Immunosenescence research: the fight for healthy ageing

The January 2017  issue of the BSI’s official journal Clinical & Experimental Immunology is a special issue on immunosenescence, containing a fascinating set of review articles summarising our current knowledge in this area and what we still need to find out.  Here, BSI member Dr Natalie Riddell, Lecturer in Immunology, University of Surrey, discusses the key papers highlighted in this issue.

The key to successful ageing is to ‘die young as late as possible’ (adapted from Ashley Montagu), but only those who maintain a robust and regulated immune system in their later years are likely to achieve this. This month’s Clinical & Experimental Immunology is a special issue highlighting the current state of play in immunosenescence research.

Intrinsic & extrinsic factors that contribute towards immune senescence. From Masters et al. doi: 10.1111/cei.12851

Immunosenescence describes the complex set of changes that occur in all components of the immune system, as well as the local environment, that result in loss of immune function as we age. It is a double-edged sword that is characterised by reduced immune protection to infections and cancers, along with concomitant increased inflammation and age related inflammatory disease. Demographic predictions for the UK suggest that more than 25% of the population will be over 65 years old by 2030, and most individuals are expected to live to at least 80 (Office for National Statistics, National Life Tables 2012–2014). Despite advances in medicine, many older adults currently still endure ill health for at least the last decade of life. Thus the aim of immunosenescence research is not to extend lifespan, but to extend healthy lifespan in the older population.

Feeling the effects of infections
Determinants of susceptibility to West Nile virus. From Montgomery, Clin. Exp. Immunol doi:10.1111/cei.12863

A chief indicator that immune function is lost with ageing is the increased incidence and severity of some infections. One such infection is West Nile virus, which is an emerging virus that is asymptomatic in 80% of infections.1 However, the incident of severe infection is raised by 20% in the over 60s, as discussed by Montgomery in this CEI review. The rate and severity of illness to established infections such as influenza, varicella zoster virus (shingles), Streptococcus pneumonia and tetanus is also increased in the older population.2-4 Increased illnesses correlates with lower cell-mediated immunity and/or lower antibody responses to these infections in the elderly. Repeated vaccination throughout life may maintain immunity and limit gaps in immune protection.3

Understanding the dynamics of age and vaccine effectiveness

Repeated vaccination, however, is not a straightforward solution. Vaccinating older individuals is problematic, as the effectiveness of most vaccines decrease with age, with maximal responses often as low as 30% in the over 70s.5 Nevertheless, vaccination programmes demonstrate the ability to reduce disease burden in the elderly as well as offering a tool to observe immune responses in vivo in humans.

Kim et al. suggest that moving away from empirical research to either systems analysis or hypothesis driven approaches may advance our vaccinology understanding.5 Interrogation of peripheral blood responses following vaccination, termed ‘systems vaccinology’, has led to the identification of immune signatures and pathways that are correlated to immune responses. Systems analysis can extend further than vaccinology in immunosenescence research and, indeed, the emerging and exciting field of ‘immunomics’ has vast potential for characterising age-associated alterations in immune function.

Of mice and men

Hypothesis driven approaches to vaccinology can utilise the knowledge gained from mechanistic mouse models and our molecular understanding of intrinsic defects to human cells.5 However, caution is required when extrapolating data from murine models, as there are substantial differences between immune ageing in mice and humans.6 Nevertheless, model systems and ex vivo analyses of molecular alterations in aged human cells have identified multiple changes in the vaccination response with age and the aged immune system in general. The most striking alterations occur within the adaptive immune compartment, and have been better characterised within T cells. They include reduced lymphocyte repertoire, increasing clonality and increasing autoreactivity.5,7,8 Recent work has focused on intrinsic cell defects, which alter T cell activation threshold, induction of cellular senescence and differentiation into short-lived effector or long-lived memory cells.

