Gene therapy using IL-27 ameliorates Sjögren's syndrome-like autoimmune exocrinopathy

Abstract

IntroductionSjögren'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.MethodsRecombinant 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.ResultsMice 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.ConclusionsThese 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.

The Immunobiology of Interleukin-27

“…In the clinical setting, a polymorphism in IL-27p28 has been associated with the severity of rheumatoid arthritis (186), and increased levels of IL-27 have been observed in the synovial fluid of patients with rheumatoid arthritis, which correlates with reduced local levels of IL-17 and IL-6 (184,187). The literature on Sjögren's syndrome parallels that of arthritis, in that IL-27 can be used to inhibit disease in a murine model (188), and elevated IL-27 is associated with this condition in humans (189). For both of these diseases, it has largely been assumed that the protective effects of IL-27 revolve around its ability to limit Th17 responses; what needs to be determined is whether IL-27 has a direct or indirect impact on pathological B cell responses.…”

Mouse Models of Primary Sjogren’s Syndrome

“…For instance, CD4+ T cells expressing the signature cytokine IL-17 (T H 17 cells) were shown to be involved during SjS pathogenesis [77–79]. It was also demonstrated that IL-27, known as a natural inhibitor of T H 17 cell activity, could suppress the development of SjS in C57BL/6.NOD- Aec1Aec2 mice [80]. Interestingly, both the administration of exogenous IL-7 [81] and induction of IL-7 by innate immune stimulation [82] resulted in accelerated SjS onset in C57BL/6.NOD- Aec1Aec2 mice [83].…”

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“…18 It also has been proposed that IL-27 can show as effective therapeutic agent suppresses differentiation of Th17 cells in autoimmune diseases like Sjögren syndrome. 10,[43][44][45][46] …”