Research in Skin Inflammation

In the skin, T lymphocytes are critical modulators and effectors of acquired defense responses such as delayed-type hypersensitivity (DTH). T lymphocytes and other leukocytes are recruited to the challenged site via the interaction of selectins, integrins, immunoglobulin gene superfamily molecules with their ligands, and cytokines including the large and growing chemokine group. Endogenous proinflammatory agents such as Tumor Necrosis Factor (TNF)-alpha and Interleukin-1 (IL-1) modulate lymphocyte recruitment via up-regulation of endothelial adhesion molecules and chemokines. In vitro evidence suggests that endothelial cell-derived chemokines may play a crucial role in inducing firm arrest of leukocytes on endothelial cells prior to transmigration. However, the investigation of the expression patterns and regulation of chemokines in human skin has been limited. Our goal is to qualitatively and quantitatively investigate changes in chemokine expression patterns in human skin using a DTH response to mumps antigen as a model T cell mediated immunological response. We will study the effects of intradermal injection of mumps antigen on cutaneous chemokine expression in healthy human volunteers over a five-day period. Skin biopsies of treated and mock-treated areas will be obtained and processed for state-of-the-art, real-time quantitative RT-PCR analysis of mRNA for chemokines and related molecules of interest. Routine and immunohistological analysis of chemokine receptor, chemokines, cytokines and other cell markers on fixed and frozen tissue will also be performed in an attempt to correlate chemokine expression patterns with the influx of leukocyte subsets into skin. Our hypothesis is that the chemokines will be up-regulated, but that the kinetics and expression patterns of individual chemokines may not be identical, thus possibly accounting for the differential recruitment of T lymphocytes and other leukocytes during the course of the DTH response. Chemokine expression as determined by quantitative RT-PCR will be compared with results obtained semi-quantitatively by immunohistochemical staining. This study may increase the understanding of the pathogenic mechanisms of inflammatory diseases that are characterized by the recruitment of T lymphocytes, thus possibly identifying targets for the treatment of cutaneous inflammatory diseases such as psoriasis.