May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
The Potential Role of CD4+CD25int T-Cells in Inflammatory Diseases Refractory to Treatment With Glucocorticoids
Author Affiliations & Notes
  • R. Lee
    Univ of Bristol, Bristol, United Kingdom
    Clinical Science at South Bristol,
  • L. B. Nicholson
    Univ of Bristol, Bristol, United Kingdom
    Cellular and Molecular Medicine,
  • P. Newcomb
    Univ of Bristol, Bristol, United Kingdom
    Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology,
  • C. M. Dayan
    Univ of Bristol, Bristol, United Kingdom
    Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology,
  • A. D. Dick
    Univ of Bristol, Bristol, United Kingdom
    Clinical Science at South Bristol,
  • Footnotes
    Commercial Relationships R. Lee, Share in revenue from a patent for the use of anti-CD25 as a steroid sensitising agent, P; L.B. Nicholson, None; P. Newcomb, None; C.M. Dayan, Share in revenue from a patent for the use of anti-CD25 as a steroid sensitising agent, P; A.D. Dick, Share in revenue from a patent for the use of anti-CD25 as a steroid sensitising agent, P.
  • Footnotes
    Support National Eye Research Centre Grant RJ4750
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 1506. doi:https://doi.org/
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    • Get Citation

      R. Lee, L. B. Nicholson, P. Newcomb, C. M. Dayan, A. D. Dick; The Potential Role of CD4+CD25int T-Cells in Inflammatory Diseases Refractory to Treatment With Glucocorticoids. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1506. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: 30% of patients with posterior segment intraocular inflammation (uveitis) are refractory to treatment with moderate doses of steroids. Murine studies have shown that CD4+CD25+cells are resistant to glucocorticoid (GC) induced apoptosis and we hypothesise that this T-cell subset is responsible for perpetuating disease in steroid-resistant patients. As clinical steroid resistance is easily defined in ulcerative colitis, we wished to define with this paradigm whether steroid-resistant patients have a subpopulation of CD4+ T-cells which continue to proliferate despite exposure to GCs, and to compare the effect of GCs on human CD4+CD25- and CD4+CD25int T-cells.

Methods:: PBMCs from 16 healthy human volunteers and 7 patients with ‘steroid-resistant’ ulcerative colitis were cultured with CD3 / CD28 in the presence of supratherapeutic concentrations of dexamethasone (Dex). CD3+CD25- and CD3+CD25int T-cells, flow cytometrically sorted from PBMCs, were also stimulated and exposed to increasing concentrations of Dex. The proliferative response of CD4+ T cell subpopulations after 5 days culture was quantified by CFSE dilution.

Results:: (i.) CD3+ CD4+ cells from patients with steroid-resistant disease have a characteristic CFSE profile, with a clearly defined proliferating subpopulation (57.1%) despite high concentrations of Dex. The proportion of proliferating cells is much reduced in normal volunteers (19.0%; p=0.0002). (ii.) CD4+ lymphocytes from CD3+CD25int cell cultures proliferate well in the presence of supra-therapeutic concentrations of Dex (10-6M), while CD25- cell proliferation is fully suppressed at moderate Dex concentrations (10-7M)

Conclusions:: Human CD4+CD25int cells are resistant to the anti-proliferative effects of GCs, and patients with clinically defined steroid-resistant disease have a distinct population of steroid-resistant CD3+CD4+ T-cells. This suggests that CD4+CD25int cells may be responsible for perpetuating steroid-resistant inflammatory diseases and represent a potential target for therapeutic intervention. Our flow-cytometric assay also has potential clinical application as a predictive test of treatment response for individual patients.

Keywords: immunomodulation/immunoregulation • corticosteroids • flow cytometry 
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