Background
We have shown that bronchiolitis obliterans syndrome (BOS) is associated with attenuated suppression of pro-inflammatory cytokines and granzyme B by steroid-resistant peripheral blood CD28nullCD137+ T cells and natural killer T (NKT)-like cells. We hypothesized that we could target these steroid-resistant lymphocytes by inhibiting costimulation through CD137.
Conclusions
Blocking CD137 expression in CD28null T cells and NKT-like cells is associated with down-regulation of IFN-γ, TNF-α, and granzyme B. Targeting CD137 reduces pro-inflammatory/cytotoxic expression in steroid-resistant CD28null T and NKT-like cells and may have therapeutic implications for patients with BOS.
Methods
Isolated peripheral blood mononuclear cells from transplant patients with stable lung function, patients with BOS, and healthy controls were stimulated with anti-CD3 with and without blocking anti-CD137 and with and without 10(-6) mol/liter methylprednisolone (MP) (with and without stimulatory anti-CD137). Pro-inflammatory cytokine profiles and expression of the cytotoxic mediator, granzyme B, by CD28null T and NKT-like cells were determined using flow cytometry.
Results
There was a significant decrease in the percentage of CD28null T and NKT-like cells producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and granzyme B in all individuals in the presence of anti-CD137 blocking antibody compared with anti-CD3 alone (eg, 30% decrease in CD8+CD28null TNF-α+ cells). Stimulatory anti-CD137 was associated with an increase in pro-inflammatory/cytotoxic cells. Treatment with anti-CD137 blocking with prednisolone further reduced IFN-γ, TNF-α, and granzyme B in these cells. Conclusions: Blocking CD137 expression in CD28null T cells and NKT-like cells is associated with down-regulation of IFN-γ, TNF-α, and granzyme B. Targeting CD137 reduces pro-inflammatory/cytotoxic expression in steroid-resistant CD28null T and NKT-like cells and may have therapeutic implications for patients with BOS.