Small airways disease in an Operation Desert Storm Deployer: Case report and review of the literature on respiratory health and inhalational exposures from Gulf War I.

Constrictive Bronchiolitis (CB) has been reported in US Operation Iraqi Freedom/Enduring Freedom (OIF/OEF) deployers but not in those from prior US conflicts. A 62-year old presented with progressive dyspnea 13 years after deployment to the Persian Gulf in 1991-1992, where he was exposed to burning oil well fire emissions, dust storms, and other potential airborne hazards. In 2014, after a chest computed tomography (CT) scan demonstrated diffuse mosaic attenuation, he underwent surgical lung biopsy, which revealed CB. Deployers from both GWI and OIF/OEF share many exposures. As respiratory symptoms are a feature associated with Gulf War medically unexplained illness, there may be a role for renewed interest in evaluating GWI Veterans with unexplained respiratory symptoms for conditions such as CB, which may result from exposures relevant to deployers from both conflicts.

Human leukocyte antigen-G expression in differentiated human airway epithelial cells: lack of modulation by Th2-associated cytokines.

BACKGROUND: Human leukocyte antigen (HLA)-G is a nonclassical class I antigen with immunomodulatory roles including up-regulation of suppressor T regulatory lymphocytes. HLA-G was recently identified as an asthma susceptibility gene, and expression of a soluble isoform, HLA-G5, has been demonstrated in human airway epithelium. Increased presence of HLA-G5 has been demonstrated in bronchoalveolar lavage fluid recovered from patients with mild asthma; this suggests a role for this isoform in modulating airway inflammation though the mechanisms by which this occurs is unclear. Airway inflammation associated with Th2 cytokines such as IL-4 and IL-13 is a principal feature of asthma, but whether these cytokines elicit expression of HLA-G is not known. METHODS: We examined gene and protein expression of both soluble (G5) and membrane-bound (G1) HLA-G isoforms in primary differentiated human airway epithelial cells collected from normal lungs and grown in air-liquid interface culture. Cells were treated with up to 10 ng/ml of either IL-4, IL-5, or IL-13, or 100 ng/ml of the immunomodulatory cytokine IL-10, or 10,000 U/ml of the Th1-associated cytokine interferon-beta, for 24 hr, after which RNA was isolated for evaluation by quantitative PCR and protein was collected for Western blot analysis. RESULTS: HLA-G5 but not G1 was present in dAEC as demonstrated by quantitative PCR, western blot and confocal microscopy. Neither G5 nor G1 expression was increased by the Th2-associated cytokines IL-4, IL-5 or IL-13 over 24 hr, nor after treatment with IL-10, but was increased 4.5 ± 1.4 fold after treatment with 10,000 U/ml interferon-beta. CONCLUSIONS: These data demonstrate the constitutive expression of a T lymphocyte regulatory molecule in differentiated human airway epithelial cells that is not modulated by Th2-associated cytokines.

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine.

BACKGROUND: While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of bronchiolitis obliterans syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role. METHODS: Transplant derived airway epithelial cells differentiated in air liquid interface culture were treated with IL-1ß and/or cyclosporine, after which secretion of cytokines and growth factor and gene expression for markers of epithelial to mesenchymal transition were analyzed. RESULTS: Secretion of IL-6, IL-8, and TNF-α, but not TGF-ß1, was increased by IL-1ß stimulation. In contrast to previous studies using epithelial cells grown in submersion culture, treatment of differentiated cells in ALI culture with cyclosporine did not elicit cytokine or growth factor secretion, and did not alter IL-6, IL-8, or TNF-α production in response to IL-1ß treatment. Neither IL-1ß nor cyclosporine elicited expression of markers of the epithelial to mesenchymal transition E-cadherin, EDN-fibronectin, and α-smooth muscle actin. CONCLUSION: Transplant derived differentiated airway epithelial cell IL-6, IL-8, and TNF-α secretion is not regulated by cyclosporine in vitro; these cells thus may participate in local inflammatory responses in the setting of immunosuppression. Further, treatment with IL-1ß did not elicit gene expression of markers of epithelial to mesenchymal transition. These data present a model of differentiated airway epithelial cells that may be useful in understanding epithelial participation in airway inflammation and allograft rejection in lung transplantation.

Current trends in immunosuppression for lung transplantation.

Lung transplant has become an established therapy in the treatment of end-stage lung disease. Many of the advances in the modern immunosuppression regimen have provided more quality and quantity of life to transplant patients. Immunosuppression agents target various aspects of the immune system to maximize graft tolerance while minimizing medication toxicities and side effects. Lung transplant regimens follow typical protocols but are always tailored to the individual patient based upon previous and current medical problems. Despite the various advances, acute and chronic rejections still occur in the majority of all lung transplants. For these reasons, long-term lung transplantation success remains a challenge. Further improvement in immunosuppression will be geared toward minimizing rejection and infection as well as being tailored to the individual patient. This review details the current armamentarium of immunosuppression medications and the current body of evidence supporting the current trends of usage.

Association of soluble HLA-G with acute rejection episodes and early development of bronchiolitis obliterans in lung transplantation.

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of bronchiolitis obliterans syndrome (BOS). Soluble HLA-G, a mediator of adaptive immunity that modulates regulatory T cells and certain classes of effector T cells, may be a useful marker of survival free of BOS. We conducted a retrospective, single-center, pilot review of 38 lung transplant recipients who underwent collection of serum and bronchoalveolar lavage fluid 3, 6 and 12 months after transplantation, and compared soluble HLA-G concentrations in each to the presence of type A rejection and lymphocytic bronchiolitis in the first 12 months and to the presence of BOS at 24 months after transplantation. Lung soluble HLA-G concentrations were directly related to the presence of type A rejection but not to lymphocytic bronchiolitis. Our data demonstrate that soluble HLA-G concentrations in bronchoalveolar lavage but not in serum correlates with the number of acute rejection episodes in the first 12 months after lung transplantation, and thus may be a reactive marker of rejection.

Conventional and novel approaches to immunosuppression.

Immunosuppressive therapy has contributed significantly to improved survival after solid organ transplantation. Nevertheless, treatment-related adverse events and persistently high risk of chronic graft rejection remain major obstacles to long-term survival after lung transplantation. The development of new agents, refinements in techniques to monitor immunosuppression, and enhanced understanding of transplant immunobiology are essential for further improvements in outcome. In this article, conventional immunosuppressive regimens, novel approaches to preventing graft rejection, and investigational agents for solid organ transplantation are reviewed.