Elucidating the role of tissue-resident immune cells in alveolar epithelial regeneration and lung fibrosis
Potential applicants with at least a 2:1 in their first degree, are invited to email Prof Ho to discuss this project, to commence December/Jan 2018/19. Research assistants with similar degree and aptitude are welcomed.
The lung is a distinct organ in terms of regeneration and self-renewal. In the steady-state, cell turnover is low, but after injury, it possesses tremendous ability to regrow its epithelium - a whole new lung segment can regenerate after partial pneumonectomy. Yet, in end stage lung disease including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), regeneration is rare or occurs abnormally. The project examines the role of tissue-resident immune cells (innate lymphoid cells, Tregs, resident alveolar macrophages) in maintaining steady-state quiescence and coordinating appropriate repair after injury of the alveolar epithelium. The work will focus on the use of improved bleomycin murine model to examine the in vivo changes in tissue resident immune cells in the lungs, its co-localisation with regenerating alveolar epithelium and alveolar progenitor cells during injury and regeneration/repair. Findings will be tested in the appropriate transgenic mice and human diseased lungs in collaboration with the MRC-QUOD organ transplant programme in Newcastle. Lung stem cell identification will be performed in collaboration with Dr Emma Rawlins from the Gurdon Institute in Cambridge.
Contact details: Lingemail@example.com
Dr Laura Denny (Senior Post Doctoral Scientist)
Dr Andrew Achaiah (Clinical Fellow)
Mr Chaitanya Vuppusetty (Graduate RA and Lab manager)
Dr Praveen Weerantunga (Clinical Fellow and DPhil student)
Dr Harry Tian Hu (NDM Prize DPhil Student)
Dr Vishal Nathwani (Clinical Fellow and DPhil student)
DPhil FRCP MD
Professor of Respiratory Immunology
- Consultant in Respiratory Medicine
- NIHR BRC Respiratory Theme Co-Lead
- UK NIHR Respiratory-Translational Research Collaboration
Immune mechanisms in lung fibrosis
My research group studies how immunological responses impact on mechanisms of lung injury, regeneration and repair. Our projects are divided into mechanistic and translational studies. Broadly, the programme has two aims – (1) to understand the contribution of myeloid cells to lung immunopathology and fibrosis and (2) to bring new treatment and improved management to patients with fibrotic lung diseases focusing on idiopathic pulmonary fibrosis (IPF) and fibrotic sarcoidosis.
We have a focus in immune pathology in the tissue and have developed methods to spatially deconvolute diseased lungs using single cell imaging mass cytometry and single cell transcriptomics. This allows us to understand the organisation and interaction between immune cells and diseased lung structures matched to in depth view of the gene expression profile of these cells.
Contribution of myeloid cells to lung immunopathology
This part of our programme focuses on the immunobiology of myeloid cells and underpins our clinical studies.
In the last few years major strides have been made in understanding the biology of macrophages in the lungs. For example, it is now well established that there are two major types of macrophages – that derived from the bone marrow (monocyte-derived macrophages), and those that originate from the yolk sac at birth (resident alveolar macrophages), the latter endowed with self-renewing properties. However the functions of these macrophages in health, and their contribution to disease are not clear. In addition, although the functional plasticity of the macrophages is evident, the signals that influence the development and activity of these functional subsets are unclear. This part of our programme examines these questions, and provides the basis for potential targeting of the monocyte-macrophage pathway for new therapeutics. Current projects include baseline subtyping of macrophages in health and disease, to transcend current categorization of these cells (eg M1 M2). We use scRNA sequencing and functional typing in murine models of lung fibrosis and human samples from IPF and fibrotic sarcoidosis. We have a particular interest in understanding how viral infections (eg influenza) impact on lung fibrosis.
New treatment and improved management of patients with fibrotic lung diseases.
IPF is a devastating lung disease with a median survival of less than 5 years from diagnosis, worse than many cancers. Current treatment (only two) merely reduces the rate of progression of disease but does not halt worsening and scarcely increased the number of surviving years. The course of disease is punctuated by episodes of accelerated fibrosis (called AE-IPF) which heralds death as patients diagnosed with such episodes have an 80% mortality within 3 months. Major advances have been made over the last decade in understanding the mechanisms of the disease, though very little work has focused on this phase of accelerated fibrosis We are concentrating our efforts on understanding the cause, preventing and improving the outcome from AE-IPF. In recent years, we have shown that levels of monocytes correlated with amount of fibrosis in lungs of IPF patients, and are particularly high in patients with AE-IPF. We are particularly interested in understanding the role of monocyte in AEIPF and also as biomarkers to detect the onset of this phase of disease. In addition, we have a priority in working in the lungs of IPF patients to understand the role of different groups of lung macrophages in fibrogenesis.
