Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis.
Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a chronic demyelinating disease with clinical and histological similarities with the human demyelinating disease multiple sclerosis (MS). Following MHV infection, chemokines including CXC chemokine ligand (CXCL)10 (IFN inducible protein 10 kDa), CXCL9 (monokine induced by IFN-gamma), and CC chemokine ligand 5 (RANTES) are expressed during both acute and chronic stages of disease suggesting a role for these molecules in disease exacerbation. Previous studies have shown that during the acute phase of infection, T lymphocytes are recruited into the CNS by the chemokines CXCL10 and CXCL9. In the present study, MHV-infected mice with established demyelination were treated with antisera against these two chemokines, and disease severity was assessed. Treatment with anti-CXCL10 reduced CD4+ T lymphocyte and macrophage invasion, diminished expression of IFN-gamma and CC chemokine ligand 5, inhibited progression of demyelination, and increased remyelination. Anti-CXCL10 treatment also resulted in an impediment of clinical disease progression that was characterized by a dramatic improvement in neurological function. Treatment with antisera against CXCL9 was without effect, demonstrating a critical role for CXCL10 in inflammatory demyelination in this model. These findings document a novel therapeutic strategy using Ab-mediated neutralization of a key chemokine as a possible treatment for chronic human inflammatory demyelinating diseases such as MS.
Liu
M T
MT
Departments of Molecular Biology and Biochemistry, University of California Irvine, 3205 Biological Sciences II, Irvine, CA 92612, USA.
Keirstead
H S
HS
Lane
T E
TE
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D018352:Coronavirus Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018792:Encephalitis, Viral / Q000276:immunology / Q000473:pathology / Q000628:therapy; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D006517:Murine hepatitis virus; D009186:Myelin Sheath / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; C080810:CXCL9 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma