Cytokine Secretion Profile of Autoreactive T Cells

Project Details

Description

DESCRIPTION (provided by applicant): T helper (Th) 1 and Th2 cytokines are
important regulators of protective humoral and cell-mediated immune responses
and play a role in certain inflammatory immunopathological disorders. Multiple
sclerosis (MS) is an inflammatory demyelinating disease of the human central
nervous system of unknown etiology and pathogenesis. Current postulates suggest
that autoreactive T cells secreting Th1 cytokines are activated by a process
involving molecular mimicry and/or bystander activation and migrate into the
central nervous system (CNS) and initiate the inflammatory and demyelinating
cascade. The long term objectives of this proposal are to elucidate the role of
cytokines in the pathogenesis of MS and to provide novel tools for therapeutic
intervention in this disorder. Interferon-y (IFN-y), a Th1 cytokine, is a
pivotal mediator in the demyelinating disease process and has been shown to
exacerbate MS symptoms when used to treat patients. Interleukin-12 (IL-12) is a
potent inducer of IFN-y production and promoter of Th1-type responses, while
the newly-discovered interleukin-18 (IL-18) shares some functional
characteristics with IL-12 and has also been implicated in promoting IFN-y
secretion. Conflicting reports regarding the role of IL-12 in MS have been
published and the role of IL-18 has not yet been studied in this neurological
disease. Studies from this laboratory have observed enhanced IFN-y and reduced
transforming growth factor-B (TGF-B) production by autoantigen-reactive T cells
as well as decreased secretion of IL-12 p40, a natural IL-12 antagonist in MS.
We have also observed a novel finding that IL-18 may be produced by
autoantigen-reactive T lymphocytes.

We hypothesize that defects in the production of IL-12 p40 and abnormal IL-18
secretion by Th1 cells contribute to dysregulated IFN-y production in MS. We
propose to investigate these predictions by investigating the roles of IL-12
and IL-18 in regulating IFN-y production in MS. Elucidating the mechanisms that
control IFN-y production is essential for unraveling the pathogenesis of MS and
may be of therapeutic benefit.
StatusFinished
Effective start/end date3/1/957/31/07

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $314,000.00
  • National Institute of Neurological Disorders and Stroke: $307,673.00
  • National Institute of Neurological Disorders and Stroke: $314,000.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $314,000.00
  • National Institute of Neurological Disorders and Stroke

ASJC

  • Clinical Neurology
  • Neurology
  • Immunology

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.