Therapeutic Targeting Steroid Resistant Pro-Inflammatory NK and NKT-Like Cells in Chronic Inflammatory Lung Disease

Abstract

The innate immune system drives the initiation of inflammation and progression to chronic inflammation in two important chronic inflammatory lung diseases involving the small airways, chronic obstructive pulmonary disease (COPD) and bronchiolitis obliterans syndrome (BOS), following lung transplantation. Recently natural killer T cell like (NKT-like) cells, which represent a bridge between the innate and adaptive immune response as well as the innate natural killer cell (NK) cells, have been shown to be important cells in these two chronic lung diseases. Importantly these cells have been shown to be resistant to commonly used anti-inflammatory drugs such as glucocorticoids and as such their inflammatory nature has been difficult to suppress. Mechanisms leading to steroid resistance in both diseases has recently been shown. Glucocorticoids switch off inflammatory genes by first entering the cell and binding to glucocorticoid receptors (GCRs). The steroid-GCR complex must then be chaperoned into the nucleus via several heat shock proteins, where they engage histone deacetylase 2 to switch off pro-inflammatory gene transcription. Many of these mechanisms are altered in NK and NKT-like cells in COPD and BOS requiring novel intervention using combinations of currently available drugs. Evidence will be presented to show how these drugs can overcome these mechanisms of drug resistance ex vivo advising novel therapeutic strategies for the treatment these two important chronic inflammatory lung diseases.

Keywords

• steroid resistant NK and NKT-like cells
• chronic inflammatory lung disease
• COPD
• BOS
• IFNγ and TNFα
• CD28null