BOS is associated with decreased HDAC2 from steroid resistant lymphocytes in the small airways

Abstract

Summary Immunosuppression therapies including corticosteroids fail to prevent bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways, following lung transplantation. We reported increases in steroid‐resistant proinflammatory lymphocytes and their loss of histone deacetylase 2 (HDAC2), an important mediator of steroid action, in the blood of stable lung transplant recipients. We noted similar increases in the steroid‐resistant lymphocytes in both the blood and small airways in BOS compared with the large airways. We hypothesized that these small airway cells would also exhibit a loss of HDAC2, and that these changes could be reversed by treatment with theophylline (HDAC2 activator). Blood, bronchoalveolar lavage and large and small airway brushings were collected from lung transplant patients with BOS (n = 12) or stable lung function (n = 18) and healthy aged‐matched controls (n = 13). Intracellular proinflammatory cytokines [interferon (IFN‐γ) and tumour necrosis factor (TNF)‐α and HDAC2 were measured in CD8+ T, natural killer (NK) T‐like and NK cells from cultured small airway brushings ± 5 mg/l theophylline ± 1 µM prednisolone using flow cytometry. Increased small airway CD8 T, NK T‐like and NK cells were identified in BOS versus stable transplant and controls. In BOS, these cells exhibited increased IFN‐γ/TNF‐α and a loss of HDAC2. HDAC2 expression by small airway CD8+ T cells correlated with forced expiratory volume in 1 s (FEV1) (R = 0·880, P = 0·031). Theophylline and prednisolone synergistically up‐regulated HDAC2 in CD8+ T cells. BOS is associated with loss of HDAC2 from steroid‐resistant proinflammatory CD8+ T, NK T‐like and NK cells in the small airways. Therapeutically increasing HDAC2 in these lymphocytes may reduce steroid resistance and improve graft survival.

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

“…HDAC2 has also been reported to be decreased in CD8+NKT-like cells following lung transplant [26] and importantly in steroid resistant CD8+NKT-like and NK cells in the small airways in patients with BOS compared with stable patients and controls [27] which correlated with disease severity (FEV 1 ). Addition of low dose theophylline and 1 µM prednisolone resulted in the synergistic upregulation of HDAC2 in CD8+NKT-like cells [27] (Figure 3) and NK cells (unpublished data) also suggesting that therapeutic upregulation of HDAC2 in these lymphocytes may reduce steroid resistance and inflammation caused by these cells and improve graft survival. Importantly, identifying CD8+NKT-like and NK cells in small airway brushings using flow cytometry [27] overcomes the limitations associated with inadequate biopsy sampling techniques [28].…”

“…Addition of low dose theophylline and 1 µM prednisolone resulted in the synergistic upregulation of HDAC2 in CD8+NKT-like cells [27] (Figure 3) and NK cells (unpublished data) also suggesting that therapeutic upregulation of HDAC2 in these lymphocytes may reduce steroid resistance and inflammation caused by these cells and improve graft survival. Importantly, identifying CD8+NKT-like and NK cells in small airway brushings using flow cytometry [27] overcomes the limitations associated with inadequate biopsy sampling techniques [28].…”

Effector immune cells in chronic lung allograft dysfunction: A systematic review

“…Other studies also noted increased BALF NK cells (CD56+) in BOS patients versus healthy controls, but not versus stable LTR [45,46]. In addition, more NK cells were seen in small airway brushings in BOS patients compared to stable LTR and controls, with no changes in large airway brushings [45,46]. In a study by Fildes et al, more NK cells (CD16+) were found on transbronchial biopsies from BOS patients than from stable patients [47].…”

“…Ward et al found increased NK cells (CD56/CD16+) in both BOS and stable patients compared to healthy controls [34]. Other studies also noted increased BALF NK cells (CD56+) in BOS patients versus healthy controls, but not versus stable LTR [45,46]. In addition, more NK cells were seen in small airway brushings in BOS patients compared to stable LTR and controls, with no changes in large airway brushings [45,46].…”

Capitalizing on the concept of local immune suppression by inhalation for lung transplant recipients

“…With systemic cyclosporine and tacrolimus, early rejection is suppressed, but a persistent alloresponse to bronchiolar cells then frequently develops results in chronic lung allograft dysfunction (CLAD) manifesting commonly as bronchiolitis obliterans syndrome (BOS). The latter process typically affects small airways and is largely unaffected by systemic immunotherapies 2,3 . Moreover, unfortunately freedom from BOS at 5 years post‐transplantation is decreasing (57%, 1996 to 2001 to 47%, 2008 to 2013).…”