Lung transplantation is a widely accepted therapeutic option for end stage lung disease. However, clinical outcomes are yet challenged by primary graft failure, which is responsible for the majority of early mortality, and by chronic allograft dysfunction and chronic rejection, accounting for more than 30% of deaths after the third postoperative year. Lung transplantation offers a 50% recipient and graft 5-yr survival, which is significantly lower than for liver, kidney, and heart transplantation (over 70%). The ongoing lung's exposure to the environment is likely the determining factor, with a significant role being played by the performance of the defense mechanisms. Pulmonary surfactant proteins (SP) A, B, C, and D are one of the first host defense mechanisms the lung can mount. SP-A in particular, is an opsonin produced by the type II pneumocytes, and is active in the innate and adaptive immune system including regulating macrophage and lymphocyte responses. Of note, SP-A biologic activity seems to be genetically determined, and SP-A polymorphisms have been associated with various lung diseases including respiratory distress syndrome, idiopathic pulmonary fibrosis, and emphysema. We hypothesize that SP-A gene variability is responsible for the different tolerance of lung grafts to transplant-related noxious events. The two SP-A genes SP-A1 and SP-A2 have several polymorphisms within the coding region, SP-A1 (6A, 6A2- 20), and SP-A2 (1A, 1A0-13). In preliminary studies performed to test our hypothesis, donor lung SP-A1 and SP- A2 genetic variants were associated with survival and development of chronic lung dysfunction following transplantation. SP-A2 genotypes 1A0-1A2,3,5,9, were correlated with lower levels of SP-A mRNA within allografts at implantation and lower SP-A protein levels in the broncho-alveolar lavage fluid post transplantation. Moreover, patients who died within 30 days of transplantation had significantly lower levels of SP-A mRNA in their lung allografts at implantation. These preliminary findings obtained from a small cohort of patients suggest a new paradigm where genetically determined SP-A function contributes to allograft function and survival. We are proposing to evaluate, in an appropriately powered study, if SP-A gene polymorphisms predict primary graft dysfunction and/or chronic lung graft dysfunction, and if these polymorphisms could serve as biomarkers of lung graft dysfunction. We also propose to study the interaction between immunosuppressive drugs and SP- A expression and determine whether this is dependent on SP-A variants. In vitro studies have shown variable SP-A expression in response to steroids, one of the primary immunosuppressive drugs in lung transplantation. This proposal will generate novel information improving our understanding of lung allograft dysfunction. It is conceivable that the information obtained will stimulate the interest for a multi centre study to investigate if SP- A polymorphism may be integrated in the donor lung selection criteria and/or to implement post transplant tailored immunosuppression.
Lung transplantation related research has to date predominantly focused on recipient related immune biology, as done for other solid organ transplant research. This proposal will focus on donor innate immunity and will study surfactant protein A as a key molecule in the lung allograft organ specific, innate immunity. Surfactant protein A will be studied both at a genetic and protein level as a predictor and biomarker of lung allograft dysfunction. This study will increase our understanding of lung allograft dysfunction which is the major limiting factor for the long term success of lung transplantation.
|Aramini, B; Kim, C; Diangelo, S et al. (2013) Donor surfactant protein D (SP-D) polymorphisms are associated with lung transplant outcome. Am J Transplant 13:2130-6|
|D'Ovidio, F; Kaneda, H; Chaparro, C et al. (2013) Pilot study exploring lung allograft surfactant protein A (SP-A) expression in association with lung transplant outcome. Am J Transplant 13:2722-9|