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

• Published in: The Journal of immunology (1950) Vol. 167; no. 3; pp. 1821 - 1829
• Main Authors: Furlan, R, Brambilla, E, Ruffini, F, Poliani, P L, Bergami, A, Marconi, P C, Franciotta, D M, Penna, G, Comi, G, Adorini, L, Martino, G
• Format: Journal Article
• Language: English
• Published: United States 01.08.2001
• Subjects: Animals; Antigens, CD - biosynthesis; Apoptosis - genetics; Apoptosis - immunology; Blood-Brain Barrier - genetics; Blood-Brain Barrier - immunology; Brain - immunology; Brain - metabolism; Brain - pathology; Cell Movement - genetics; Cell Movement - immunology; Cerebral Ventricles - immunology; Cerebral Ventricles - virology; Chronic Disease; Cisterna Magna; Disease Progression; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Female; Genetic Vectors - administration & dosage; Herpesvirus 1, Human - genetics; immune privilege; Injections; Injections, Spinal; Interferon-gamma - administration & dosage; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Lymphocyte Count; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Lymphocyte Subsets - pathology; Mice; Mice, Inbred C57BL; Receptors, Tumor Necrosis Factor - biosynthesis; Receptors, Tumor Necrosis Factor, Type I; Spinal Cord - immunology; Spinal Cord - metabolism; Spinal Cord - pathology; Subarachnoid Space - immunology; Subarachnoid Space - virology; Virus Replication - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.3.1821

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-gamma gene leads to persistent (up to 4 wk) CNS production of IFN-gamma 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-gamma-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-gamma-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-gamma-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-gamma 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-gamma-treated mice compared with controls. Our results further challenge the exclusive detrimental role of IFN-gamma 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.