Alveolar Macrophage based personalized therapy for the delivery of IL-37 in inflammatory airway disease like COPD

Alveolar Macrophages (AM) are self-renewing, tissue resident immune cells in the lung. Interleukin 37 (IL-37) has anti-inflammatory properties to prevent hyper-inflammation and tissue damage. It has been shown to counteract cigarette smoke induced inflammation by inhibiting expression and secretion of pro-inflammatory cytokines. The aim of this work is the development of a cell-based personalized therapy with AM that have been modified by adeno-associated virus (AAV) to express IL-37. The modified AM will be re-transplanted into the lung in the disease model of chronic obstructive pulmonary disease (COPD) to mitigate inflammation. AM were transduced with AAV expressing green fluorescent protein (GFP) to find the optimal AAV serotype, multiplicity of infection (MOI), and incubation time by confocal microscopy. Transducing AM with AAV2/6 at a MOI of 87.500 resulted in the highest transduction rate (10–30 %) and protein production after 6 days shown by enzyme-linked immunosorbent assay (ELISA) and Western Blot. Lipopolysaccharide (LPS) stimulation sharply increased IL-37 protein synthesis and secretion in a dose dependent manner. In a COPD animal model, mice were transplanted by intubation with AM expressing IL-37 and smoked 3 days. In bronchoalveolar lavage (BAL) the mice showed lower concentrations of the pro-inflammatory cytokine KC compared to controls. In summary in AM the therapeutic transgene IL-37 can be expressed and secreted after stimulation with LPS. In animal experiments mice transplanted with IL-37 expressing AM showed lower inflammation in BAL after 3 days of smoking which is an important and promising step towards the development of a cell based therapy.