|Budget Amount *help
¥37,300,000 (Direct Cost: ¥37,300,000)
Fiscal Year 2000: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1999: ¥17,300,000 (Direct Cost: ¥17,300,000)
Fiscal Year 1998: ¥16,300,000 (Direct Cost: ¥16,300,000)
To investigate the pathogenetic roles of HTLV-I to develop HTLV-I-associated diseases, including ATL, HAM/TSP, arthropathy and others, we analyzed rat models, which were previously established by the infection or transgene of HTLV-I.
1) An HTLV-I infected rat model for HAM/TSP (HAM rat) : In this project, we clarified the pathogenetic role of HTLV-I in HAM rat. Majority of infected cells in the spinal cords is microglia/macrophages and the provirus expansion and increase of pX expression are observed at early asymptmatic stage. Expression of Tax, encoded in pX region, in microglia/macrophages transactivates TNF-α production, and TNF-α induces apoptosis of oligodendrocytes with down-regulation of bcl-2, then demyelination develops. Infiltration and proliferation of activated microglia/macrophages as a scavenger are also progressed demyelination. At the late stage, astrocytes proliferate locally to repair the damage in the lesion.
2) An HTLV-I LTR-env-pX transgenicrat model developed colla
gen vascular diseases (env-pX rat) : In env-pX rats, in vitro and in vivo immune hyper-responsiveness of lymphocytes and dysfunction of immune regulatory T cells were observed. Results of cell or tissue transfer experiments of bone marrow, spleen and thymus suggest that three different mechanisms relate to develop diseases of env-pX rats. The transgene expressed in thymus is primitive to develop the vasculitis, and that in peripheral lymphocytes is to develop dermatitis. Arthritis and other diseases develop when the target tissues possess the transgene. On the other hand, HAM rat like encephalomyelopathy develops in one of two env-pX rat lines after linebreeding in closed colony.
3) A transgenic rat model carrying pX under the control of p561ck type 1 promoter developed thymoma (lck-pX rat) : Frequency of thymomas was correlated with expression levels of the transgene. The thymoma develops from medullary epithelial cells and the cells were originated from non-adherent mononuclear cells of bone marrow. Less