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*
Neuroimmunology Unit, Montreal Neurological Institute, and
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and
Department of Cell Biology and Immunology, Vrije Universiteit, Amsterdam, The Netherlands
Organ-specific autoimmune diseases are characterized by
infiltrates, including T lymphocytes and activated macrophages.
Macrophages and secondarily activated tissue resident counterparts can
both present Ag to and contribute to cytokine secretion by T
lymphocytes. We have previously shown a crucial role of peripheral
macrophages in experimental allergic encephalomyelitis (EAE), a
Th1-mediated demyelinating disease that serves as a an animal model for
multiple sclerosis (MS), by their depletion using mannosylated
liposome-encapsulated dichloromethylene diphosphonate
(Cl2MDP). Here we describe studies to investigate the
mechanisms by which macrophages contribute to the lesion formation in
EAE, by studying the effect of Cl2MDP-containing
mannosylated liposomes (Cl2MDP-mnL) on adoptively
transferred EAE in SJL/J mice. Adoptive transfer of EAE with myelin
basic protein-reactive CD4+ T cells to SJL/J mice was
abrogated by Cl2MDP-mnL treatment. CD4+ T cell
and MHC II+ B220+ B cell extravasation from
blood vessels and Th1 cytokine production were not inhibited. However,
invasion of the central nervous system intraparenchymal tissues by
lymphocytes, F4/80+, Mac-1+, and
MOMA-1+ macrophages was almost completely blocked after
treatment with Cl2MDP-mnL. Furthermore, in
Cl2MDP-mnL-treated mice, the myelin sheaths appeared
completely normal, whereas, in the control groups, marked demyelination
occurred. Production of TNF-
and inducible nitric oxide synthase,
both associated with macrophage/microglial activation, was inhibited.
This intervention reveals a role for macrophages in regulating the
invasion of autoreactive T cells and secondary glial recruitment that
ordinarily lead to demyelinating pathology in EAE and multiple
sclerosis.
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