Converging pathways

Importantly, several of the review articles in this special issue demonstrate that nutrient sensing (AMPK), activation signalling (pERK, Akt/mTOR),  senescence signalling (p38) and inhibitory receptor signalling (KLRG1, PD-1) appear to converge and are actively maintained in senescent T cells and are not a passive response induced by cellular dysfunction.5,9,10 Thus, these signalling pathways are potential therapeutic targets to improve functional responses when desired, for example during vaccination or cancer therapy. Such approaches are yet to be tested in vivo and the potential to cause collateral damage by removing the brake on potent inflammatory cells must be considered. Nutrient availability (ATP/AMPK), cellular metabolism (mTORC) as well as local environmental cues (cytokine data from murine models) are also paramount to the lineage commitment of activated cells and alter the production of T regulatory, T effector and T memory response.5

Inflamm-ageing

It’s become increasingly apparent that innate immunity also changes with age and contributes to immunosenecence. This may be of particular importance in the ageing lung as pulmonary infections are the primary cause of morbidity and mortality in the elderly, as discussed by Boe et al.11 Innate cells appear to have reduced TLR signalling via MAPK and NFƙB resulting in reduced inflammatory cytokine production as well as altered chemotaxis responses, decreased phagocytosis and antigen presentation capacity. Evidence suggests that the resolution of infection and thus inflammation is prolonged due to reduced clearance of apoptotic cells and debris by macrophages.11 These age-associated alterations in innate immunity may contribute to increased systemic inflammation termed ‘inflamm-ageing’ observed in aged tissues.10

Innate immune functions of alveolar macrophages. From Boe et al. Clin Exp Immunol doi: 10.1111/cei.12881
The stromal microenvironment

Masters et al. discuss the often overlooked contribution of the stromal microenvironment as an extrinsic factor to immunosenescence and inflammation.12 Accumulation of senescent stromal cells which demonstrate the senescent associated secretory phenotype (SAPS), may alter tissue structure and function, and increase local inflammation.13 The impact of altered lymphoid stromal microenvironment may be widespread and include altered haematopoiesis, reduced lymphatic flow and disrupted secondary lymphoid organisation, which consequently will alter antigen transportation and presentation to T cells.12

Altered stromal microenvironments in non-lymphoid organs may also impact immune function. For example, low grade inflammation in the tumour microenvironment can attract detrimental regulatory cells and neutrophils which can inhibit tumour immunity and promote tumorigenic factors.14

Similarities between ageing and other conditions

Lastly, increased systemic inflammation seen during ageing is also apparent in chronic infections such HIV or cytomegalovirus,10,15 obesity7 and individuals enduring chronic psychological stress.16 Similarly, the main features of immunosenescence are apparent in many of these conditions, including decreased antibody responses, increased infections, malignancies and also incidences of inflammatory associated disorders such as cardiovascular disease.7,10,15,16 Inflammation and premature immunosenescence are, therefore, prevalent features of many common conditions of modern life, such as obesity and stress, and could have negative health consequences for large proportions of society well before old age is reached. Thus potential preventative therapies as well as treatment or interventions aimed at reversing immunosenescence will have widespread implications for the improved health of old as well as some younger individuals.

Natalie Riddell, Lecturer in Immunology, University of Surrey

Clinical & Experimental Immunology’s January 2017 special issue on immunosenescence can be downloaded from their website. All papers included in it are free to access.

