Targeting Endogenous Mesenchymal Stromal Cells with Ruxolitinib to Treat Sialadenitis in Sjogren's Syndrome

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PROJECT SUMMARY Sjӧgren’s disease (SjD), a common systemic autoimmune disease characterized by marked oral and ocular sicca, has no disease modifying treatments available. Our long-term goal is to develop new effective therapies for SjD. The objective of this application is to determine the mechanism through which ruxolitinib inhibits IFN- induced pro-inflammatory salivary gland mesenchymal stromal cells (MSCs) and define the effects of ruxolitinib on disease activity in SjD mouse models. The central hypothesis of the proposed studies is that IFN- stimulated SG-MSCs, through STAT1 signaling, are pro-inflammatory and that ruxolitinib inhibits this pro- inflammatory phenotype and ultimately reduces SG inflammation and restores saliva production in SjD mouse models. The rationale for this hypothesis is based on our new data showing ruxolitinib abolishes IFN-induced MSC activation and reduces MHCII upregulation in vitro through STAT1. These new data are pivotal because they identify a possible mechanism by which the pro-inflammatory aspect of MSCs can be modified. The central hypothesis will be tested by pursuing two specific aims: (1) Determine the effect of ruxolitinib on SG- MSC immunobiology in vitro and (2) define the effects of ruxolitinib on SG-MSC and whole gland phenotype and function in vivo. Under the first aim, SG-MSCs from SjD and control patients will be treated with IFN ± ruxolitinib and phenotype and functional differences will be examined in vitro. Chromatin immunoprecipitation- sequencing will be performed to determine the mechanism by which ruxolitinib imparts change in the immunomodulatory profile of SG-MSCs. For the second aim, two SjD mouse models will be treated with ruxolitinib or vehicle. SG-MSCs will be isolated and interrogated from each treatment group. Next, a global salivary gland and systemic evaluation will be performed. The research proposed in this application is innovative because traditionally the anti-inflammatory profile of IFN-treated MSCs has been the focus of research. This proposal focuses on how IFN creates a pro-inflammatory MSC phenotype that can be inhibited with ruxolitinib. Furthermore, SjD research has focused on JAK1 inhibition and we propose the use of a JAK1 & 2 inhibitor to treat SjD. The proposed research is significant because ruxolitinib holds promise as a feasible modality to promote anti-inflammatory resident MSCs and for systemic SjD treatment. Should this pilot study determine the mechanism by which ruxolitinib creates anti-inflammatory MSCs or that ruxolitinib improves SjD in mice, these finding will be harnessed toward novel MSC-based or systemic treatment of SjD.