Bronchiolitis obliterans syndrome is associated with increased p-glycoprotein expression and loss of glucocorticoid receptor from steroid resistant pro-inflammatory CD8+T cells

Summary

Immunosuppressive therapy fails to suppress the production of pro-inflammatory cytokines, particularly by CD8+T cells, in stable lung transplant recipients and those undergoing chronic rejection, suggesting that some patients may become relatively resistant to immunosuppressants such as glucocorticoids (GC). We have shown loss of GC receptor (GCR) from the CD8+ cells, and we hypothesized that the drug membrane efflux pump, p-glycoprotein-1 (Pgp), may also be involved in lymphocyte steroid resistance following lung transplant.

Pgp/GCR expression and IFNγ/TNFα pro-inflammatory cytokine production was measured in blood lymphocytes from 15 stable lung transplant patients, 10 patients with bronchiolitis obliterans syndrome (BOS) and 10 healthy aged-matched controls (± prednisolone ± Pgp inhibitor, cyclosporin A ± GCR activator, Compound A) using flow cytometry.

Both Pgp+ and Pgp- lymphocyte subsets from all subjects produced IFNγ/TNFα pro-inflammatory cytokines. Pgp expression was increased in CD8+Pgp+T cells and correlated with IFNγ/TNFα expression and BOS grade. Reduced GCR was observed in CD8+Pgp-T, NKT-like and NK cells from stable patients compared with controls, and further reduced in CD8+Pgp-T cells in BOS. Addition of 2.5ng/ml cyclosporine A and 1µM prednisolone significantly inhibit IFNγ/TNFα production by CD8+Pgp+ T cells from BOS patients. Addition of 10µM Compound A and 1µM prednisolone significantly inhibit IFNγ/TNFα production by CD8+Pgp- T cells from BOS patients.

BOS is associated with increased Pgp expression and loss of GCR from steroid resistant pro-inflammatory CD8+T cells. Treatments that inhibit Pgp and upregulate GCR in CD8+T cells may improve graft survival. This article is protected by copyright. All rights reserved.