Research groups
Websites
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MRC Human Immunology Unit
Research Unit
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Nuffield Department of Medicine
Department
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Oxford Sarcoidosis Service
NHS
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Oxford BRC Stratification of Lung Disease
Research Theme
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NIHR Inflammatory Respiratory Disease
Translational Research Collaboration
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CAMS-Oxford Centre for Translational Immunology
Centre
DPhil available
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: Ling-pei.ho@imm.ox.ac.uk
Group Members
Dr Laura Denny (Senior Post Doctoral Scientist)
Dr Peng Ding (Post Doctoral Scientist)
Dr Andrew Achaiah (Clinical Fellow)
Ms Yuyuan Duan (Graduate RA)
Mr Chaitanya Vuppusetty (Graduate RA and Lab manager)
Dr Praveen Weerantunga (Clinical Fellow and DPhil student)
Dr Harry Tian Hu (NDM Prize DPhil Student)
Ling-Pei Ho
DPhil FRCP MD
Associate Professor Respiratory Immunology
- Consultant in Respiratory Medicine
- NIHR BRC Interstitial Lung Disease Theme Lead
- Chair, UK NIHR Respiratory-Translational Research Collaboration
Immune mechanisms in lung fibrosis
My research group studies how immunological responses impact on mechanisms of lung injury 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.
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.
Key publications
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M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza
Journal article
Cole SL. et al, (2017), JCI Insight, 2
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MONOCYTES FROM IPF PATIENTS SHOW PRECONDITIONED PRO-REPAIR FEATURES
Conference paper
Fraser E. et al, (2016), THORAX, 71, A30 - A31
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Contribution of innate immune cells to pathogenesis of severe influenza virus infection.
Journal article
Cole SL. and Ho L-P., (2017), Clin Sci (Lond), 131, 269 - 283
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MAIT cells are activated during human viral infections
Journal article
Van Wilgenburg B. et al, Nature Communications
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Accumulation of Human-Adapting Mutations during Circulation of A(H1N1)pdm09 Influenza Virus in Humans in the United Kingdom
Journal article
Elderfield RA. et al, (2014), Journal of Virology, 88, 13269 - 13283
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Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals
Journal article
Zhang Y-H. et al, (2013), Nature Communications, 4
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High Levels of Virus-Specific CD4+T Cells Predict Severe Pandemic Influenza A Virus Infection
Journal article
Zhao Y. et al, (2012), American Journal of Respiratory and Critical Care Medicine, 186, 1292 - 1297
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Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection
Journal article
Kok WL. et al, (2012), Journal of Leukocyte Biology, 91, 357 - 368
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IFITM3 restricts the morbidity and mortality associated with influenza
Journal article
Everitt AR. et al, (2012), NATURE, 484, 519 - U146
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Activation of Invariant NKT Cells in Early Phase of Experimental Autoimmune Encephalomyelitis Results in Differentiation of Ly6Chi Inflammatory Monocyte to M2 Macrophages and Improved Outcome
Journal article
Denney L. et al, (2012), The Journal of Immunology, 189, 551 - 557
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Phenotypes of organ involvement in sarcoidosis.
Journal article
Schupp JC. et al, (2018), The European respiratory journal, 51
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CTAS - A CT score to quantify disease activity in pulmonary sarcoidosis
Journal article
Ho L., Thorax
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Abnormalities in iNKT cells are associated with impaired ability of monocytes to produce IL-10 and suppress T-cell proliferation in sarcoidosis
Journal article
Crawshaw A. et al, (2014), European Journal of Immunology, 44, 2165 - 2174
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Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers.
Journal article
Bloom CI. et al, (2013), PLoS One, 8
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Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis
Journal article
Ho L-P. et al, (2005), The Lancet, 365, 1062 - 1072