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,
Departments of
*
Molecular Biology and Biochemistry and
Anatomy and Neurobiology, and
Reeve-Irvine Research Center, University of California, Irvine, CA 92612
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-
), 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- 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.
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