| Summary: | The tight-skin (Tsk/+) mutant mouse serves as an experimental model for human
scleroderma, a connective tissue disorder characterized by excessive deposition of collagen and
other extracellular matrix molecules predominantly within the dermal regions, leading to the
development of fibrosis. The pathogenesis underlying this disease is currently unclear; however,
cells of the immune system have been proposed to be involved in the regulation of fibrosis in
both mouse and man. Thus, the potential contribution of immunoregulatory factors in disease
development were examined using the Tsk/+ model. These studies identified a crucial role for
CD4+ T-helper 2 (Th2) cells in regulating the development of dermal fibrosis in the Tsk/+
mutant mice. The ability of CD4+ Th2-cell derived cytokines, in particular IL-4, to modulate
dermal collagen deposition in Tsk/+ mice was demonstrated using in vitro and in vivo
approaches. Specifically, inhibiting IL-4, a Th2 cell-derived cytokine and a requisite factor in the
induction CD4+ Th2 cell differentiation, prevented the development of dermal fibrosis in Tsk/+
mice. These studies suggested a pivotal role for Th2 cells and/or Th2-derived EL-4 in the Tsk/+
disease process. Furthermore, augmentatation of CD4+ Th2 responses, via deletion of the genes
for either IL-12 or IFN-y, increased dermal collagen deposition within Tsk/+ mice, also
supporting a model in which CD4+ Th2 cell activity is required for dermal pathology in these
mice. Moreover, the emergence of a Th2 immune response apparently required for dermal
fibrosis in Tsk/+ mice appears to require the contribution of yδ T cells as the absence of these
cells prevented the evolution of the Tsk/+ dermal fibrosis. These studies will help to provide a
framework in understanding the role of Th cells in the development of the fibrotic disease in
Tsk/+ mice, with potential relevance to human scleroderma. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate
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