We previously showed increased steroid resistant CD28null CD8+ senescent
lymphocyte subsets in peripheral blood from COPD patients. These cells
expressed decreased levels of the glucocorticoid receptor (GCR),
suggesting their contribution to the steroid resistant property of these
cells. COPD is a disease of the small airways. We therefore hypothesized
that there would be a further increase in these steroid resistant
lymphocytes in the lung, particularly in the small airways. We further
hypothesized that the pro-inflammatory/cytotoxic potential of these
cells could be negated using prednisolone with low-dose cyclosporin A.
Blood, bronchoalveolar lavage, large proximal and small distal airway
brushings were collected from 11 COPD patients and 10 healthy
aged-matched controls. The cytotoxic mediator granzyme b,
pro-inflammatory cytokines IFNγ/TNFα, and GCR were determined in
lymphocytes subsets before and after their exposure to 1µM prednisolone
and/or 2.5ng/mL cyclosporin A.
Particularly in the small airways, COPD subjects showed an increased
percentage of CD28null CD8 T-cells and NKT-like cells, with increased
expression of granzyme b, IFNγ and TNFα and a loss of GCR, compared with
controls. Significant negative correlations between small airway GCR
expression and IFNγ/TNFα production by T and NKT-like cells (eg, T-cell
IFNγ R= -.834, p=.031) and with FEV (R= -890) were
shown. Cyclosporine A and prednisolone synergistically increased GCR
expression and inhibited pro-inflammatory cytokine production by
CD28null CD8- T and NKT-like cells.
COPD is associated with increased pro-inflammatory CD28null CD8+ T and
NKT-like cells in the small airways. Treatments that increase GCR in
these lymphocyte subsets may improve morbidity in COPD patients.