Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis ofcentral nervous system-infiltrating lymphocytes

The exclusive detrimental role of proinflammatory cytokines in demyelinatin g diseases of the CNS, such as multiple sclerosis, is controversial. Here w e show that the intrathecal delivery of an HSV-1-derived vector engineered with the mouse IFN-gamma gene leads to persistent (up to 4 wk) CNS producti on of IFN-gamma and inhibits the course of a chronic-progressive form of ex perimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by my elin oligodendrocyte glycoprotein (MOG)(35-55). Mice treated with the IFN-g amma -containing vector before EAE onset showed an earlier onset but a mild er course of the disease compared with control mice treated with the empty vector. In addition, 83% of IFN-gamma -treated mice completely recovered wi thin 25 days post immunization, whereas control mice did not recover up to 60 days post immunization. Mice treated with the IFN-gamma -containing vect or within 1 wk after EAE onset partially recovered from the disease within 25 days after vector injection, whereas control mice worsened. Recovery fro m EAE in mice treated with IFN-gamma was associated with a significant incr ease of CNS-infiltrating lymphocytes undergoing apoptosis. During the recov ery phase, the mRNA level of TNFR1 was also significantly increased in CNS- infiltrating cells from IFN-gamma -treated mice compared with controls. Our results further challenge the exclusive detrimental role of IFN-gamma in t he CNS during EAE/multiple sclerosis, and indicate that CNS-confined inflam mation may induce protective immunological countermechanisms leading to a f aster clearance of encephalitogenic T cells by apoptosis, thus restoring th e immune privilege of the CNS.