Functional Repair of Human Donor Lungs by IL-10 Gene Therapy

Treatment of damaged donor lungs with the cytokine interleukin-10 improves their function, allowing previously unacceptable organs to be used for transplantation. Living Well After Lung Replacement Bumper stickers that counsel motorists to “just breathe” abound—easier said than done when it comes to patients with serious lung disorders. Lung transplantations are on the rise, from 203 in 1990 to more than 1200 in 2008 in the United States. Earlier this year, transplant surgeons at Johns Hopkins presented evidence that more is better—hospitals that perform 20 or more lung transplants per year have the best patient survival rates. However, successful surgeries require healthy donor lungs, a resource that remains in short supply. Now, Keshavjee and colleagues describe a gene therapy treatment protocol to repair lungs after removal from the donor and before transplantation into patients. Candidates for lung transplantation are patients suffering from end-stage lung diseases, such as emphysema, cystic fibrosis, pulmonary fibrosis, and pulmonary arterial hypertension. Organ donors are people who have undergone brain death, a process that is as violent as it sounds: Brain death is accompanied by the spewing of inflammation-inducing molecules called cytokines that damage more than 80% of donated lungs. These injured organs are highly inflamed, and their alveoli—the gas exchange machinery in lungs—are disrupted and only mildly functional. To avoid primary graft dysfunction—lung damage that occurs within the 72 hours after transplantation—transplant surgeons usually reject such injured organs. A method is needed to heal these fixer-upper organs so that they can be used to give patients a new lease on life. Using IL-10, an anti-inflammatory cytokine, Keshavjee’s team devised a treatment to quell inflammation in the injured donor lungs and refurbish the alveoli. Although the standard technique for the handling of organs is to keep them on ice in a sealed bag, this IL-10 gene therapy approach must be performed at body temperature so that the lung’s cellular machinery can express the gene efficiently. The researchers then carried out prolonged ex vivo lung perfusion (EVLP) and kept the lungs breathing outside the body in conditions that mimic physiological ones. Pig lungs that were subjected to IL-10 gene therapy and EVLP for 12 hours displayed reduced inflammation and enhanced function when transplanted into donor pigs, relative to control organs. The same treatment was applied to human lungs deemed unsuitable for transplantation, and these organs, relative to controls, displayed the presence of anti-inflammatory cytokines, repair of alveoli, and improved function, determined by measuring gas exchange and pulmonary vascular resistance. This procedure can yield a larger number of usable lungs and thus more successful transplantations so that patients can “just breathe. ” More than 80% of potential donor lungs are injured during brain death of the donor and from complications experienced in the intensive care unit, and therefore cannot be used for transplantation. These lungs show inflammation and disruption of the alveolar-capillary barrier, leading to poor gas exchange. Although the number of patients in need of lung transplantation is increasing, the number of donors is static. We investigated the potential to use gene therapy with an adenoviral vector encoding human interleukin-10 (AdhIL-10) to repair injured donor lungs ex vivo before transplantation. IL-10 is an anti-inflammatory cytokine that mainly exerts its suppressive functions by the inactivation of antigen-presenting cells with consequent inhibition of proinflammatory cytokine secretion. In pigs, AdhIL-10–treated lungs exhibited attenuated inflammation and improved function after transplantation. Lungs from 10 human multiorgan donors that had suffered brain death were determined to be clinically unsuitable for transplantation. They were then maintained for 12 hours at body temperature in an ex vivo lung perfusion system with or without intra-airway delivery of AdhIL-10 gene therapy. AdhIL-10–treated lungs showed significant improvement in function (arterial oxygen pressure and pulmonary vascular resistance) when compared to controls, a favorable shift from proinflammatory to anti-inflammatory cytokine expression, and recovery of alveolar–blood barrier integrity. Thus, treatment of injured human donor lungs with the cytokine IL-10 can improve lung function, potentially rendering injured lungs suitable for transplantation into patients.