Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models.
Vibha N. Lama, John A. Belperio, Jason D. Christie, Souheil El-Chemaly, Michael C. Fishbein, Andrew E. Gelman, Wayne W. Hancock, Shaf Keshavjee, Daniel Kreisel, Victor E. Laubach, Mark R. Looney, John F. McDyer, Thalachallour Mohanakumar, Rebecca A. Shilling, Angela Panoskaltsis-Mortari, David S. Wilkes, Jerry P. Eu, Mark R. Nicolls
A summary of preclinical models used for lung transplant research.
There are a number of preclinical models (right) to study the three major complications of lung transplantation (left): (i) Primary graft dysfunction (PGD), which occurs as a consequence of organ procurement, cold storage and implantation; (ii) acute rejection (AR), which is mediated through cell- and antibody-mediated immune responses; and (iii) chronic rejection or CLAD, which pathologically manifests as RAS and OB. PGD can be modeled through in vitro culture systems to assess cellular responses to cold hypoxia and warm reperfusion. Ischemia-reperfusion injury associated with PGD can be modeled by the hilar clamp model in vivo. Limiting PGD and prolonging transplant survival can be studied through the use of ex vivo lung perfusion (EVLP) in animal models. Orthotopic lung transplantation in animal models is a highly rigorous approach that can be used to study PGD as well as AR, immune tolerance, lymphatic biology, obliterative bronchiolitis (OB), and restrictive allograft syndrome (RAS). Heterotopic and intrapulmonary tracheal transplant models are high-throughput procedures useful for modeling AR processes. Orthotopic tracheal transplantation models large airway changes in acute and chronic rejection and is especially useful for studying microvascular changes. The graft-versus-host disease (GVHD) model, which relies on bone marrow transplantation of MHC-mismatched cells, produces OB-like lesions. Illustrated by Rachel Davidowitz.