|Budget Amount *help
¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1991 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1990 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1989 : ¥900,000 (Direct Cost : ¥900,000)
In order to approach the mechanisms of inflammatory demyelination in the central nervous system, we first examined the interaction between oligodendrocytes and immune system. Neither lymphokines, monokisses nor myelin basic protein (MBP) -reactive T cells were cytotoxic to isolated mouse oligodendrocytes in vitro. Microglia and astrocytes failed to present MBP antigen to the MBP-reactive T cell lines, though both cell types were induced to express Ia antigens by gamma-interferon. Crude lymphokines were found to facilitate maturation of oligodendrocytes rather than toxic to these cells.
Second, we analysed the production and pathophysiological functions of cytokines in the CNS. Microglia produced interleukin (IL) -1, 6, TNF-alpha and another unknown factor which induced astrocyte proliferation. This factor may have a role in the development of gliosis. In addition to these cytokines, astrocytes produced M-CSF, GM-CSF, TGF-beta and other unknown factors, one of which facilitated tight junction formation by endothelial cells, and the other factor suppressed the functions of microglia. TGF-beta also suppress the cytokine production by microglia.
Retrovirus infection and transfection of Human T-cell Leukemia Virus Type 1 transactivator also induced IL-1 and IL-6 production, but not TNF-alpha production, by astrocytes. This transfection also induced surface expression of class I major histocompatibility complex antigens on these glial cells. Since overexpression of MHC antigens reportedly induces oligodendrocyte damage, this transfection model may be useful tool to induce de- or dysmyelination.
These observations suggested that immunoregulatory cytokines were produced in the CNS, and these cytokines might play a important role on the cell-cell interaction in neural cells. Virus could be a possible inducer of these cytokines, which then play a significant role on the development of various neurological disorders including inflammatory demyelination.