Psoriasis is a common chronic inflammatory skin disease that causes significant impact on quality of life for those afflicted. The cause of psoriasis is unknown, but T cells and dendritic cells within affected skin are believed to mediate disease. IL-23, a recently discovered cytokine that consists of p19 and p40 subunits, is now believed to be critical in the development of several classic autoimmune inflammatory diseases in mice. In these diseases, IL-23 stimulates survival and proliferation of a specific set of unique T cells that produce IL- 17A (named """"""""Th17 cells""""""""). Another cytokine, TGF?1, has now been shown to induce initial differentiation of naive T cells into Th17 cells. In humans, recent reports indicate that IL-23 produced by keratinocytes and activated dendritic cells, TGF?1 produced by keratinocytes, and IL-17A produced by Th17 cells are increased in psoriatic skin. Furthermore, monoclonal antibodies that target p40 (a component of IL-23) have shown marked clinical efficacy in psoriasis patients in phase I and II studies. These data suggest that IL-23, TGF?1, and IL-17A are playing critical roles in psoriasis pathogenesis.
In Specific Aim 1, we will determine how TGF?1, IL-23, and Th17 cytokines (IL-17A, IL-17F, IL-6, and TNF-a) activate keratinocytes and induce migration of inflammatory dendritic cells from blood into skin. The hypotheses for this aim are that TGF?1 and IL-17A stimulate keratinocytes to produce CCL20 (a skin-homing chemokine) and IL-23; CCL20 promotes chemotaxis of inflammatory dendritic cells from blood into skin; and IL-23 produced by both keratinocytes and inflammatory dendritic cells drive survival and proliferation of IL-17-producing Th17 cells in psoriasis lesions.
In Specific Aim 2, we will create and characterize two transgenic mouse strains that over-express IL-23 in either keratinocytes or Langerhan cells, determine the functional consequences of IL-23 over-expression in each of these two cell types, and test the ability of anti-IL-23 and anti-IL-17 approaches to ameliorate inflammatory skin disease. The hypothesis for this aim is that transgenic mice that over-express IL-23 within keratinocytes or Langerhan cells develop psoriasis-like skin disease that is dependent upon IL-23 to stimulate survival and proliferation of Th17 cells.
In Specific Aim 3, we will determine which specific leukocytes produce IL-23 in the skin and blood of patients with psoriasis and how IL-23 expression is regulated in these cells. The hypothesis for this aim is that psoriatic skin contains blood-derived inflammatory dendritic cells that over-produce IL-23, and IL-23 expression is regulated by TGF?1 and IL-17A in these cells. Taken together, this research will promote detailed understanding of the immunologic basis for psoriasis, will bolster the rationale of IL-23 as a therapeutic target in psoriasis, and will stimulate research into the role of IL-23 in the pathogenesis of other autoimmune inflammatory diseases in humans. Psoriasis is a common (2-3% of the population) chronic inflammatory skin disease of unknown etiology that causes significant impact on quality of life for those afflicted. Taken together, this research will promote detailed understanding of the immunologic basis for psoriasis, will bolster the rationale of interleukin 23 as a therapeutic target in psoriasis, and will stimulate research into the role of interleukin 23 in the pathogenesis of other autoimmune inflammatory diseases in humans. ? ? ?