We also have a major focus on the management of patients with sarcoidosis, a T cell mediated granulomatous disease. I lead the Oxford Sarcoidosis Clinical Service, part of the Oxford Interstitial Lung Disease tertiary referral centre with an integrated clinical research programme in patient stratification, measurement of disease activity and mechanisms of fibrosis in pulmonary sarcoidosis.
We work closely with our industrial partners at the interface of disease mechanisms and drug development.
COVID-19 therapeutics: Challenges and directions for the future. Robinson PC, Liew DFL, Tanner HL, Grainger JR, Dwek RA, Reisler RB, Steinman L, Feldmann M, Ho LP, Hussell T, Moss P, Richards D, Zitzmann N. Proc Natl Acad Sci U S A. 2022;119:e2119893119.
Multi-modal characterization of monocytes in idiopathic pulmonary fibrosis reveals a primed type I interferon immune phenotype. Fraser E, Denney L, Blirando K, Vuppusetty C, Antanviciute A, Zheng Y, Repapi E, Iotchkova V, Ashley N, St Noble V, Benamore R, Hoyles R, Clelland C, Rastick JM, Hardman CS, Alham NK, Rigby RE, Rehwinkel J, Ho L.P. Frontiers Immunology 2021;12:623430.
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity. COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium. Cell. 2022;185(5):916-938.e58.
Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Monk P, Marsden R, Tear V, Brookes J, Batten TTN, Mankowski M, Gabbay F, Davies D, Holgate S, Ho L.P, Clark T, Djukanovic R, and Wilkinson T. Lancet Respiratory Medicine. 2020, 12;S2213
Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Mann E, Menon M, Knight S, Konkel J, Jagger C, Shaw T, Krishnan S, Rattray M, Ustianowski A, Bakerly ND, Dark P, Lord G, Simpson A, Felton T, Ho L.P, NIHR Respiratory TRC, Feldmann M, CIRCO, Grainger J, Hussell T. Science Immunology. 2020, 5;51
M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza. SL Cole, J Dunning, WL Kok, KH Benam, A Benlahrech, E Repapi, F Martinez, L Drumright, TJ Powell, M Bennett, R Elderfield, MOSAIC Investigators, T Dong, J McCauley, EFY Liew, S Taylor, W Barclay, V Cerundolo, PJ Openshaw, AJ McMichael and L.P Ho. J Clin Invest Insight 2017; 6;2:e91868
Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial. Fisher BA, et al. Lancet Respir Med. 2022;10(3):255-266.
Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. PHOSP-COVID Collaborative Group. Lancet Respir Med. 2022:S2213-2600(22)00127-8.
Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. Zhao Y, Qin L, Zhang P, Li K, Liang L, Sun J, Xu B, Dai Y, Li X, Zhang C, Peng Y, Feng Y, Li A, Hu Z, Xiang H, Ogg G, Ho LP, McMichael A, Jin R, Knight JC, Dong T, Zhang Y. JCI Insight. 2020, 5;13:e139834
Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Monk PD et al. Inhaled Interferon Beta COVID-19 Study Group.Lancet Respir Med. 2021;9(2):196-206.
Alveolar and lung interstitial macrophages: Definitions, functions, and roles in lung fibrosis. Shi T, Denney L, An H, Ho LP, Zheng Y. J Leukoc Biol. 2021;110(1):107-114.
Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. F Martinez, L Helming, R Mueller, A Varin, B Melgert, C Draijer, B Thomas, M Fabbri, A Crawshaw, L.P Ho, N Ten Hacken, V Jiménez, N Kootstra, J Hamann, D Greaves, M Locati, A Mantovani and S Gordon. Blood 2013; 28;121(9):e57-69.
High Levels of Virus-specific CD4+ T Cells Predict Severe Pandemic Influenza A Virus Infection. Zhao, Y-H Zhang, L Denney, D Young, T Powell, Y-C Peng, N Li, H-P Yan, D Y Wang, Y L Shu, A J McMichael, L.P Ho and T Dong. Am J Resp Crit Care Med. 2012;186(12):1292-7.
Invariant NKT cells decrease immunepathology in lethal influenza A virus infection by reducing accumulation of inflammatory monocytes in the lungs WL Kok, L Denney, K Benam, C Clelland, AJ McMichael, and L.P Ho. J Leuk Biol. 2012; 91:357.
IFITM3 restricts the morbidity and mortality associated with influenza. Everitt AR, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012, 484;519
Gene-set Analysis of Lung Samples Provides Insight into Pathogenesis of Progressive, Fibrotic Pulmonary Sarcoidosis. HE Lockstone, Sanderson S, Kulakova N, Baban D, Leonard A, Kok WL, McGowan S, McMichael AJ, Ho LP. Am J Respir Crit Care Med. 2010;181(12):1367-75.