References

  1.  Montgomery RR 2016 Age-related alterations in immune responses to West Nile virus infection. Clinical & Experimental Immunology doi:10.1111/cei.12863
  2.  Arnold N & Messaoudi I 2016 Herpes zoster and the search for an effective vaccine. Clinical & Experimental Immunology doi:10.1111/cei.12809
  3.  Weinberger B 2016 Adult vaccination against tetanus and diphtheria: the European perspective. Clinical & Experimental Immunology doi:10.1111/cei.12822
  4.  Fleming DM & Elliot AJ 2005 The impact of influenza on the health and health care utilisation of elderly people. Vaccine 23 Suppl 1, S1–9 doi:10.1016/j.vaccine.2005.04.018
  5.  Kim C et al. 2016 The life cycle of a T cell after vaccination – where does immune ageing strike? Clinical & Experimental Immunology doi:10.1111/cei.12829
  6.  Smithey MJ et al. 2015 Lost in translation: mice, men and cutaneous immunity in old age. Biogerontology 16 203–208 doi:10.1007/s10522-014-9517-0
  7.  Frasca D et al. 2016 Ageing and obesity similarly impair antibody responses. Clinical & Experimental Immunology doi:10.1111/cei.12824
  8.  Dunn-Walters DK 2016 The ageing human B cell repertoire: a failure of selection? Clinical & Experimental Immunology 183 50–56 doi:10.1111/cei.12700
  9.  Akbar AN 2016 The convergence of senescence and nutrient sensing during lymphocyte ageing. Clinical & Experimental Immunology doi:10.1111/cei.12876
  10.  Fulop T et al. 2016 Intracellular signalling pathways: targets to reverse immunosenescence. Clinical & Experimental Immunology doi:10.1111/cei.12836
  11.  Boe DM et al. 2016 Innate immune responses in the ageing lung. Clinical & Experimental Immunology doi:10.1111/cei.12881
  12.  Masters AR et al. 2016 Immune senescence: significance of the stromal microenvironment. Clinical & Experimental Immunology doi:10.1111/cei.12851
  13.  Tchkonia T et al. 2013 Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. Journal of Clinical Investigation 123 966–972 doi:10.1172/JCI64098
  14.  Hurez V et al. 2016 Considerations for successful cancer immunotherapy in aged hosts. Clinical & Experimental Immunology doi:10.1111/cei.12875
  15.  Nasi M et al. 2016 Ageing and inflammation in patients with HIV infection. Clinical & Experimental Immunology doi:10.1111/cei.12814
  16.  Bauer ME et al. 2015 Neuroendocrine and viral correlates of premature immunosenescence. Annals of the New York Academy of Sciences 1351 11–21 doi:10.1111/nyas.12786

 

Openness in animal research

The Babraham Institute is a world-class research institution who focus on fundamental biological questions of how cells and organisms develop and respond to the environment. As much of their research concentrates on understanding the basic science behind how our cells and bodies work, the use of animals for some areas of research remains essential for future scientific breakthroughs.  Here, Louisa Wood, Communications Manager at the Babraham Institute, discusses how the Institute have approached facilitating openness in animal research and why this is important to their overall aims.

mouse-in-house-smaller

Why be open?

At the Babraham Institute, we’re working to provide accurate information about how animals are used in our research in order to raise awareness of why it’s necessary and why, at the moment, it’s the only option for gaining the comprehensive insight we need to try and answer the unknowns. The use of animals in research is an essential component of our fundamental biological research which aims to understand development, the ageing process and what goes wrong in disease. To give some examples, animal research from our Institute has increased our understanding of a mechanism important in placental growth and associated with pre-eclampsia, helped us explain why older people have less effective immune systems and contributed to the development of a drug for leukaemia.

Providing accurate information, explaining the benefits of what research using animals can tell us, and also being clear about how animal use is strictly regulated and how research animals are cared for, goes a long way to answering many questions and addressing misconceptions.

Moving towards openness in animal research

The Babraham Institute has a history of engaging the public on our use of animals in research, hosting ethics workshops for school students to explore the controversies, discussing our research at science festivals and public talks and inviting visitors to our animal facility. Signing the Concordat on Openness in Animal Research in 2014 was a natural next step which has allowed the Institute to develop new activities and initiatives to become even more transparent about its use of animals in research. An exciting project was the installation of cameras into our animal facility (more below) which has significantly enhanced our communications with visitors to the Institute. We also expanded the information available on our website and in brochures and committed ourselves to clearly identifying research involving animals in our news items and press releases.

One of our Concordat commitments (there are four) is that we’ll be more proactive in engaging with the media. We had an opportunity recently to contribute to an ‘Impact’ programme produced by students from the Cambridge TV School discussing animal research. Remembering the aggression of animal activist organisations which made the headlines in the past, inviting ‘the media’ in was a big step both for the Institute and especially for Laura, one of our animal technicians, and Klaus, a researcher, who were interviewed for the programme. However, we recognise that there’s no substitute for people who work with animals and those whose research involves animals speaking out about what they do and why it’s necessary. The same principle has led to the Institute creating a touring exhibit presenting information about careers in animal technology, which visits careers fairs and schools and gives people the chance to discuss the opportunities and details with staff from our animal facility.

