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Protects C57BL/6 Mice from Chronic-Progressive Experimental Autoimmune Encephalomyelitis by Increasing Apoptosis of Central Nervous System-Infiltrating Lymphocytes1
*
Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy;
Department of Clinical and Experimental Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy;
Laboratory of Neuroimmunology, Neurological Institute "C. Mondino," University of Pavia, Pavia, Italy;
Roche Milano Ricerche, Milan, Italy; and
¶ Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
The exclusive detrimental role of proinflammatory cytokines in
demyelinating diseases of the CNS, such as multiple sclerosis, is
controversial. Here we show that the intrathecal delivery of an
HSV-1-derived vector engineered with the mouse IFN-
gene leads to persistent (up to 4 wk) CNS production of IFN-
and inhibits the course of a chronic-progressive form of experimental
autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by myelin
oligodendrocyte glycoprotein (MOG)35–55. Mice treated with
the IFN--containing vector before EAE onset showed an earlier onset
but a milder course of the disease compared with control mice treated
with the empty vector. In addition, 83% of IFN--treated mice
completely recovered within 25 days post immunization, whereas control
mice did not recover up to 60 days post immunization. Mice treated with
the IFN--containing vector within 1 wk after EAE onset partially
recovered from the disease within 25 days after vector injection,
whereas control mice worsened. Recovery from EAE in mice treated with
IFN- was associated with a significant increase of CNS-infiltrating
lymphocytes undergoing apoptosis. During the recovery phase, the mRNA
level of TNFR1 was also significantly increased in CNS-infiltrating
cells from IFN--treated mice compared with controls. Our results
further challenge the exclusive detrimental role of IFN- in the CNS
during EAE/multiple sclerosis, and indicate that CNS-confined
inflammation may induce protective immunological countermechanisms
leading to a faster clearance of encephalitogenic T cells by apoptosis,
thus restoring the immune privilege of the CNS.
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