MULTIPLE-SCLEROSIS - IMMUNOMODULATORY EFFECTS OF HUMAN ASTROCYTES ON T-CELLS

Using a human culture system, we have previously shown that interferon -gamma-and rumour necrosis factor-a-stimulated astrocytes are capable of presenting antigens to T lymphocytes, but do not support antigen-de pendent T cell proliferation. To gain further insight into the mechani sms involved in the local regulation of intracerebral T cell responses , lye have investigated the effects of astrocytes on T cell proliferat ion induced by peripheral blood-derived mononuclear cells(PBMC). We fo und that astrocytes derived from human embryonic brain were able to su ppress PBMC-dependent proliferation of antigen-specific, CD4(+) T cell lines. Interferon-gamma production by PBMC-stimulated T cells was als o suppressed by astrocytes, and this inhibition was seen as early as 6 h after initiation of co-culture. The inhibitory effect was observed in the presence of both HLA matched and mismatched astrocytes and was mediated by astrocyte-derived soluble factor(s) rather than by direct cellular- contact. Inhibition of T cell proliferation was incompletely reverted by indomethacin, suggesting that prostaglandins were partial ly involved in the suppressive effect. The cytotoxic mediator nitric o xide was not involved in astrocyte-mediated inhibition These observati ons led us to further investigate the contribution of other mediators known to down-regulate inflammatory processes. Our astrocyte cultures did not synthesize interleukin (IL)-4 or IL-10, whereas they secreted both the latent and active forms of transforming growth factor-beta 2. Transforming growth factor-beta was, however found not to participate in astrocyte-induced inhibition in vitro. The inhibitory properties o f human astrocytes may contribute to confinement of inflammatory lesio ns in multiple sclerosis and other inflammatory diseases of the centra l nervous system.