Psoriasis is a common and chronic inflammatory disease involving both skin and joints of afflicted individuals. During the past ten years several paradigm shifts have occurred in the understanding of the pathophysiology of psoriasis manifested by a change in emphasis from the epidermal keratinocyte to the T cell;from a focus on adaptive immune reactions to include consideration of innate immunity;and an increasing emphasis on dendritic antigen presenting cells (APCs), and resident immunocytes in pre-psoriatic skin. Despite remarkable progress in the realm of biopharmaceuticals that can significantly improve both skin and arthritic manifestation of psoriasis, precise molecular and cellular delineation of the immunopathogenic events responsible for creation and maintenance of lesions have yet to be elucidated. The principal long-term objective of this proposal is to identify and characterize the immunophenotype and cytokine production profile for resident T cells and APCs that actually cause the disease. Two major aims are devised to systematically examine key cellular and molecular mediators including identification and characterization of: Pathogenic APCs (Aim 1), and Pathogenic T Cells (Aim 2). All of these aims will rely heavily on two well-characterized and validated animal models in which symptomless or pre-psoriatic skin is engrafted onto specific immunodeficient strains of mice (i.e. SCID and AGR129 mice). By utilizing entirely human components maintained in their normal 3-dimensional configuration and microenvironment, these in-vivo results obtained in both xenogenic models will be relevant to the human disease state. Definitive mechanistic conclusions establishing cause:effect relationships will be derived from these proposed studies. Successful completion of both aims will greatly advance our understanding of the immunopathogenesis of psoriasis by identifying and characterizing primary effector immunocyte subsets, leading to novel therapeutic strategies that can target specific molecules/cell types to achieve maximal efficacy. Highly selective therapeutic targeting will minimize side effects including nonspecific immunosuppression that may be associated with opportunistic infections, or increased incidence of malignancies, in psoriatic patients with chronically damaged skin.
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