Abstract
BackgroundGlucocorticoid (GC) resistance is a major barrier in COPD treatment. We have shown increased expression of the drug efflux pump, Pgp1 in cytotoxic/pro-inflammatory lymphocytes in COPD. Loss of lymphocyte co-stimulatory molecule CD28 (lymphocyte senescence) was associated with a further increase in their pro-inflammatory/cytotoxic potential and resistance to GC. We hypothesized that lymphocyte senescence and increased Pgp1 are also associated with down-regulation of the GC receptor (GCR).MethodsBlood was collected from 10 COPD and 10 healthy aged-matched controls. Flow cytometry was applied to assess intracellular pro-inflammatory cytokines, CD28, Pgp1, GCR, steroid binding and relative cytoplasm/nuclear GCR by CD28+ and CD28null T, NKT-like cells. GCR localization was confirmed by fluorescent microscopy.ResultsCOPD was associated with increased numbers of CD28nullCD8+ T and NKT-like cells. Loss of CD28 was associated with an increased percentage of T and NKT-like cells producing IFNγ or TNFα and associated with a loss of GCR and Dex-Fluor staining but unchanged Pgp1. There was a significant loss of GCR in CD8 + CD28null compared with CD8 + CD28+ T and NKT-like cells from both COPD and controls (eg, mean ± SEM 8 ± 3% GCR + CD8 + CD28null T-cells vs 49 ± 5% GCR + CD8 + CD28+ T-cells in COPD). There was a significant negative correlation between GCR expression and IFNγ and TNFα production by T and NKT-like cells(eg, COPD: T-cell IFNγ R = −.615; ) and with FEV1 in COPD (R = −.777).ConclusionsCOPD is associated with loss of GCR in senescent CD28null and NKT-like cells suggesting alternative treatment options to GC are required to inhibit these pro-inflammatory/cytotoxic cells.
Highlights
Glucocorticoid (GC) resistance is a major barrier in Chronic obstructive pulmonary disease (COPD) treatment
Pgp1 expression by CD28+ and CD28null T, NKT-like cells There were no significant differences in Pgp1 expression by stimulated CD28+ or CD28 null CD8- or CD8+ CD3+ T or NKT-like cells from either COPD patients or controls ( Data for controls and NKT-like cells not shown)
GC receptor (GCR) expression by CD28+ and CD28null T and NKT-like cells There was a significant decrease in the percentage of CD28null/CD8- and CD28nullCD8+ T cells and NKTlike cells expressing GCR in both COPD groups and controls compared with their CD28+ T and NKT-like cells (Data for T cell and NKT-like cell subsets from COPD group shown in Figure 2a and b respectively)
Summary
We have shown increased expression of the drug efflux pump, Pgp in cytotoxic/pro-inflammatory lymphocytes in COPD. Existing treatments are largely symptomatic and the use of anti-inflammatory corticosteroids has no proven disease modifying effect [1]. The mechanisms underlying this resistance, in lymphocytes, are largely unknown [2] Our group has reported increased production of Th1 pro-inflammatory cytokines IFN-γ and TNF-α by CD8+ T cells in peripheral blood and lungs [3] and higher levels of the cytotoxic mediators granzyme b and perforin in peripheral blood. CD8/CD28null clones divide faster and live longer than CD8CD28+ T cells due to
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