We are proud to be funding the following research:

The Lungitude Foundation also supports the legacy of The Margaret Pratt Heart Lung Transplant Research Foundation which has funded the following projects:

$180,000 over 2 years (2017 & 2018)

  • A study of QuantiFERON-CMV-Directed CMV prophylaxis versus Standard Of Care to reduce late Cytomegalovirus (CMV) reactivation in patients undergoing lung transplantation.
  • A monitoring study using QuantiFERON to measure ‘net’ immunosuppression post lung transplantation.
  • A phase 2 randomised, placebo controlled trial of bone-marrow derived mesenchymal stromal Cell infusions as treatment for new on-set chronic lung allograft dysfunction.
  • Identifying non-invasive biomarkers of acute and chronic lung allograft dysfunction following lung transplantation.

$120,000* over 4 years (2017-2021)
Match funded by The Alfred Foundation’s supporters – Total of $240,000

  • Defeating Lung Transplant Rejection: Antibodies and Strategies to Reject Them

The Jeff Gittus Lung Transplant Fellowship was announced in 2019, funded generously by Liz Gittus and the Gittus Family. The Fellowship provides one annual fellowship grant of up to $10,000 for a research project of 12-18 months total duration, that focuses specifically on improving lung transplant patient outcomes.

For further information please visit our Grants Section.

Defeating Lung Transplant Rejection: Antibodies and Strategies to Control Them
Lungitude Foundation / Alfred Foundation Matched Funding Project

The major cause of reduced long-term survival after lung transplantation is chronic graft rejection – also known as Chronic Lung Allograft Dysfunction (CLAD) – that disappointingly occurs in ~50% of all lung transplant recipients by 5 years. Antibodies that attack transplanted lung tissue, known as donor specific antibodies (DSA) are a suspected cause of CLAD (called antibody-mediated rejection). Our immune system is designed to recognise “foreign” invaders such as bacteria and viruses and produce antibodies to them. However, the transplanted lung is seen as “foreign” to the recipient’s immune system, causing DSA to be produced which attack the donor lung. Defeating Transplant Rejection: Antibodies and Strategies to Control Them, aims to identify and understand the mechanisms of antibody production that mediate destruction for the purpose of ultimately identifying targeted therapies to prevent rejection.

DSAs are routinely measured prior to transplant to try to avoid transplantation of a lung where the recipient has existing DSA to that particular organ, where possible. DSAs are also measured after transplantation to determine if new DSAs are being produced. The key is selecting the “best matched” donor organ in order to prevent new DSAs being produced. Researchers have continued to make inroads to this project, with 3 students (2 PhD and 1 medical student) joining to work on this research. One of these PhD students, Mr Steven Hiho, is based at the Australian Red Cross Blood Service and has already been a co-author on a recent publication on this project (see below). In this manuscript, researchers showed that “eplet” mismatches between the donor and recipient in a protein called HLA-DQ can lead to the production of DSA. Mr Hiho’s future work is aimed at identifying the “high-risk” mismatches that cause trouble for the recipient so that the team can avoid these mismatches in future transplants. This process is underway but has been delayed by a change in the definition of CLAD according to international guidelines. This therefore requires the researchers’ entire cohort in this study (~400 recipients) to be re-analyzed by this new definition of CLAD. Researchers have started this process and anticipate completion around mid 2019.

Another aspect of Mr Hiho’s project is to compare old donor/recipient matching techniques with newer, more sensitive methods and relate this to lung transplant outcomes. It is hoped that this research will lead to better methods of donor selection being adopted on a national level (see other project below).

In 2018, a medical student, Ms Catia Fernandes Monteiro, completed a pilot project aimed at identifying the specific immune cells that cause damage to the lung following the production of DSA. The research on this project was extremely productive and successful, ascertaining that a group of white blood cells called “natural killer” or NK cells have heightened activity in recipients with DSA. This research has been presented at a conference and several seminars and written for publication in 2019.

In an exciting new development in this project researchers now believe that the antibodies that are produced by the donor’s immune cells can also contribute to antibodies present in recipients. These novel findings were recently accepted for publication in the top-ranked transplantation journal, American Journal of Transplantation. Researchers will continue to pursue this area of research as it has the potential to cause a paradigm shift in the way we think about antibodies that can cause damage to a transplanted lung.

Publications:

“HLA class II Eplet mismatch predicts De Novo DSA formation post lung transplant”.
Walton DC, Cantwell L, Hiho S, Ta J, Wright S, Sullivan LC, Snell GI, Westall GP. Transplant Immunology 2018 51:73- 75.