Opening up a barrier facility

mouse-with-technician-smallThe animal research at the Babraham Institute uses mice and some rats. The animals are housed in a state-of-the-art facility which maintains the animals in an exceptionally clean environment. Everything that enters the unit, from animal feed and bedding to computers, printer paper and even people’s lunch, is cleaned on entry in order to protect the animals from unintended infections. The people who look after the animals shower into the unit every day and don hospital-style scrubs. It’s essential to our research that the animals are of a known health status; any accidental infection by an environmental pathogen might change the outcome of an experiment.

Having a barrier facility obviously means restrictions on access, so we looked at alternative ways to allow people to learn about the facility and how the animals are cared for and used. In March 2015, we installed cameras, a bit like CCTV but these cameras don’t record and they’re not operational all the time. The cameras can swivel and zoom and provide direct line of sight to the different parts of the facility. We even have roaming hand-held cameras to show areas not covered by the fixed cameras. As a consequence of the cameras, we’ve been able to ‘open up’ our facility to a wide range of audiences: public groups, teachers and students who visit to discuss the ethics of using animals in research, research funders and even construction workers and engineers. Compared to just 37 people physically touring the facility in 2012–2013, 169 people have taken part in a virtual tour (led by a facility manager) from March 2015 to September 2016.

Our use of the cameras to engage people with the use of animals in research was recognised by a commendation by Understanding Animal Research’s Openness Awards in 2015 and also by the Biotechnology and Biological Sciences Research Council (BBSRC) as part of their Excellence with Impact competition in 2016.

Communicating and training to achieve openness

Of course, none of this would be possible without training, supporting and encouraging our staff and students. We’ve received excellent support from Understanding Animal Research, including onsite training for our researchers on how to talk about using animals and advice on communicating about animal research via social media. Encouraging communication about animal research is a long way away from historical advice to not disclose details of your work due to fear of being targeted by animal activists. Continuing this culture change will take a significant amount of time but the more we witness the positive outcomes associated with being open, the more the use of animals in research becomes a discussed and debated part of research as a whole, rather than something which is hidden away unsaid.

Louisa Wood

Communications Manager, Babraham Institute

Image credits: Babraham Institute


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Immunology update – Christmas 2016

Welcome to our last installment before Christmas of our regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

New imaging technique may guide treatment of inflammatory disorders

Common variable immunodeficiency disease (CVID) is the most common severe
adult primary immunodeficiency, affecting 1 in 25,000 adults. Patients do not produce antibodies to combat infection, despite normal levels of B cells, and are at higher risk of developing inflammatory and autoimmune disorders. A subset of those diagnosed with CVID develop granulomatous lymphocytic interstitial lung disease (GLILD), which is associated with poor outcome. Our understanding of GLILD pathogenesis is inadequate, and a method to monitor disease progression and guide treatment is imperative.

In a study carried oupper-chest-figureut at the University Hospital of Wales, and published in Clinical  & Experimental Immunology, researchers repurposed a combined imaging technique already used for cancer imaging. The technique, called FDG PET-CT, uses the anatomical data obtained by CT scan, and overlays it with metabolic data of glucose uptake by cells in tissues. The team observed a patient with GLILD before and after combination therapy, and noticed clear improvements in both anatomical and functional activity between the metabolic images before and after treatment. The combined FDG PET-CT shows that GLILD is only the pulmonary facet of a highly metabolically active multisystem disease.

BSI member Dr Stephen Jolles, who led the study, says, “This study is the first time that the imaging technique, FDG PET-CT, has been used to assess the combined lung structure and metabolic activity in a patient with GLILD before and after treatment. The images are striking and enlightening in that they reveal the highly metabolically active multi-systemic nature of the disease. It remains to me amazing the ability of this technique to overlay structure with metabolic functional activity in this way.” It is expected that this technique will be used to inform treatment of a number of other inflammatory disorders.

