- Psoriasis is a common and enigmatic skin disease causing significant morbidity. No cure is available and current treatments provide only temporary relief associated with various side effects. Two major obstacles (one conceptual and one technological) have hindered progress in understanding and treating this complex cutaneous disorder. First, there has been great dispute as to whether psoriasis is fundamentally a disease of the immune system or keratinocyte. Undoubtedly, multiple factors contribute to the pathophysiology of psoriasis. However, there is now compelling evidence that the T lymphocyte is a key and central causal agent of psoriasis. Second, there has been no suitable animal model for studying the disease. This deficiency has now been overcome by an engraftment of human skin onto immunodeficient (SCID) mice. After transplantation, symptomless skin can be converted into full-fledged psoriatic plaques by injection of activated, autologous T cells derived from the blood of psoriatic patients. The hypothesis to be tested is that psoriasis is mediated by a specific subset of pathogenic T lymphocytes from the blood, which when activated and upon entrance into skin trigger proliferative responses by endothelial cells and keratinocytes. The long-term goal is to phenotype and genotype the pathogenic T cell responsible for causing psoriasis. The novel SCID mouse model engrafted with human skin will be used throughout the project In the first aim, requirements for T cell activation will be determined. In the second aim, causation of psoriasis by CD4+ or CD8+ T cells and a requirement for preferential expression of T cell receptor Vbeta repertoire will be examined.
The third aim concerns establishment of pathogenic T cell lines and cell clones.
The final aim will identify differentially expressed mRNA in pathogenic and regulatory T cells and psoriatic keratinocytes. The applicants expect that these studies will enhance our understanding of the causation of psoriasis and provide a basis for developing new and more effective treatments for this common and chronic disease.
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