EXPERIMENTAL PRODUCTION AND MODULATION OF HUMAN CYTOTOXIC DERMATITIS IN HUMAN-MURINE CHIMERAS

Human dermatitis involving cytotoxic interaction between effector lymp hocytes and epithelial target cells has thus far been documented in vi vo only as naturally occurring disease or as an iatrogenic complicatio n of organ engraftment. In this report, we reproduce human cytotoxic d ermatitis via local microinjection of heterologous human lymphocytes i nto human skin xenografted to mice with severe combined immune deficie ncy syndrome. Injection sites develop progressive T cell epidermotropi sm culminating in cytotoxic dermatitis resembling human lichen planus within 4 weeks. Effector T cells express a CD8(+), TIA-1(+) phenotype, proliferate locally, express interleukin-2 surface receptors, and dem onstrate interferon-gamma mRNA induction after microinjection. Migrati on of these T cells into the epidermis is closely linked to experiment al induction and coincident expression of intercellular adhesion molec ule by keratinocytes. T cell apposition to keratinocytes is associated with endonuclease-mediated DNA fragmentation (apoptosis) in the latte r cell type, Intraepidermal T cell migration and related lesion format ion is partially abrogated by systemic administration of antisense oli gonucleotide to ICAM-1 mRNA. These findings demonstrate that human cyt otoxic tissue injury directed against epithelial targets call be produ ced and modulated in chimeric mice.