Use of IL-6-elafin genetically modified regulatory macrophages as an immunotherapeutic against acute bacterial infection in the lung

Abstract

AbstractBackgroundPseudomonas aeruginosa (P.a) infections are a major public health issue in ventilator-associated pneumoniae, cystic fibrosis and chronic obstructive pulmonary disease (COPD) exacerbations. This bacterium is multidrug resistant and there is an urgent need to develop new therapeutic approaches.ObjectiveEvaluate the effect of direct pulmonary transplantation of gene-modified (elafin and IL-6) syngeneic macrophages in a mouse model of acute of P.a infection.MethodsWild type (WT) or Elafin-transgenic (eTg) alveolar macrophages (AMs) or bone marrow derived macrophages (BMDMs) were recovered from broncho-alveolar lavage or generated from WT or eTg mice bone marrow. Cells were modified with adenovirus IL-6 (Ad-IL6), characterized in vitro (RNA expression, protein secretion, surface markers) and transferred by oropharyngeal instillation in the lungs of naïve mice. The protective effect of the transferred macrophages was assessed during P.a acute infection (survival studies, mechanistic studies of the inflammatory response).ResultsWe show that the transfer in the lung of a single bolus of syngeneic AMs or BMDMs genetically modified with IL6 and Elafin provided protection in our pneumonia P.a-induced model. Mechanistically, Elafin-modified AM had an IL-6-IL-10-IL-4R-IL-22-antimicrobial molecular signature which, in synergy with IL-6, conferred, post-transfer, a regulatory phenotype to the alveolar unit.ConclusionHere we introduce an immunotherapy approach employing gene-modified syngeneic macrophages to target bacterial airway infections. The absence of adverse events during our experiments suggests that our approach is well tolerated and supports the feasibility of translating this therapy to patients suffering from lung acute bacterial infections.