacZ) were injected into 6 or 14 week-old C57BL/6.NOD-Aec1Aec2 mice. Changes in IL-27, IL-17, and IL-10 cytokine levels in peripheral blood were determined by ELISAs, while flow cytometry analyses were used to quantify cytokine-positive splenocytes. Histological assessment of salivary glands, anti-nuclear autoantibody (ANA) staining, and stimulated saliva flow rates were used to profile SjS disease severity.
Mice systemically treated with intravenous rAAV2-IL27 injections at either 6 or 14 weeks of age exhibited long-term elevated levels of serum IL-27 with concomitantly reduced levels of IL-17 compared with sera from mice injected with rAAV2-LacZ or saline out to 20 weeks post-inoculation. Most importantly, disease profiles revealed that rAAV2-IL27 treatment had little effect on lymphocytic focus (LF) scores, but resulted in structural changes in LF, lower titers of ANAs with changes in staining patterns, and a less severe clinical disease as determined by saliva flow rates.
These data support the concept that IL-27, when provided exogenously, can induce a suppressive effect on SjS development and thus may be an effective therapeutic agent for regulating TH17 pro-inflammatory activity in autoimmune diseases where the TH17 system has been shown to play an important role in their pathogenesis.