MCCIR AZ GSK Update Seminar Series
|Dates:||8 February 2016|
|Times:||15:30 - 16:30|
|What is it:||Seminar|
|Organiser:||Faculty of Life Sciences|
|Who is it for:||University staff, Current University students|
|Speaker:||Triin Major, Will Critchley|
The next MCCIR AZ/GSK Update Seminar is taking place on Monday the 8th of February 2016
Altered immunogenicity of porcine hearts via ex vivo perfusion
There are approximately 1.8 million patients living with heart failure in the UK. Heart transplantation still represents the only effective treatment for patients with end stage disease who are refractory to maximal treatment. However, the number of transplants performed is limited by the availability of suitable donor organs leading to high mortality on the waiting list. Increasing the utilisation of available organs may require the use of marginal, higher risk donors including donation after circulatory death. Ex vivo heart perfusion was developed as a method to improve preservation and aid evaluation of potential donor organs. However, the process of perfusion may have auxiliary benefits beyond extended preservation. This study investigated the effect of 8 hours of ex vivo perfusion on myocardial immune content to determine whether passenger leukocyte transfer would be modulated. We demonstrate that ex vivo perfusion results in a significant reduction in donor organ immunogenicity via the removal of passenger leukocytes. This appears to occur in a selective manner in response to circulating cytokines/chemokines released into the circuit, which may saturate the inflammatory response of the organ prior to transplantation. Additionally, ex vivo perfusion of the organ induces improvements in tissue status at a molecular level compared to baseline, indicating that this process is sufficient to maintain the organ in a transplantable condition over 8 hours, which is a significant improvement over current methods.
Is NLRP3 inflammasome activation involved in irreversible acute lung injury?
Ex vivo lung perfusion (EVLP) is a technique used to evaluate and recondition marginal donor lungs that otherwise would be discarded for transplantation. We have identified that interleukin-1? (IL-1 ?) can be used as a prognostic indicator of non-recovery during clinical EVLP. IL-1? is a pro-inflammatory cytokine that can contribute to acute tissue injury. Its secretion is dependent on inflammasome assembly, so we hypothesised that inflammasome inhibitor therapy could represent a novel strategy to prevent acute lung injury during EVLP. We performed a double blinded randomised study using an NLRP3 inflammasome inhibitor during porcine EVLP. ASC+ inflammasome particles were measured as an indicator of inflammasome activity, and the cellular outflow and cytokine profile of the organs were assessed. Whilst we demonstrated a decrease in inflammasome particles, there were no differences between the control and the inhibitor groups in terms of cytokine profile, cellular outflow or organ function. We then repeated the treatment using kidney perfusion to determine if this was an organ-specific phenomenon, but again found that inflammasome inhibition had no impact on IL-1? or renal function. As the concentration of IL-1? increased during both lung and kidney perfusion despite inflammasome inhibition, we then measured pro-IL-1?, the inactive intracellular precursor molecule. In (n=10) human lungs that did not recondition and were rejected for transplant, a significant increase in pro-IL-1? was detected (compared to n=10 lungs that reconditioned and were used for transplantation). This suggests that pro-IL-1? is released following necrosis or necroptosis rather than actively secreted as part of a specific inflammatory process. We now aim to assess the mechanism of cell death in non-recoverable donor lungs and perform additional studies using inhibitors of necrosis and necroptosis.
Travel and Contact Information
Michael Smith Lecture Theatre
Michael Smith Building