Pulmonary fibrosis is a potentially fatal disease characterized by an increase in lung fibroblast number and a substantial accumulation of collagen and extracellular matrix components. This disorder can be caused as a result of radiation or chemotherapy treatment of malignancy, occupational exposure to pesticides and certain dusts, or can arise spontaneously in diseases such as sarcoidosis and idiopathic pulmonary fibrosis (IPF). The development of pulmonary fibrosis is generally associated with a major inflammatory response, frequently including a massive infiltration of T lymphocytes. The major objective of this proposal is to investigate the role of T lymphocytes in the induction of pulmonary fibrosis. Evidence for the involvement of thymically-derived cells in the development of bleomycin-induced pulmonary fibrosis in mice has been demonstrated by a number of laboratories, but the precise role of these cells in the fibrotic process is not currently known, nor whether particular T-cell subsets are involved, nor whether their influence is mediated through the T-cell receptor (TCR). This project was designed to investigate the role of T lymphocytes in the fibrotic process using a transgenic mouse model that we have developed, in which the structural and functional TCR repertoire is profoundly perturbed. This perturbation has been achieved through the construction of transgenic mice expressing only a single TCR, to the exclusion of the millions of endogenous TCR's normally expressed. These animals, which are substantially restricted in the potential TCR diversity their T-lymphocytes can express, offer the opportunity to test whether severe defects in the TCR repertoire influence susceptibility to the development of pulmonary fibrosis. Thus, this model allows us to directly test the hypothesis that T lymphocytes mediate their effects on the fibrotic process through their TCRs. A series of transgenic mice have been generated which express the rearranged TCR genes from a TH cell specific for hen-egg lysozyme. Analysis of these mice has determined that the expression of the TCR transgenes significantly disrupts the functional TCR repertoire, manifested by a dramatic alteration in the antigen response profile of these mice. The TCR transgenes also drastically alter the susceptibility of transgenic mice to the experimental induction of pulmonary fibrosis by bleomycin sulfate. TCR transgenic mice exhibit a severely high degree of pulmonary fibrosis upon administration of bleomycin, unlike genetically matched nontransgenic animals which are relatively resistant to drug-induced disease. In this proposal, the influence of the TCR transgenes on the susceptibility to pulmonary fibrosis will be determined, with a focus on identifying the mode of transgene action, and on defining the immunological mechanism underlying this process.
| Thatcher, Thomas H; Sime, Patricia J; Barth, Richard K (2005) Sensitivity to bleomycin-induced lung injury is not moderated by an antigen-limited T-cell repertoire. Exp Lung Res 31:685-700 |
| Wei, C; Callahan, B P; Turner, M J et al. (1998) Regulation of human prostate-specific antigen gene expression in transgenic mice: evidence for an enhancer between the PSA and human glandular kallikrein-1 genes. Int J Mol Med 2:487-96 |
| O'Brien, D P; Baecher-Allan, C M; Burns Jr, R P et al. (1997) Elimination of T-cell-receptor beta-chain diversity in transgenic mice restricts antigen-specific but not alloreactive responses. Immunology 91:375-82 |
| Baecher-Allan, C M; Barth, R K (1993) PCR analysis of cytokine induction profiles associated with mouse strain variation in susceptibility to pulmonary fibrosis. Reg Immunol 5:207-17 |
