Northwestern Medicine scientists have discovered a potential therapeutic target in the donor lung that may prevent primary graft dysfunction (PGD) in lung transplant recipients, according to findings published in the Journal of Clinical Research (JCI).
GR Scott Budinger, MD, chief of Pulmonary and Critical Care in the Department of Medicine and the Ernest S. Bazley Professor of Airway Diseases, was the study’s senior author.
“In solid organ transplants, lung transplant success rates are low, with only half of patients surviving beyond five years — and a leading cause of early and later complications after lung transplantation is PGD,” said Budinger, who is also a professor of Cell and Developmental Biology. .
Northwest scientists have been working for years to address PGD, a potentially fatal injury to the vulnerable transplanted lung that occurs in the first few days after surgery.
In 2017, they published a pivotal discovery: After transplantation, blood immune cells called nonclassical monocytes (NCMs), held in the donor lung, activate a pathway that draws harmful neutrophils from the host to the newly transplanted lung. Those findings suggested that targeting NCMs in donor lungs could potentially prevent the development of PGD. Still, the treatment options that emerged from that study were limited.
“Most treatment options available for PGD are symptomatic treatments, not necessarily treating the actual disease process itself. So it was critical to further elucidate the mechanism to consider even disease-modifying therapies,” said the study’s lead author, Melissa Querrey, PhD, a fourth-year student in the Medical Scientist Training Program (MSTP).
With the current study, the team has conducted the first study (led by Ankit Bharat, MBBS, chief of thoracic surgery in the Department of Surgery and the Harold L. and Margaret N. Method Professor of Surgery, who is also a co-author of the JCI study) one step further, finding the pathways that activate these cells after transplantation. More importantly, they found that a protein on these cells, CD11b, can act as a molecular “brake” to reduce their activation.
A critical finding of this paper is that an activator of the CD11b inhibitory system LA-1, administered only to the donor lung before transplantation, significantly reduced the severity of transplant-induced early lung injury, according to Budinger.
“This is important because treatment of the donor lung before transplantation is possible using ex vivo perfusion or “lung in a box” systems,” Budinger says. “Since the recipient never needs to receive the drug, this strategy will likely reduce all of the drug’s side effects.”
In addition to advancing this therapeutic approach in the ex vivo perfusion system, researchers have their sights set on potential benefits on a larger scale.
“We want to explore the utility of the same route and therapy in other related inflammatory lung diseases,” Querrey said.
Other Northwestern co-authors of this study are: Stephen Chiu, MD, a fellow in the Department of Thoracic Surgery; Emilia Lecuona, PhD, associate professor of surgery in the Department of Thoracic Surgery; Quiang Wu, PhD, associate professor of surgery in the Department of Thoracic Surgery; Haiying Sun, PhD; Megan Anderson; Megan Kelly; Sowmya Ravi, MPH; and Alexander Misharin, MD, PhD, assistant professor of medicine in the pulmonary and critical care division.
Budinger and Bharat are members of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
This study was supported by National Institutes of Health grants HL145478, HL147290, HL147575, U19AI35964, P01AG049665, P01AG04966509S1, P01HL154998, R01HL147575, and Veterans Affairs grant I01CX001777.