T-CELL FUNCTION IN A MURINE MODEL OF MULTIPLE SCLEROSIS

  • Rodriguez, Moses (PI)

Project: Research project

Project Details

Description

The etiologies of primary demyelinating diseases such as multiple
sclerosis (MS) are unknown. One testable hypothesis is that destruction
of myelin and oligodendrocyte results from an immune attack directed
against antigen triggered by virus infection. We have used infection to
mice with Theiler's murine encephalomyelitis virus (TMEV), a
picornavirus, to study the role of the immune response in demyelination
and in neurologic disease. The long term goal of these experiments is
to reveal the immune mechanisms of demyelination and neurologic disease
with the hope that this will provide new insights into the treatment of
MS. There are two major specific aims in the proposed experiments.
First, in order to determine which viral genes are involved in inducing
a protective immune response and which genes are targeted in the
pathogenic phase of demyelinating disease, we have divided the TMEV
genome into three regions so that they can be expressed individually in
target cells in vitro and as transgenes in vivo. Fibroblasts transfected
with the TMEV coding blocks will be used to determine the location of the
genes recognized by T cells appearing early during the protective host
response to viral infection and late during the pathogenic phase of
disease. The same coding blocks expressed as transgenes in resistant and
susceptible strains will presumably induce tolerance to sets of viral
antigens, permitting to assess the significance of immune recognition of
these antigens in resistance to viral infection and in the pathogenesis
of demyelination. In the second specific aim we will utilize beta2-
macroglobulin deficient (-/-) mice which when infected with TMEV develop
prominent demyelination but no neurologic deficits. These experiments
have direct relevance to MS, in which frequently there is a discrepancy
between demyelination provides a unique opportunity to dissect those
components of the immune response important in demyelination versus those
important in neurologic deficits. We will first determine the nature of
the immune response (CTL, Th1, and Th2) in CNS of infected Beta-2m (+/+)
and Beta-2m (-/-) of susceptible and resistant haplotypes. We will then
take advantage of the Beta2-m (-/-) model to establish the immunologic
basis of neuronal injury in the demyelinated host. Using a new technique
in the mouse to measure motor and sensory spinal cord conduction in vivo,
we will determine those components of the immune response responsible for
neurophysiologic abnormalities. These experiments have the potential to
elucidate new strategies for the treatment of human CNS demyelinating
disorders.
StatusFinished
Effective start/end date8/1/9412/31/11

Funding

  • National Institutes of Health: $282,972.00
  • National Institutes of Health
  • National Institutes of Health: $333,000.00
  • National Institutes of Health: $266,728.00
  • National Institutes of Health: $320,109.00
  • National Institutes of Health
  • National Institutes of Health: $323,343.00
  • National Institutes of Health: $323,343.00
  • National Institutes of Health: $323,343.00
  • National Institutes of Health: $258,962.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $274,730.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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