| Budget Amount *help |
¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 1995: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1994: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Research Abstract |
To elucidate the functional role of human and murine T cells indigenously residing in the epidermisthe following studies were performed. First, we attempted to isolate T cells that had persisted within the lesional epidermis of patients with fixed drug eruption (FDE) ; and their antigen-specificity, function, and T cell receptor (TCR) repertoire were examined. These epidermal T cells did not show NK-like cytotoxic activity, but they could be induced to display cytolytic activity against various target cells including keratinocytes, by ligation of the CD3/TCR-alphabeta complex. Some of these T cells appeared to be self-reactive and they produced T_H1 type cytokines, such as IFN-gamma and TNF-beta, upon stimulation. Comparative analyzes to TCR Valpha and Vbeta expression in these T cells and the paired PBL by PCR demonstrated that they utilize a very limited range of Valpha and Vbeta genes.
As a second approach, we attempted to elucidate the functional role of murine epidermal T cells exp
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ressing monomorphic Vgamma5 TCR,using mice (delta^<-/->) congenitally lacking gammadelta^+ T cells as a result of disruption of the TCR Cdelta gene segment. In the epidermis of delta^<-/-> mice, congenital lack or gammadelta^+ dendritic epidermal cell (dEC) was substituted for by alphabeta^+ dEC.delta^<-/-> mice developed significantly enhanced DTH responses and cutaneous GVHD following intradermal injection of autoreactive GVHD-causing T cells. Surprisingly, site-restricted resistance to the cutaneous GVHD that was induced in delta^<+/+> and delta^<+/-> mice after spontaneous recovery was not induced in the epidermis of delta^<-/-> mice. The reconstitution of delta^<-/-> mice with gammadelta^+ dEC precursors restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that effector functions of epidermal T cells are potentially diverse and uncontrolled activation of epidermal T cells with self-destructive potential would likely be detrimental to epidermal integrity and that normal epidermis also contains regulatory "protective" T cells that can suppress the sutoaggressive responses. Less
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