IL-12 regulates psoriatic plaque formation by inhibiting γδ T cells (P4033)

Abstract

Abstract Cytokines are key mediators of immune responses and IL-23 is a critical player in psoriasis pathogenesis. New effective monoclonal antibody directed against common subunit p40 of both IL-12 and IL-23 is currently used in clinics to treat plaque type psoriasis. Recently was shown that Aldara cream, a drug commonly used in the treatment of benign skin disorders, is a potent stimulator of psoriasis-like plaque formation and implicates proinflammatory cytokines like IL-17A, IL-17F and IL-22 in the disease pathogenicity. Using this model we found that mice deficient in p40 as well as mice treated with neutralizing anti-p40 mAbs have a substantially reduced skin inflammation upon Aldara treatment. As anti-p40 Abs target both IL-12 and IL-23, we hypothesed, that IL-12 might have a protective role in psoriatic plaque formation. We found that skin inflammation was highly increased in mice lacking IL-12 (IL-12p35-/-) or when IL-12 signalling (IL-12Rb2-/-) was disrupted. Local injection of IL-12Fc significantly reduced skin inflammation that was corroborated by reduced leucocytes infiltrations as well diminished IL-17A expression in the skin. IL-12 stimulated CD27- γδ T cells secrete lower levels of IL-17A and F compared to their unstimulated controls suggesting direct effect of IL-12 on γδ T cells. Taken together, our findings suggest a protective role of IL-12 in psoriatic inflammation and support the need of introducing more specific treatment targeting the IL-23/IL-17 axis.