J Immunol 2001 Oct 1;167(7):4091-7
Liu MT, Keirstead HS, Lane TE.
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-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.
PMID: 11564831