“Transfer of donor anti-HLA antibody expression to multiple transplant recipients: A potential variant of the passenger lymphocyte syndrome?”
Kummrow M, Hiho S, Hudson F, Cantwell L, Mulley WR, D’Orsogna L, Testro A, Pavlovic J, MacDonald P, Sullivan LC, Snell GI, Westall GP. Am J Transplant. 2019 Jan 17.

Image credit – ThoughtCo 

Assessing New Tools for Improving Donor-Recipient Matching

The last few years has seen the creation of several new computer programs to assess “compatibility” between a lung transplant recipient and a potential donor. These programs use differences between donor and recipient proteins and give a “score” of compatibility between any particular pair. This PhD project will compare the effectiveness of these different computer programs in their ability to predict which patients will have less rejection. Initially, researchers will look at patients that have been previously transplanted and assign them ‘compatibility scores’ with each computer program and compare these scores with rejection. By doing so, researchers can guide the Red Cross on which computer program they should use to give a “score” between a recipient and a potential donor.

In addition, researchers predict that not all protein “mismatches” are equal in their ability to cause rejection. Researchers plan to interrogate each computer program to identify individual “taboo” protein mismatches that are seen repeatedly in patients that have rejection, rather than to use the overall “score” generated by the program.

When researchers identify such “taboo” mismatches they will undertake a laboratory assessment to determine how the body reacts to these proteins to result in rejection of the transplanted lungs. This project fits extremely well into The Alfred’s key goals of seeking a better understanding of what might cause CLAD, and developing better tools for donor- recipient matching may be key to preventing the development of CLAD, with the added aims of improving and prolonging life post lung transplantation.

Image – Steven Hiho

Investigating the link between viral infection and rejection following lung transplantation

Rejection of the transplanted lung is linked to infection, with the most important being cytomegalovirus (CMV). Monitoring whether the immune system of a particular lung transplant patient can control the amount of CMV in their blood, would provide information regarding duration of antiviral medication treatment. It is important to define the optimal duration of antiviral medications as these drugs are very expensive, can have significant side effects and can result in resistant strains of CMV too. Hence there is a requirement for using appropriate immune-system monitoring ‘assays’ to predict the risk of CMV infection in individual transplant recipient. A commercially available test called the QuantiFERON-CMV assay is currently available and is being used by the Alfred after Lung Tx was shown to be beneficial (via previous research funded by Lungitude) to test if a patient’s immune system is able to control CMV.

However, this QuantiFERON-CMV monitoring assay only measures responses from one cell type called ‘killer T cells’. A new test called T-Track CMV measures the function of several other important immune cells (effector cells) and claims to be a better predictor of a patient’s ability to fight CMV. In this second project, researchers aim to directly compare the utility/benefit of QuantiFERON-CMV with the new T-Track CMV assay to predict the occurrence of CMV infection following lung transplantation.

Researchers will use stored blood collected from 40 post-transplant patients who have already been enrolled into the previous Biomarkers I project and use these samples to run the T-Track CMV assay. Researchers will then compare the T-Track CMV results with the same patients QuantiFERON-CMV test results to see if the new test is more predictive of CMV infection or immunity.

Image credit – Medscape

Measurement of Biomarkers II

This project extends the previous Biomarker I study- Identifying of biomarkers of immune function and infection in the blood and lung aiming to predict episodes of acute rejection and the onset of chronic lung allograft dysfunction (CLAD) following LTx. This project, which commenced in April 2018, will follow a cohort of 100 post lung transplant patients for 3 years with specimens collected at all bronchoscopies and also at defined clinical time-points.

An additional Research Nurse/Coordinator will be funded to facilitate collection and recording of data for of all the bronchoscopic (BAL) and blood specimens taken at each bronchoscopy. Funding will also employ a Research Lab Assistant in the Monash laboratory to process the specimens being collected for this project as well as the other 2 projects outlined previously.

Image credit – Thoracic Key

Laptop Computer and SPSS Statistical Software

Funding of a dedicated Lung Transplant Research Laptop/ software and SPSS Statistical Software:

  • Computers, software or any other forms of IT for use in clinical research need to be funded via research grants or staff have to use their own personal computers and personally purchase and pay the cost for statistical software.
  • Alfred staff are not permitted to install statistical software packages and other research programs on hospital computers.
  • The laptop computer will be kept in the Lung Transplant Department, and will be available for use by various members of the Lung Tx research team for all projects supported by Lungitude and other clinical research, under the supervision of Prof Greg Snell & A/Prof Bronwyn Levvey
  • Research Staff will be able to use the computer to record and collate research data, undertake statistical analysis of the various research projects underway, and also for preparing manuscripts and power-point presentations for conferences and meetings.
  • The computer also has the capability for use in research webinars and teleconferences, facilities that are not widely available in the Respiratory Medicine Dept. and limited also around the hospital.

