Targeting the Pentraxin 3-Complement Axis to Mitigate Injury Post Lung Transplanation
Abstract
Topic Area(s): Acute lung injury/lung injury Central Problem to Be Addressed: Lung transplantation (LTx) is the only treatment option for those with severe end-stage lung disease such as chronic obstructive pulmonary disease, interstitial lung disease, and cystic fibrosis, without which many patients die. This is even more relevant to military personnel, in whom chronic lung disease appears to have doubled in the last decade and is more likely to occur compared to the general population. However, LTx is not without significant risks. It has worse outcomes compared to kidney, liver, and heart transplantation, with nearly half the recipients dying around 5 years post-LTx. A major reason for this is primary graft dysfunction (PGD). PGD is a form of acute lung injury, which occurs because taking lungs out from the donor, transporting them, and placing them into the recipient can result in a massive activation of the recipient’s immune system. This results in the immune system attacking the lung, causing the lungs to be flooded with fluid from the circulation and their inability to transport oxygen. Because of PGD, patients remain on the ventilator for a longer period post-LTx, and in some cases, need additional life support (such as extracorporeal membrane oxygenation, or ECMO). PGD is a major cause of death within the first 30 days post-LTx. However, even among patients who live till the first year post-LTx, PGD is a risk factor for chronic rejection and long-term mortality. Sadly, there are no treatments currently available for PGD other than supportive care. One of the reasons for this is a lack of understanding in what specific components of the immune response are responsible for PGD. Thus, we urgently need treatments for reducing acute lung injury post-LTx. Better understanding of how PGD occurs is crucial to achieve this objective because treatments that are not targeted at what is driving PGD are likely to fail. Premise: Clinical studies among lung transplant recipients from multiple centers suggests that pentraxin-3 (PTX3), an immune protein, is associated with an increased PGD risk. Moreover, work from others and us using patient samples suggests that the complement cascade, which is one of the first members of the immune system to be activated during injury, contributes to PGD. Interestingly, it has been long known that PTX3 can activate the complement cascade. However, no one has studied this “PTX3-complement axis” with the goal of reducing PGD, which should be logical given it has a strong basis from patient-level data. Through this Discovery Award, we propose to understand how PTX3 activates the complement system in recipients developing PGD. We then propose using a mouse LTx model to test components of the immune response that are driving this axis. Finally, we aim to use novel therapeutics to target this axis as a part of an overarching goal of reducing PGD severity. Innovation of the Idea: Our proposal is therapeutically novel because no treatments have been successful for PGD, partly because they have not been targeted. Targeting PTX3 itself is conceptually innovative because PTX3 activates the complement cascade through two different pathways. Based on the clinical premise, we would be developing a personalized therapy that would mitigate PGD in at-risk recipients. Also, there is no accepted method for non-invasively measuring PGD in mice. Hence, mice need to be sacrificed at each time point for measuring PGD (24, 48, and 72 hours in humans). By using microcomputed tomography (microCT) to quantify PGD, we may potentially provide a technical innovation to reduce the number of mice used in such models and longitudinally track the development and resolution of lung injury. Using a novel technique called multiplexed immunofluorescence, which has been extensively used in cancer immunology to better understand immune responses to difficult-to-treat tumors, we propose investigating
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010143
Entities
People
- Hrishikesh Kulkarni
Organizations
- United States Army
- Washington University in St. Louis