CYTOKINE SECRETION PROFILE OF AUTOREACTIVE T CELLS

Project Details

Description

Cells of the immune system communicate with each other by cell-cell
contacts and via the production of soluble protein factors or cytokines.
Cytokines are critical in the regulation of immune responses.
Heterogeneity of CD4+ helper T cells based on cytokine secretion patterns
has been well documented in the murine system. Studies in humans have also
observed helper T cell clones exhibiting Th1 or Th2-like profiles
accumulating in the tissues or blood of patients with different diseases.
Dysregulated expansion of one or the other subsets may be a contributing
factor in the development of autoimmune diseases.

Multiple sclerosis is a chronic demyelinating disease of the human central
nervous system of unknown etiology and pathogenesis. MS is believed to be
an autoimmune disorder, triggered by an infectious agent(s) in which
autoreactive T cells specifically migrate into the central nervous system
and initiate the inflammatory, demyelinating reaction. We now propose to
study cytokine production both in vitro and in vivo in this autoimmune
disorder of the central nervous system. Our hypothesis is that there is a
dysregulation in the production of Th1-like cytokines which play a role in
the demyelination process. It is also proposed that the cytokine secretion
pattern seen in the blood may be different from that produced in areas of
active disease.

T cell clones-specific for a putative target autoantigen, myelin basic
protein will be generated from multiple sclerosis and other neurological
disease patients as well as from healthy controls. Cerebrospinal fluid
lymphocytes will also be cloned and examined for oligoclonality of T cell
receptor beta chain gene rearrangements. All the clones will be analyzed
for production of a large panel of cytokines by competitive polymerase
chain reaction methodology. The cell surface phenotype of representative
clones will be ascertained by two color immunofluorescence and
cytofluorographic analysis. The in vivo study of cytokine production in
central nervous system tissue will be performed in patients with acute
multiple sclerosis and controls by immunocytochemical staining and in situ
hybridization. The effect of the cytokines produced by autoreactive T
cells on cultured human oligodendrocytes will be determined and attempts
will be made to neutralize the activity of these cytokines with other
cytokines. The present study on the cytokine secretion profile of
autoreactive T cell clones (found in the blood and cerebrospinal fluid)
may provide information regarding the nature and regulation of these
potentially pathogenic T cells. Analysis of the effects of cytokines on
glial cells and the identification of cytokine production in vivo may
elucidate the role of these products in the pathogenesis of the disease
and may provide novel immunologic tools for specific therapeutic
intervention in MS.
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
  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)
  • Immunology

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