Image credit – SPSS

Transplant Gym Patient Donations

Lungitude also facilitated patient funding for the Transplant Gym including the donation of a state of the art bike in memory of Tash Tripp.

Image – Tash Tripp’s family and supporters

A New System of Donor and Recipient Matching: HLA Matchmaker

Each of us (except identical twins) has a different set of HLA proteins that sit on the surface of the cells within the lung (and other organs). This genetic signature differs between transplant recipients and their donor lung and is what drives the immune system of some transplant recipients to “reject” their lung. Historically, there have been relatively crude tools to assess the compatibility of the HLA of the donor with that of the recipient. In collaboration with the Red Cross, The Alfred’s Lung Transplant Service Team are exploring how the HLA Matchmaker program may allow them in the future to better match donor lungs with the “best fit” recipient. By improving donor/recipient matching, they will reduce the likelihood of subsequent rejection thereby increasing survival following lung transplantation.

The HLA Matchmaker program allows the team to determine HLA proteins at a molecular level. Through a greater understanding of the precise shape and size of the HLA molecules, they can better predict which HLA proteins are more likely to switch on the transplant recipient’s immune system and trigger an episode of rejection. In recent work that they published in the prestigious “American Journal of Transplantation” they used the HLA Matchmaker program to show that lung transplant recipients whose HLA proteins were structurally very different to those of their donor were more likely to develop chronic rejection. In collaboration with the labs of Professor David Tarlinton (Monash University) and Professor Andrew Brookes (University of Melbourne) they will now explore how these structural differences in the HLA molecule switch on the immune system.

The success of this program will be two-fold. Through better matching of donors and recipients they will improve donor organ allocation, but additionally through a greater understanding of the immune pathways leading to rejection they can better target their anti-rejection therapies.

Image credit – bethematch.org

Molecular Microscope Diagnostic System (INTERLUNG STUDY)

The Alfred Lung Transplant Service’s ‘Molecular Microscope’ Diagnostic System collaboration (the INTERLUNG Study) with the University of Alberta investigators and other international lung transplant units is now well underway. The Study collects small pieces of the transplanted lung in people with a small drop in lung performance, from both the sponge of the lung and the airways leading to it, and analyses them in the standard way under an ordinary microscope, comparing these to genetic analyses in Canada. The standard approach is often non-specific and does not help to guide treatment. The new genetic approach appears to be giving different answers that suggest alternative treatments – potentially helping lungs at a time before lung function is lost permanently.

Historically, small pieces of the sponge of the lung are obtained to check for rejection, but the INTERLUNG Study is suggesting the potential of getting similar, or even better, results f rom bits of the lung airways. This would be an important innovation – noting airway tissue is easier and safer to obtain.

The INTERLUNG Study is ongoing, as the team now tries to link the genetic results with long-term lung performance and different types of rejection. The work will be presented at next year’s International Society of Lung Transplant Meeting and a portion will be submitted for publication soon.

Lung transplant research at The Alfred continues to flourish. The Margaret Pratt Foundation has supported the research team in the running of several projects, and The Alfred’s Lung Transplant Research Team we have been excited by the progress of the research. Researcher Yvonne Cristiano has provided an update on these projects below.

  1. A study of QuantiFERON-CMV-Directed CMV prophylaxis versus Standard Of Care to reduce late Cytomegalovirus (CMV) reactivation in patients undergoing lung transplantation.

It was an exciting moment this year when our final participant completed this study in April.  Since then the data has been analysed and we are thrilled to find that the primary aim of the project was met. The finding that QuantiFERON-CMV-Directed Care could reduce the incidence of CMV reactivation in the transplanted lung has led to a change in our clinical practice. QuantiFERON-CMV monitoring has now been introduced into our protocols for the care of our patients post lung transplant and our CMV management. This project was conducted over 5years involving 118 participants, and now with the introduction of this new clinical test, we hope to see this correlating to a reduction in CMV reactivation and the side effects CMV has on lung transplant recipients.

  1. A monitoring study using QuantiFERON to measure ‘net’ immunosuppression post lung transplantation.

This project recruited its 80th and final patient in July this year, with participant completion scheduled for July 2018. The QuantiFERON-Monitor blood tests measures the overall strength of a person immune system, which we are collecting at several time point during the first year after transplant. This project aims to show us the potential of this blood test to provide extra information regarding an individual’s immune system, and the possibility for guiding anti-rejection medications after transplantation.