Read the press release

Read the full article: Jolles et al. 2016 Clinical & Experimental Immunology doi:10.1111/cei.12856


New approach uses genetic evidence to guide drug design

microbiology-163470_1280Over 80 autoimmune diseases, such as type 1 diabetes, multiple sclerosis and Crohn’s disease, affect hundreds of thousands of people in the UK. There are no cures, although treatments are available to manage the symptoms. While many of these treatments suppress the immune response, they also increase the  patients’ susceptibility to opportunistic infection. A research team at the University of Oxford, which included BSI member Dr Hayley Evans, studied the genetics behind autoimmune diseases in a bid to guide drug design.

In the study, published in Science Translational Medicine, researchers conducted a meta-analysis across patients with autoimmune disorders and healthy individuals. The team identified a genetic mutation that exerts a protective effect across 10 different autoimmune diseases. A single mutation was identified in the protein non-receptor tyrosine kinase 2 (TYK2), which promotes cytokine signalling during infection. Dysregulation of cytokine signalling is understood to induce autoimmunity. To study its apparent protective effect, a mouse model of the multiple sclerosis-like disease, EAE, which was also homozygous for the TYK2 mutation, led to complete protection against the autoimmune disease. In addition, analysis of Biobank genotype resources indicated that people carrying this mutation were healthy, and no more susceptible to mycobacterial, bacterial, viral, or fungal infection. Professor Lars Fugger, who led the study, said, “We found that people carrying the protective TYK2 genetic variant were no more likely to have serious infection or to develop cancer than people without the variant.” In essence, cytokine signalling through TYK2 for those carrying genetic markers for autoimmune diseases is low enough to protect against autoimmunity, but high enough to prevent immunodeficiency.

The hope is to create a drug that mimics the effects of this mutation. Further research is needed to understand how the mutation affects TYK2 protein structure and function, and to ensure that, despite predictions, the drug does not induce unwanted side effects.

Read the press release

Read the full article: Dendrou et al. 2016 Science Translational Medicine doi: 10.1126/scitranslmed.aag1974


Weight loss condition linked to poor cancer immunotherapy outcomes

Cancer immunotherapies activate the body’s immune system to target and destroy cancer cells. While there is much potential for this method of treatment, it has only shown promise in very few patients. One possible explanation for this inconsistency has been explored by researchers at the Cancer Research UK Cambridge Institute, who have delved into the mechanism behind a weight loss condition, cachexia, which affects many cancer patients. Cancer cachexia is found in patients with advanced stages of the disease. It causes loss of appetite, weight loss, wasting, fatigue, and cannot be reversed by increasing nutritional intake.

Brain

The research, published in Cell Metabolism, identified the role of a particular protein, IL-6, released by cancer cells even before cachexia manifests. IL-6 alters the ability of the liver to respond to caloric deprivation by preventing the liver from generating available sources of energy that compensate for decreased caloric intake. This energy deficit magnifies the host stress response, releasing high levels of glucocorticoid hormone that suppresses the immune response.

Senior author, Professor Douglas Fearon, said, “The results raise the distinct possibility of future cancer therapies that are designed to target how the patient’s own body responds to cancer, with simultaneous benefit for reducing weight loss and boosting immunotherapy.”

Professor Douglas Fearon is one of the plenary speakers at the BSI/NVVI Joint Congress, taking place in Liverpool on 6 – 9 December 2016. He will give his presentation at 11:30 on Friday 9 December.

Read the press release

Read the full article: Flint et al. 2016 Cell Metabolism doi: 10.1016/j.cmet.2016.10.010


Pan-herpesvirus inhibition by small molecule inhibitor

2827134663_3f851d6b90_oHerpesviruses are associated with a wide range of acute or chronic diseases, including genital lesions, chicken pox, glandular fever, and various cancers. Current treatments employ nucleotide, nucleoside or pyrophosphate analogues that specifically inhibit the herpesvirus DNA polymerases. Ultimately, drug-resistant strains emerge from immunocompromised patients to circumvent these inhibitors. As such, it is necessary for further development of drugs against herpesviruses, particularly those that induce cancer.

