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|Title:||Targeting peripheral blood pro-inflammatory CD28null T cells and natural killer T-like cells by inhibiting CD137 expression: Possible relevance to treatment of bronchiolitis obliterans syndrome|
|Citation:||Journal of Heart and Lung Transplantation, 2013; 32(11):1081-1089|
|Publisher:||Elsevier Science Inc|
|Greg Hodge, Sandra Hodge, Paul N. Reynolds, Mark Holmes|
|Abstract:||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. 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.|
|Keywords:||blocking CD137; BOS; CD28null T cells; IFN-γ; lung transplant; TNF-α|
|Rights:||Crown copyright © 2013|
|Appears in Collections:||Medicine publications|
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