  1. A phase 2 randomised, placebo controlled trial of bone-marrow derived mesenchymal stromal Cell infusions as treatment for new on-set chronic lung allograft dysfunction.

Managing chronic rejection after lung transplantation continues to be a challenge for all Lung Transplant teams. This projects is being led by Prince Charles Hospital in Queensland. The Alfred has recently obtained Ethics Approval to be a part of this project, and we have had our first patient undergo this therapy. The idea of using mesenchymal stromal cells to decrease the immune system and stop the progression of rejection is a novel therapy, with great potential to assist in the long term survival of lung transplant recipients. This project will continue over the next 5 years, with it anticipated to complete in 2022.

  1. Identifying non-invasive biomarkers of acute and chronic lung allograft dysfunction following lung transplantation.

Throughout this project many non-invasive biomarkers have been examined, some of these include Ativan, Follistatin, Natural Killer Cells, B Cells, De novo DSA and Cytokines of Aspergillus. There are 137 patients taking part in this project, with the final patient due to complete their participation in January 2018. This project has successfully answered many questions and in doing so raised many more. Analysis of the data from this project remains ongoing, along with analysis of the specimens. As a result of this project, we in the process of development a subsequent project (Biomarker 2), which aims to investigate the biomarkers influencing chronic lung allograft dysfunction (CLAD) further.

Defeating Lung Transplant Rejection: Antibodies and Strategies to Control Them

The major cause of reduced long-term survival after lung transplantation is chronic graft rejection – also known as Chronic Lung Allograft Dysfunction (CLAD) – that disappointingly occurs to some degree in 49% of all lung transplant recipients by 5 years. It is dif cult to predict which patients will develop CLAD, which occurs despite these patients being treated with anti-rejection drugs life-long.

Antibodies that attack the donor lung (antibody-mediated rejection – AMR) have been suspected as an important potential cause of lung failure and CLAD post lung transplantation. Our immune system naturally forms antibodies as a protective response against bacteria and viruses. In the context of transplantation, antibodies are good when they are ready to attack foreign invaders that can lead to illness, but antibodies can also be ready to attack foreign tissue – such as the donor lung.

Currently, antibodies that can attack transplanted lung tissue, known as donor speci c antibodies (DSA), can be measured prior to transplantation with the aim of selecting a donor organ that minimises the risk of rejection. DSA levels can also be measured post transplantation to see if the patient’s immune system is actually causing harm to the patient’s new lungs. Identi cation and de nition of speci c types of DSA and their incidence in patients undergoing lung transplantation is key to understanding how the immune system makes such antibodies and how they contribute to AMR and ultimately to chronic rejection.

The team from The Alfred Lung Transplant Service are collaborating with the Red Cross / Victorian Transplant Immunology Service to be able to more ef ciently detect and measure the presence of these graft-damaging antibodies in lung transplant patient’s blood samples. This collaboration also aims to develop a computerised matching program that will accurately identify problematic antibodies pre- transplant that will enable a better match between a donor and potential lung recipient, reducing the risk of antibodies causing the development of CLAD after transplant.

The funding provided by this grant has thus far enabled the recruitment of a senior post-doctorate researcher, Dr Lucy Sullivan, to oversee the conduct of this very important project. So far the computer matching program has been used to demonstrate in a sub-set of lung transplant patients that better matching of donor to recipient protects against CLAD. This research was published in the prestigious journal, American Journal of Transplantation. Additionally, in a small group of recipients the team have shown that better matching also reduces the appearance of these antibodies.

This research was presented at the International Society of Heart and Lung Transplant conference in San Francisco in April 2017.

In collaboration with researchers at Monash University, the team have also started a project to identify the specific immune cells that produce these antibodies. So far, they have shown that the number of “B cells” is significantly increased in lung transplant patients that also have damaging antibodies. They are now investigating the characteristics and appearance of these “B cells”. Furthermore, in collaboration with Doherty Institute they are using advanced laboratory techniques to identify other specific immune cells that cause damage to the lung following the production of antibodies. They believe these cells to be a group of white blood cells called “natural killer” or NK cells. So far, they have identified that certain groups of NK cells will kill other cells when antibodies are present.

The results, to date, from all aspects of this project are very pleasing, and the team anticipate being able to make considerable progress as they continue into 2018-19. Already this study is contributing greatly to their understanding of how and why harmful antibodies are produced and how to potentially avoid this process occurring after lung transplantation.

Publication:
HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.
Walton DC, Hiho SJ, Cantwell LS, Diviney MB, Wright ST, Snell GI, Paraskeva MA, Westall GP.
Am J Transplant. 2016 Sep;16(9):2695-703. doi: 10.1111/ajt.13798. Epub 2016 Apr 21