Tissue surveillance and orchestration of immunity

Inflammation, tissue recovery and repair

Dr James Fildes

Principal Investigator

Dr James Fildes

Tel: 0161 275 1328

Email: james.fildes@manchester.ac.uk

See: University research profile | Lab members

Human lungs connected to the ex-vivo lung perfusion circuit. The lungs are ventilated via an endotracheal tube and perfused via cannulation of the pulmonary artery.

The immune system is intrinsically involved in the resolution of acute injury, via clearance of apoptotic and necrotic cells, induction of tissue remodelling and regulation of the inflammatory response. When continued immune activation and tissue remodelling is observed following resolution of acute injury, a chronic disease phenotype occurs. This is frequently seen following injury to the heart and lungs, where the local tissue environment can directly influence the type, longevity and severity of the inflammatory response from acute injury through to health, or chronic disease.

Our group are developing a pig and human organ perfusion laboratory at the MCCIR, capable of performing prolonged functional assessments of ventilated lungs and beating hearts. Using this unique system we can explore the transition from health to disease and from disease to health with the aim of identifying pathways and developing new therapies for the future. We utilise a high throughput large animal organ perfusion system (using surplus abattoir material) incorporating disease models, preclinical drug safety, pharmacokinetic studies and cTIMP designs with real time clinical and biochemical assessments. Because we use abattoir animals we require no home office approval, enabling rapid translation of hypotheses and drug testing from pre-clinical models into human systems.

Fluorescence in situ hybridisation of X and Y chromosomal DNA in blood derived monocytes following lung transplantation. The image shows both male and female cells in the circulation following male donor to female recipient lung transplantation.

We can translate preclinical data into ‘first in human’ systems using ex-vivo organ perfusion of diseased and phenotyped human organs explanted prior to transplantation (includes cardiomyopathy, acute and chronic heart failure, COPD, interstitial lung disease, pulmonary hypertension and cystic fibrosis), or unusable donated human organs as healthy controls. In 2014 we are developing a multi-organ perfusion system (heart, lung, kidney and liver) to enable the study of organ-organ interactions including effects of inflammation and injury, resolution of injury, and drug effect/safety studies.

Using these systems we have identified a large reservoir of non-classical monocytes within the human lung which can be manipulated to differentiate into regulatory (IL-10+) rather than inflammatory dendritic cells (DC). We are now attempting to manipulate DC generation via transfer of endogenous proteins into the human lung using different vectors and ex-vivo lung perfusion. As monocyte differentiation is dictated by the local tissue environment, we are also attempting to resolve lung injury using transfer of anti-apoptotic molecules and assessing the effects of mechanical unloading of the lungs (via extra-corporeal membrane oxygenation) using a systems biology approach.

In the heart, we are studying cell trafficking and fate following myocardial infarction (MI). Clinically, patients either recover from MI or go on to develop chronic heart failure, and this process is intrinsically linked to monocyte phenotype and differentiation to macrophages (conversion from M1 to M2 during resolution of injury) in in vivo models. We are now exploring this using ex-vivo models and clinical cases of repair (ventricular assist device implantation, or ‘artificial heart’, heart transplantation and extracorporeal membrane oxygenation), combined with a systems biology approach.

Disease areas

Pre lung and heart transplant aetiologies (COPD, CF, ILD, PH, CHF)

Advanced heart failure1

Extra-corporeal membrane oxygenation2,3

Heart and lung preservation2,4

Heart transplantation1,2

Lung transplantation2

Kidney transplantation5

In collaboration with;

1 – Dr Steve Shaw, Heart Failure Physician (advanced heart failure, left ventricular assist devices, cardiac transplantation)

2 – Prof Nizar Yonan, Director of Transplantation, UHSM

3 – Dr Ignacio Malagon, Consultant Cardiac Anaesthetist UHSM, Co-director ECMO Service, UHSM

4 - Profs Stig Steen and Trygve Sjoberg, Skane University Hospital, Sweden

5 - Prof Marc Clancy, Director of Renal Transplantation, Glasgow Western Infirmary, Scotland

Other roles: Director of Laboratory Research, North West Cardiothoracic Transplant Centre, UHSM

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