Principal Investigator at the Manchester Collaborative Centre for Inflammation Research (MCCIR)

NHS Principal Research Scientist at the Transplant Centre, University Hospital of South Manchester

Dr Fildes was appointed as a research scientist at University Hospital of South Manchester (UHSM) in 2003. He completed a PhD in Immunology in 2006 and became Principal Research Scientist that year, establishing a transplant research facility at UHSM with an international reputation in transplant research. He was given honorary status at the University of Manchester in 2007 and promoted to senior lecturer in 2010. In January 2013 he joined the Manchester Collaborative Centre for Inflammation Research as a Principal Investigator. He employs a multi-disciplinary team of physicians, surgeons and basic science researchers.

The group are interested in understanding how organs can be repaired for the purposes of transplantation and what mechanisms are involved in the progression or recovery from acute injury. Our focus is on identifying, developing and testing novel therapeutics using preclinical and human models. To do this we have established a multi-organ perfusion laboratory in the MCCIR capable of performing ex-vivo heart, lung, kidney, liver and lim perfusion. We are part of the ventricular assist device (VAD), extra-corporeal membrane oxygenation (ECMO) and heart and lung transplant programmes at University Hospital of South Manchester. We also collaborate closely with clinical ex-vivo perfusion programmes across the UK and Europe to enable translational studies in humans.

The group runs internationally competitive transplant research in the following areas; 

1. Assessing the role of the donor immune compartment in post-transplant alloreactivity – We were the first group to describe the ‘resident’ immune system of the donor heart, lung, kidney, pancreas and limb. This important paradigm shift demonstrates that the donor organ can drive post-transplant alloreactivity and requires therapeutic intervention. We were the first to demonstrate that immunodepletion of the donor lung prevents acute rejection in preclinical systems. We are now testing different preservation and perfusion strategies and immune checkpoint therapeutics to immuno-deplete and immuno-exhaust the donor organ in an attempt to drive anergy and tolerance.

2. Protecting or recovering the donor organ from ischaemia reperfusion injury (IRI) – IRI is a major obstacle to successful transplantation. By combining immediate organ perfusion with novel therapies that protect resident donor tissue we are attempting to ‘stop’ the progression of IRI and restore cell survival pathways, thus preventing clinically relevant IRI.

3. Developing bespoke organ preservation and perfusion solutions to enable safe physiological storage of donor tissue - Donor organ preservation has not advanced in decades despite a clinically relevant need to increase donor organ availability. We are developing and validating organ specific preservation and perfusion solutions that can be used to preserve and control inflammation in donor tissue more effectively.  

4. Developing bespoke organ and tissue perfusion devices to incorporate fully evaluated temperatures, flow rates and pressures – Organ perfusion represents a major advance in transplant medicine. We have established a multi-organ perfusion facility where we are validating several aspects of perfusion including perfusate supplements and flow parameters to generate robust protocols for clinical practice. 

Our group have expertise in organ and tissue perfusion.

The Kidney: Abattoir kidneys are collected by the retrieval team, placed in preservation solution (using clinical protocols) and brought back to the laboratory (http://youtu.be/T75jh4HgQtQ). Kidneys are placed on our bespoke perfusion circuit and rewarmed. Once stable, kidney function can be determined via glomerular filtration rate (via inulin or creatinine clearance). Electrolyte balance, lactate production and pH can be determined via blood gas analysis. Trauma modelling can be performed via toxic or mechanical injury and therapeutic interventions can be delivered via addition to the circuit under flow. A range of biological assessments can be performed via real-time tissue and perfusate sampling.

The Heart: We have developed a beating heart perfusion model using abattoir pig hearts. In this system we can maintain hearts in both langendorff and 2 and 4 chambered ‘working’ mode (seehttp://youtu.be/Etbr2Q47pa4 for a short video). The system can be used to induce myocardial infarction and replicate cardiogenic shock, and mechanical circulatory support can be mimicked to study the effects of ventricular assistance and metabolic unloading. Clinical measurements including stroke volume, cardiac output, ejection fraction, aortic pressure, lv assessment etc can be recorded in real-time. Tissue changes and cellular infiltration can be determined via local biopsy and clinico-biochemical monitoring of the perfusate can be performed, again in real-time.

The Lung: We perform cellular/acellular ex-vivo lung perfusion (EVLP) using pig and sheep lungs collected from abattoirs. Lungs are retrieved and perfused according to clinical protocols and lung function assessments are determined in line with induction of injury (vial chemical, barometric, ischaemic and/or reperfusion trauma). Therapeutic interventions can be delivered via airway instillation or nebulisation, or via vascular delivery to the perfusate. Inflammatory responses can be determined via repeat bronchoscopy of the airway and quantification of protein/cell content in the perfusate. Tissue responses can be determined via real-time sampling of the lung.Human

The Liver: We collaborate with Prof Peter Friend and colleagues from the Oxford Transplant Centre, studying the impact of human liver perfusion on the donor immune compartment. We are also in the process of establishing an experimental liver perfusion system to enable intervention studies.

The Limb: We have established a limb perfusion model, in collaboration with Jason Wong, Consultant in Plastic and Reconstructive Surgery and Senior Lecturer at UoM. We have a series of studies underway aimed at developing prolonged limb survival on a bespoke circuit to enable reattachment of limbs following trauma. We are also working on methods to develop novel immunomodulatory therapies for transplantation.

Translation: Where findings are clinically relevant and require translation, well phenotyped diseased organs explanted prior to transplantation can be studied in a phase -1 approach. This allows rapid assessment of a pathway or therapeutic intervention without safety issues in humans.

Current Post Graduate Students:

John Stone – MRC DTP PhD & Science and Society Award - ‘Loss of transplant graft immunogenicity via the removal of passenger monocytes by ex-vivo lung perfusion’

Triin Major  – Cystic Fibrosis Trust Non-clinical PhD - ‘Loss of Graft Immunogenicity via Ex-vivo Lung Perfusion in Humans’

Will Critchley – BBSRC Doctorial Training Scholarship - ‘Homeostatic mechanisms underlying cellular repair – a systems approach’

Alex Ball – MCCIR PhD Studentship – ‘Effects of organ perfusion on mitochondrial salvage’

Edward Seville – MCCIR Mphil Studentship – ‘Developing novel systems for organ perfusion’

Parminder Chagger – MCCIR MD Studentship - ‘Ex-vivo heart perfusion and cardiogenic shock’

Becky Edge - BBSRC iCASE Studentship - 'Immune cross-talk in the human lung'