Birgitta Versluijs

172 Outcome determinants for allo-LS Less is known about the exact pathophysiology of BOS, but it is hypothesized that the first step in BOS is bronchiolar epithelium injury by conditioning, gastroesophageal re- flux or infection. BOS is regarded as a form of cGVHD, a complex immune dysregulation where failure of central tolerance leads to immune reactivity resembling autoimmune disease (T helper-2 cells, decreased regulatory T cells). B cells also play a key role in cGVHD, with autoantibodies contributing to tissue damage. These inflammatory pro- cesses result in fibrosis with eventually disruption of normal tissue architecture of for instance respiratory epithelium. The fibrotic mechanism is complex, with two mediators of special interest; transforming growth factor (TGF-beta) and platelet-derived growth factor receptor (PDGF-R). Stimulatory PDGF-R antibodies are found elevated in patients with cGVHD. 3,4 In BOS after HCT more clinical trials exist, partly based on results seen in BOS af- ter lung transplantation. 46 The only recently published trial is on inhaled Fluticasone, Azithromycin and Montelukast (FAM) therapy as treatment for new onset BOS after HCT. 47 Mechanisms of action of these agents are decrease in local lung inflammation, reduction of local IL-8 and neutrophilia, and impairment of leukotriene activity respec- tively. Leukotrienes constitute a class of inflammatory mediators with the ability to me- diate bronchoconstriction and stimulate the secretion of mucus into the airways and the extravasation of fluids and proteins into the airway tissues, all contributing to obstruc- tion. Endpoint of the FAM study was failure to therapy, defined as decline in PFT > 10%. Only 6 % of patients experienced failure to therapy, most showed stabilization of BOS progression for at least 3 months. These results compare favorable to other studies in adults with BOS. There were no side effects of FAM therapy, and steroids could be tape- red, with at least 50% in the majority of patients by 6 months. Other trials have studied Azithromycin and Inhalation steroids in combination with bronchodilators, both groups have not published their results though. The ongoing studies are on the role of Pirfenidone (antifibrotic, anti-inflammatory), Mesenchymal Stroma Cell infusions (anti-inflammatory), ciclosporin A inhalation, bortezomib (anti- TGF-beta) and an oral neutrophil elastase inhibitor. Extra Corporeal Photopheresis (ECP), an immunomodulatory treatment with a complex mechanism (apoptosis of lymphocytes after irradiation, also leading to increase in Tregs), is already successfully used in chronic allograft rejection after lung transplantation 46 and now also studied in BOS after HCT. When regarded a lung manifestation of cGVHD, BOS is also included in many studies on cGVHD in a broader context. Of interest are the ongoing trials on Rituximab, JAK- inhibition, ECP and cellular therapies like Mesenchymal Stromal Cells. 9