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260 ANTIFIBROGENIC T CELLS IN SCLERODERMA
  1. K. J. Warrington,
  2. L. D. Carbone,
  3. U. Nair,
  4. A. H. Kang,
  5. A. E. Postlethwaite
  1. Memphis, TN.

Abstract

Purpose To determine the phenotype and functional characteristics of type I collagen (CI)-specific T cells in scleroderma (SSc).

Methods Peripheral blood mononuclear cells (PBMC) were collected from SSc patients and normal controls. CFSE labeling and flow cytometry were used to follow antigen-specific T cell proliferation in response to bovine CI and β1,2 chain of CI. Phenotypic analysis and intracellular cytokine expression of proliferating cells was performed by multicolor flow cytometry and CI-specific T cell lines were generated by repeated stimulation of PBMC with CI and autologous PBMC. T cell line supernatants were assayed for cytokines using a multiplex cytokine bead array system. Normal human fibroblasts were then cultured with CI-specific T cell supernatants and CI (α2) gene transcription in fibroblasts was determined by real-time PCR.

Results 25 patients with SSc and 18 normal controls were studied. A T-cell proliferative response to CI was detected in 8 (32%) patients and in none of the controls (p = .01). Among responders, the proliferating T cell population was invariably CD3+CD4+. The CI-specific, CD4+ T cells expressed an activated, memory phenotype (CD25+CD45RO+) but did not stain for CD212. To confirm our findings, we generated CI-specific T cell lines that had the following phenotype: CD3+CD4+CD8-CD28dimCD49a+. Following activation of CI-specific T cells we detected intracellular interferon-γ but not IL-4 by flow cytometry. Supernatants from the T cell lines contained IL-2, IFN-γ, GM-CSF and TNF-α, but little or no IL-4 and IL-10, suggesting that CI-specific cells express a Th1 cytokine pattern. Moreover, supernatant from CI-specific T cells was able to suppress CI gene transcription in normal human fibroblasts.

Conclusion Circulating CI-specific memory CD4 T cells that have a Th1 cytokine profile are present in a subset of patients with SSc. These T cells may play a role in limiting fibrosis. Therefore, in vivo expansion of this T cell subset may be of therapeutic benefit in SSc. Supported by a grant from the Scleroderma Foundation and the Research Center of Excellence for Connective Tissue Disease, UTHSC.

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