DIVERSITY OF T-LYMPHOCYTES IN EARLY RHEUMATOID ARTHRITIS

Project: Research project

Project Details

Description

The long-term goal of this proposal is to understand the contribution of
T lymphocytes to joint inflammation and destruction in rheumatoid
arthritis (RA). T lymphocytes represent a major cell population in the
inflamed synovium. By analyzing the molecular diversity of synovial T
cells in early disease, we have recently observed that the repertoire of
IL-2 receptor expressing CD4+ T cells is markedly biased with the
preferential involvement of T cells utilizing a core group of T cell
receptor (TCR) Vbeta elements. Within such T cell populations, we have
identified single specificities which were clonally expanded indicating
that they have recently contacted antigen or superantigen and thus
represent potentially disease relevant T cells. Identical T cell
specificities were found in high frequencies in the peripheral blood
raising the hypothesis that stimulation and proliferation of selected T
cell specificities in early RA patients is not limited to the joint.

This application proposes a comprehensive analysis of the TCR repertoire
in early synovial lesions with the aim to dissect disease relevant T cells
from T cells nonspecifically accumulated at a site of inflammation. The
rationale for focusing on early disease comes from recent studies
demonstrating that autoimmune T cell responses induced by immunization
with self-peptides have a tendency to diversity and to involve a
heterogeneous T cell population over time. Specifically, we will expand
our studies on the subset of IL-2 responsive CD4+ T cells in early
synovitis to define whether the pattern of T cell specificities we have
defined is shared by all patients with RA and is unique for rheumatoid
synovitis as opposed to other inflammatory arthritides. We will continue
to identity and to characterize clonally expanded T cell specificities,
study their distribution in peripheral blood and the synovia, and
investigate whether the mechanism driving proliferation of selected T
cells is antigen-specific or suggestive of a superantigen. Longitudinal
monitoring of the synovial TCR repertoire will concentrate on tracing
clonally expanded TCR specificities over two years and will also address
the question whether the progression of the disease relates to the
recruitment and activation of new specificities. Identification of T cell
clones eliciting an immune response in early synovitis would provide a
unique reagent in the search for the disease inducing agents and in the
development of targeted therapeutic interventions.
StatusNot started

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $227,200.00
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases

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