Institute of Cellular Medicine

Staff Profile

Dr Venetia Bigley

Clinical Senior Lecturer, Wellcome Intermediate Clinical Fellow, Honorary Consultant Haematologist

Background

Introduction:

I am a Wellcome Intermediate Clinical Fellow and Clinical Senior Lecturer in the Institute of Cellular Medicine with research interests spanning haematology and immunology. I also practice as an honorary consultant haematologist at Freeman Hospital, specialising in bone marrow transplantation, with a particular interest in adult primary immunodeficiency disorders.


Research: As one of two Principle Investigators in the Human Dendritic Cell Laboratory, I lead a small group working to map the cellular pathways and genetic control of dendritic cell (DC) haematopoiesis, the genetic causes of DC primary immunodeficiency and the immunological consequences of these disorders. The group has also pioneered methods to probe the phenotype and function of human monocytes and DCs in clinical samples.


Clinical Practice: This immunological approach to haematology is reflected in my clinical practice, developing the bone marrow transplant service for adults with primary immunodeficiency in Newcastle, as one of two National Centres. This service is supported by a recent interim funding policy agreement by NHS England and, in collaboration with Newcastle paediatric immunology at the Great North Children's Hospital, Great Ormond Street Hospital and The Royal Free Hospital, we are now submitting a proposal to NHS England to fund bone marrow transplantation for primary immunodeficiency patients of all ages.

Qualifications:

BA (Natural Sciences), Cambridge University

BM, BChir, Cambridge University

MRCP, Royal College of Physicians (UK)

FRCPath, Royal College of Pathologists (UK)

Ph.D., Newcastle University

Membership of Learned Societies:

European Society for Immunodeficiencies

British Society of Immunology

British Society of Blood and Marrow Transplantation

Histiocyte Society

British Society of Haematology

Esteem Indicators:

Editorial Board Membership:

Frontiers in Immunology

Professional responsibilities:

Working Party Member for NHS England Policy Proposal 'all ages bone marrow transplantation for primary immunodeficiencies'.

Member of Genomics England Clinic lInterpretation Partnership (GeCIP)

Newcastle University Faculty of Medical Sciences Ethics Committee

Institute of Cellular Medicine Equality, Diversity and Inclusion Committee (EDI)

Selected Lectures at Recent National and International Meetings:

Dean's Celebratory Lecture, Newcastle University (2018)

15th International Symposium on Dendritic Cells, Aachen, Germany (2018)

28th Nikolas Symposium, Athens, Greece (2018)

Keystone Myeloid Cells, Brechenridge, USA (2018)

Northern Immunology and Allergy Meeting, Newcastle (2018)

European Society of Immunodeficiencies Annual Meeting, Edinburgh (2017)

Clinical Immunology Society (USA) Annual Meeting, Seattle, USA (2017)

Infections, Immunity, Inflammation Seminar Series, UCL, GOS Institute of Child Health, London UK (2017)

Peter Gorer Department of Immunobiology Seminar, King's College London (2016)

European Haematology Association 21st Congress, Copenhagen, Denmark (2016)

UK Primary Immunodeficiency Network, Belfast (2015)

Research

Research Interests:

1. Dendritic Cell Haematopoiesis. 

Dendritic Cells are professional antigen presenting cells which initiate and control immune responses. They act as innate effector cells, able to recognise and respond to danger signals and influence the innate immune response. However, they are best know for their role in antigen-specific priming and activation of naive T cells to drive adaptive immune responses. On the other hand, in the absence of danger signals, DCs critically maintain tolerance to non-pathogenic and self antigen. Despite the pivotal role these cells play in infection, cancer biology, vaccine medicine and autoimmunity, the cellular pathways of their development, and the genes which control their differentiation were unknown in human. Through in vitro culture of prospective progenitors, single cell transcriptomics and the study of patients with DC deficiencies, the group has mapped the pathways and defined genes important in DC development and function, including GATA2, IRF8 and IKZF1.

2. Dendritic Cell Immunodeficiency

During my PhD work we identified an immunodeficiency syndrome associated with heterozygous GATA2 mutation, encompassing dendritic cell, monocyte and lymphoid (DCML) deficiency. We successfully treated the index case with bone marrow transplantation. In collaboration with Sophie Hambleton, we defined the clinical and cellular characteristics of a patient with bi-allelic IRF8 mutations leading to complete loss of dendritic cells and monocytes. More recently, in collaboration with Sinisia Savic and Gina Doody in Leeds, we further refined the complex immunological phenotype of bi-allelic IRF8 mutations through the study of a patient with compound heterozygous mutations. A recent international collaboration allowed us to dissect the role of IKZF1 in human DC development, based on analysis of a cohort of patients with IKZF1 haploinsufficiency and myeloma patients with pharmacological IKZF1 deficiency induced by lenalidomide treatment. These studies have highlighted the importance of DCs in human health and disease and opened avenues for therapeutic manipulation.

3. Dendritic Cell Therapy

Despite the therapeutic potential of DCs, the application of monocyte-derived DCs as vaccines has proven underwhelming. One reason for this may be that these in vitro generated cells do not sufficiently resemble in vivo DCs which develop through independent haematopoietic pathways and share their specialised roles between subsets. One prime therapeutic candidate subset, cDC1, specialised for antigen cross-presentation and critical for immune responses to tumour, virus and intracellular pathogens, is very rare in human blood. We have developed a culture system to derive clinically-relevant numbers of cDC1 from primary progenitors, leading the way for further studies to develop their translational potential.

Future work will investigate the molecular mechanisms of genes important in human DC haematopoiesis, the role of these genes in health and disease and explore options for therapeutic manipulation of in vivo cells or in vitro-generated DCs for therapy.


Future work will investigate the molecular mechanisms of genes important in human DC haematopoiesis, the role of these genes in health and disease and explore options for therapeutic manipulation of in vivo cells or in vitro-generated DCs for therapy.

Grant Funding:

Newcastle Joint Research Executive Scientific Committee award, 2018

Wellcome Intermediate Clinical Fellowship, 2013-2018

Bright Red PhD Fellowship 2014-2016

Newcastle Joint Research Executive Scientific Committee award, 2014

George Walker Fellowship 2011-2013

British Society of Haematology Start up Award 2011-2013

MRC Clinical Training Fellowship 2009-2011

Tyneside Leukaemia Research Association 2008

Newcastle Healthcare Charity 2008

Teaching

Undergraduate Teaching:

Medical Sciences BSc project supervisor

Postgradulate Teaching

Medical Sciences MRes and MSc project supervisor

PhD students:

1 student completed

2 current students

The lab welcomes clinicians and scientists keen to pursue doctoral studies in human immunology, haematopoiesis or cellular therapy. 

Publications