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|Title:||Regulatory Immune-Responses Occurring within the Liver Downstream of Hepatic iNKTcell activation|
|Abstract:||Despite its` high prevalence, the pathogenesis of immune-mediated liver injury is poorly understood. Invariant Natural killer T (iNKT) cells are a distinct innate immune T cell believed to orchestrate a balance between pro-and-anti-inflammatory responses within the liver during immune mediated liver injury. However, the regulatory roles of iNKT cells in the modulation of the hepatic immune response are still poorly defined. In this work we utilized the alpha-galactosylceramide-induced hepatitis model, a model of specific iNKT cell activation, to help us dissect basic immune regulatory mechanisms occurring in the liver during hepatic innate immune activation. We have now documented the rapid recruitment and activation of innate-like regulatory B cells in the liver subsequent to iNKT cell activation. These regulatory B cells were recruited from the spleen and peritoneum. Moreover, depletion of B cells exacerbated iNKT cell-driven liver injury, in association with a profound alteration in the hepatic cytokine milieu and enhanced neutrophil recruitment. This suppression of hepatic inflammation was IL-10 and TGFβ1 independent, and involved activity of ecto-5'-nucleotidase/CD73. IL-22 is an innate cytokine which has been broadly implicated in the regulation of hepatic immunity, and IL-22BP is a secreted specific IL-22 antagonist. In our second paper, we found that activation of hepatic iNKT cells led to the striking, parallel early recruitment of both IL-22 and IL-22BP producing immune cells. Additionally, we found a marked increase in the hepatic expression of both IL-22BP and IL-22R1 in liver biopsies obtained from patients with viral and autoimmune liver diseases compared to normal livers. We also found that the inflammasome plays an important role in regulating IL-22BP expression within liver recruited immune cells and hepatocytes. In this dissertation we have uncovered previously unrecognized regulatory mechanisms induced by activated iNKT cells within the liver. These findings give insight into pathological changes occurring in various human liver diseases in which iNKT cells have been implicated, and in which liver injury is immune-mediated. These findings could potentially be used to develop new regulatory B-cell-based and/or cytokine-based therapies to beneficially alter hepatic innate immune responses in patients suffering with immune-mediated liver diseases.|
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