Trial Shows Ex-Vivo Lung Filtering Technique Cuts Transplant Rejection

Exciting new research, partly funded by the U.K. Cystic Fibrosis Trust and the Robert Luff Foundation and announced at the Trust’s U.K. CF Conference last week, shows promising results in reconditioning poorly functioning donor lungs and reducing acute organ rejection in a trial on pigs, the Trust reports.

A team of researchers from the University of Manchester collaborated with colleagues from Lund University in Sweden, to investigate a technique called ex-vivo lung perfusion (EVLP) that keeps lungs breathing outside of the body and supports them with a supply of blood-substitutes and nutrients, removing the donor’s white blood cells from the organs.

Encouragingly, little evidence of rejection within the first hour was observed in pigs receiving lungs treated with EVLP, compared with the severe rejection seen in all pigs receiving lungs using the normal transplant method.

Dr. Janet Allen, Director of Strategic Innovation at the Trust, comments in a Trust release: “These results are very encouraging. It’s an important development to transplant research, and an area the Cystic Fibrosis Trust has been funding for several years, and will hopefully contribute to the rate of survival for transplant patients in the near future.”

Researchers hope this technique will lead to an increase in numbers of lungs available for transplantation, reducing the wait list times and saving lives.

Dr. James Fildes, from the University’s Collaborative Centre for Inflammation Research and the Transplant Centre at the University Hospital of South Manchester NHS Foundation Trust who led the study, observes: “Aside from the benefits shown in this study, it is possible that EVLP could be used to deliver drugs before the lung is implanted so that the patients immune system does not recognize the transplanted organ as harmful.”

An article reporting the study, entitled “Lung Filtering Technique Can Reduce Transplant Rejection“ describes the new technique to recondition poorly functioning lungs and remove donor white blood cells that University of Manchester researchers have used in attempting to increase the number of lungs available for transplant, and at the same time reduce the risk of acute rejection.

The release notes that lung transplantation is often the only option for patients with end stage lung disease, but limited by a shortage of donor organs. And in the event that patients on wait lists are fortunate enough to receive a transplant, they will need lifelong immunosuppression to prevent their own immune system from destroying the transplanted organ — a process called acute rejection often triggered by presence of the donor lungs’ white blood cells that migrate into the recipients body and are reacted to by his/her immune system as harmful invaders.

In a paper published last month in the American Journal of Transplantation, entitled “Altered Immunogenicity of Donor Lungs via Removal of Passenger Leukocytes Using Ex Vivo Lung Perfusion“  (first published online: 14 SEP 2015, American Journal of Transplantation. doi: 10.1111/ajt.13446), Dr. Fildes with coauthors J. P. Stone, W. R. Critchley, T. Major, G. Rajan, I. Risnes, H. Scott, Q. Liao, B. Wohlfart, T. Sjöberg, N. Yonan, and S. Steen, variously of the University of Manchester Collaborative Centre for Inflammation Research and the University Hospital of South Manchester Transplant Centre in Manchester, UK; the University of Oslo Department of Pathology, Institute of Clinical Medicine Rikshospitalet in Oslo, Norway; and the Lund University and Skåne University Hospital Department of Cardiothoracic Surgery at Lund, Sweden, note that passenger leukocyte transfer from the donor lung to the recipient is intrinsically involved in acute rejection.

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The research team employed EVLP and found that with the lung kept alive, breathing outside the body and supported by a supply of blood and nutrients, they could repair organs that would normally be rejected for transplant, and they observe that given that 80% of donor lungs are currently not used, the technique is expected to significantly shorten waiting list times and increase access to transplantation.

“Because the lung is a potential entry route for infection into the body, its immune response is highly developed. In lung transplantation the situation is made worse by the processes that occur in the donor, which automatically increase the activity of the immune system,” Dr. Fildes explains.

All of this makes lung transplant recipients particularly susceptible to rejection, so they require continuous immunosuppression, which then increases risk of infection and cancer. These immune processes are therefore very important and contribute to the outlook where only five out of ten patients will survive for at least five years.

However, EVLP is becoming an established technique, although this is the first time it has been applied in this way. The researchers are hopeful that EVLP will be used in patients to reduce high rates of rejection and wastage of scarce donor lungs.

Pig recipients of transplanted lungs were monitored for 24 hours and sequential samples were collected, and the investigators observed that EVLP-reduced donor leukocyte transfer into the recipient and migration to recipient lymph nodes was markedly reduced. Recipient T cell infiltration of the donor lung was significantly diminished via EVLP. Donor leukocyte removal during EVLP reduced direct allorecognition and T cell priming, diminishing recipient T cell infiltration, a hallmark of acute rejection.

As the lungs were only monitored for 24 hours it is difficult to know the long-term effects, but even a delay would be beneficial in allowing the transplanted organ to become accepted. Used in conjunction with new immunosuppressive agents the team are developing, the researchers hope for even more benefits.

Dr. Fildes says his lab’s research focus is on exploring how ex-vivo organ perfusion can be used to alter donor organ immunity prior to transplantation, noting that “using this novel approach we have now demonstrated that perfusion can be used to deplete specific immune cells from the donor organ and reduce post-operative direct allorecognition. This reduces T cell recruitment in the absence of immunosuppression. We are also assessing how perfusion reverses cellular injury. Using an omics approach we have mapped pathways involved in tissue repair and are now testing novel therapeutics for use in donor organ retrieval and acute lung injury.” The researchers’ aim is to fast track therapeutics in the ex-vivo systems which can then be tested in diseased explanted human organs (those collected from transplant recipients).

Dr. Fildes’ lab is also studying donor organ retrieval for transplantation techniques, noting that there is significant debate in the transplant community in regard to the most effective protocol for organ preservation prior to transplantation. “We are using our models to compare currently active methods (i.e. static cold vs cold machine vs warm machine) and also test novel molecules that may augment organ preservation during retrieval, perfusion and storage,” he observes, adding that aside from the benefits shown in this study, it is possible that EVLP could be used to deliver drugs before the lung is implanted so that the patient’s immune system would not recognize the transplanted organ as harmful.

Sources:
U.K. Cystic Fibrosis Trust
University of Manchester
American Journal of Transplantation
Lund University
University Hospital of South Manchester NHS Foundation Trust