Transplant immunology

Transplant immunology

PI: Christine Lau, MD


The main focus of our research is to understand the molecular and cellular mechanisms of lung injury relevant to lung transplantation and particularly to chronic allograft rejection, or bronchiolitis obliterans (BO). Remarkable progress in lung transplantation has occurred through refinement in technique and improved understanding of transplant immunology and microbiology. Despite these improvements, chronic rejection of the lung allograft (BO) remains the major hurdle limiting long-term survival. To date, prevention of known risk factors and treatment strategies have not lessened the devastating toll this process has on lung transplant survival.

Lau_lab2.jpg
John Steidle; Yunge Zhao, MD, PhD; Christine L. Lau, MD; Abbas Emaminia, M

Current Projects:

Adenosine Signaling in Lung Transplantation Injury and Rejection

Based on the complex etiology of BO, a multi-pronged approach that affects the inflammatory and innate as well as the adaptive immune responses to injury would be most effective in mitigating BO. Ischemia-reperfusion injury is linked to the subsequent development of BO. Furthermore, early post-transplant elevation of proinflammatory mediators has been shown to be associated with alloimmunity and BO. However, unlike other solid organ transplants it is likely that frequent and repetitive subclinical injury occurs in the lung allograft since it is constantly exposed to the external environment. Thus limiting ischemia-reperfusion injury may lessen the development of BO, but likely will not alone eliminate it. The same holds true with the prevention of the other risk factors (acute rejection/viral infections/reflux). A treatment strategy that is multifaceted in prevention of inflammation and immunity is likely needed.
Adenosine and its four receptors are a critical part of the physiological negative-feedback mechanism for limitation and termination of tissue-specific and systemic inflammatory responses. Adenosine and its receptors also play roles in the adaptive immune response and in wound healing and fibrosis. One of the main projects in our laboratory is characterizing the role of adenosine, and its various receptors in chronic allograft dysfunction. We have shown the adenosine A2A receptor is important in chronic allograft injury and that agonists to this receptor can attenuate this injury (Lau and colleagues, Annals of Thoracic Surgery in press). The figure below shows allograft tracheas from mice that have been treated with adenosine A2A receptor agonists compared to no treatment controls and trachea allografts into A2A receptor knockout mice. The allografts transplanted into A2A receptor knockout (KO) recipients experienced the most inflammation and subsequent luminal obliteration, and adenosine A2A receptor agonist (ATL in figure) treated allografts showed protection from inflammation and luminal obliteration.

Trachea transplants

 

Cross Talk between Coagulation and Inflammation in Acute Lung Injury

It is clear that two powerful biologic systems, coagulation and inflammation, interact and contribute to the severity of the response. It is well documented that increased coagulation and impaired fibrinolysis play an important role in the pathogenesis of the various forms of acute lung injury. One active area of research in our laboratory is on the cross-talk between the coagulation and inflammatory systems in ischemia-reperfusion injury, which is a type of acute lung injury and is a significant risk factor in the development of BO. We have previously shown that lung ischemia-reperfusion injury triggers fibrin deposition in the murine lungs and fibrin creates a proinflammatory environment. Preventing fibrin deposition with the use of plasminogen activator inhibitor-1 (PAI-1) knockout mice (below left) reduces ischemia-reperfusion injury, inflammation, and leukocyte infiltration (below right). This finding may lead to novel treatment strategies for ischemia-reperfusion (J Thorac Cardiovasc Surg, 137:1241-1248, 2009).

Lau research Lau research

 

Increasing the Usage of Marginal Lung Donors

Many lung transplant programs have increased the volume of lung transplants performed by accepting marginal donor criteria. But even with the use of these donors the need greatly outweighs the number of available lung donors. One novel technique that has the potential to substantially increase the supply of marginal donors is the "lung box", an ex-vivo circuit (Vitrolife, Steen solution) that perfuses marginal lungs and recovers them and determines their usability. We are currently collaborating with Vitrolife and performing experiments using pig lungs with this technique (see lung box in figure below). Our long term goal is to improve the quality of human marginal lungs and apply our experimental findings to clinical operation. We are also trying to develop a mouse lung ex-vivo perfusion model, which is similar to the "lung box model", to investigate molecular and cellular mechanisms leading to improvement of marginal lungs using gene knockout mice and various synthesized small molecules.

Lung box