Abstract
BackgroundPro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids.MethodsPgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry.ResultsThere was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all).ConclusionsTreatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity.
Highlights
Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD
In this regard we have previously shown an increase in pro-inflammatory/cytotoxic T cells, NKT-like and NK cells in the peripheral blood and airways in COPD patients compared with non-COPD smokers where some changes were only noted in the lungs compared with healthy controls [3,4,5]
Blood CD4+ and CD8+ T cell counts There was a significant increase in the absolute number of CD8 T cells in blood from COPD patients compared with controls (0.43 ± 0.22 and 0.33 ± 0.16 × 109/L for COPD patients and controls respectively, P = 0.047)
Summary
Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. Better understanding of the mechanisms underlying steroid resistance in COPD, and COPD is a systemic disease and may represent a “spill-over” of inflammatory events occurring in the lungs [2] In this regard we have previously shown an increase in pro-inflammatory/cytotoxic T cells, NKT-like and NK cells in the peripheral blood and airways in COPD patients compared with non-COPD smokers where some changes were only noted in the lungs compared with healthy controls [3,4,5]. We hypothesized that Pgp may play a role in steroid resistance and would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with low dose cyclosporine A, a Pgp inhibitor, would render cells more sensitive to treatment with corticosteroids
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