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Role of immunoregulation in the development of dermal fibrosis in tight-skin mice

University of British Columbia

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.

Thesis/Dissertation

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2009-07-23

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http://hdl.handle.net/2429/11176

Experimental Medicine

University of British Columbia

UBCV

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