INITIAL EVENTS IN CNS INFLAMATION AND MODULATION IN IMMUNE MEDIATED DEMYELINATION

Project: Research project

Project Details

Description

This project will investigate initial changes occurring during CNS
inflammation associated with immune-mediated demyelination. The
hypothesis under test is that intervention in the cascade of cellular and
molecular events leading up to disruption of the blood brain barrier
(BBB) in MS, and its laboratory model, EAE, might prevent of block
progression of disease and lead to clinical amelioration. The test
objects will include a congenic strain of mouse adoptively sensitized for
chronic relapsing EAE in the CNS of which we are able to identify donor
effector cells on the basis of a T cell marker, Thy-1.2. Using this
strain, we shall correlate lymphocyte homing to the CNS with adhesion
molecule and cytokine expression at the BBB. We shall characterize the
effector T cells phenotypically and functionally (e.g. TH1 versus TH2)
in vitro following their isolation from the CNS of animals at different
stages of EAE and shall examine the effects of these T cells on myelin
and glia in vitro. The overall objective of this aim is to develop a
strategy to down-regulate proinflammatory events occurring at the BBB and
glia in EAE (and ultimately MS), and to this end, we shall test the
effects of injections of antibodies to an adhesion molecule and a
cytokine involved in early inflammation (alphaICAM-1 and alphaTNTalpha)
and the suppressive cytokine IL-10, upon the course of EAE. Adhesion
molecule and cytokine expression in the CNS will be evaluated
qualitatively and quantitatively, using Western and Northern blotting and
PCR analysis. Parallel experiments will be conducted on fresh frozen and
fixed CNS tissue from cases of MS to examine whether lesions of different
ages display different adhesion molecule pathways and quantitative
differences in adhesion and cytokine molecule expression. Cytokine and
growth factor receptors, together with markers for apoptosis, will also
be sought on oligodendrocytes in acute MS lesions for evidence of
oligodendrocyte regeneration. Finally, mice with EAE will be examined
immunocytochemically for a role for TcRgammadelta T cells and heat shock
proteins in the CNS (described here in pilot data) since TcRgammadelta
T cells have been implicated in oligodendrocyte pathology in MS. This
combination of experiments on CNS tissue from MS and EAE to analyze
cellular and adhesion molecule-related events may afford information of
therapeutic import to the human disease.
StatusFinished
Effective start/end date1/1/0112/31/06

Funding

  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke

ASJC

  • Neurology
  • Cell Biology
  • Pathology and Forensic Medicine
  • Histology
  • Immunology
  • Clinical Neurology
  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Ophthalmology
  • Physiology
  • Pulmonary and Respiratory Medicine
  • Neuroscience(all)

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