In the study, published in Nature Microbiology, researchers at the University of Leeds identified a single protein common to all herpesviruses. This protein commandeers a host cell protein complex, human TREX, to stabilise and transport herpesvirus RNA out of the nucleus for translation into viral proteins. By inhibiting the activity of a particular component of the human TREX complex, UAP56, it prevents the common viral protein from taking advantage of its protective effect, thereby inhibiting virus replication and production of infectious particles.

Following these positive results, Dr Richard Foster, who led a team on this study, said, “We still have a lot of work to do, but bringing together a target point and a compound is a significant finding. Now our job is to improve the quality and potency of the compound before it can operate as a future antiviral drug.”

Read the press release

Read the full article: Schumann et al. 2016. Nature Microbiology doi: 10.1038/nmicrobiol.2016.201


Image credits: Upper chest figure – Jolles et aI; DNA and medicine – Pixabay; Cancer ribbons – Howardrv/Flickr; Human herpesvirus 6 (HHV6) – AJ Cann/Flickr.

Immunology update – October 2016

Welcome to our sixth installment of our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Protective compound in skin inspires eczema treatments

eczema-handAtopic eczema is a common skin condition affecting 20% of children and 5% of adults in the UK. Sufferers experience red, itchy skin that can become dry and cracked. They are often at greater risk of infection by S. aureus, which can infect skin lesions and damage the skin barrier. Conventional steroid treatments are associated with unpleasant side-effects, and can lose effectiveness over time.

In a new study at the University of Edinburgh, researchers have identified therapeutic potential for a protective chemical, called human beta-defensin 2 (hBD2), which is typically missing in eczema patients. hBD2 possesses antibacterial properties and, when applied to skin cells grown in the lab, has been shown to both maintain and protect skin integrity. As such, it is a vital component against S. aureus infection.

It is hoped that this discovery could help develop alternative treatments for atopic influenza. Indeed, BSI member Dr Donald Davidson, who led the study published in the Journal of Investigative Dermatology, said: “This is a great chance to work with something that the body makes naturally to develop new therapies for atopic eczema, which affects so many people’s lives.”

Read the press release

Read the full article: Wang et al. 2016 Journal of Investigative Dermatology doi: 10.1016/j.jid.2016.08.025


New type 1 diabetes treatment tweaks the immune response

Type 1 diabetes is an increasingly common diagnosis affecting 400,000 peodiabetic-patient-blood-glucose-testple in the UK. It is an autoimmune disease caused by cells of the immune system mistakenly attacking and destroying the insulin-producing cells of the pancreas. Insulin is important for ensuring glucose in the blood is taken up by cells. As such, patients are required to take regular insulin injections.

Using the drug aldesleukin (recombinant interleukin-2), presently administered in high doses to combat kidney tumours and skin cancers, researchers at the University of Cambridge hope to tailor its dosage to modulate the immune response in type 1 diabetes. Aldesleukin raises T regulatory cell numbers, which regulate the immune response and prevent autoimmune disease. Lower doses of aldesleukin increase T regulatory cells by 10–20%, and this moderate rise appears to sufficiently pacify the attack on the pancreas, without suppressing the immune response enough to risk infection from bacteria and viruses.

Dr Frank Waldron-Lynch, the BSI member who led the trial now published in PLOS Medicine, said: “Our goal is to develop a treatment that could see the end to the need for these life-long, daily injections by curtailing the early damage caused by the patient’s own immune system.” Any treatment would initially target newly-diagnosed patients, as it would limit the damage inflicted at the pancreas, and allow the patients to continue to produce insulin for a longer time.

Read the press release

Read the full article: Todd et al. 2016 PLOS Medicine doi: 10.1371/joural.pmed.1002139


MRSA releases fatty decoys to avoid antibiotics

Methicillin-resistant Staphylococcus aureus (MRSA) is, as the name suggests, a highly resistant ‘superbug’ responsible for thousands of deaths every year. One of the very limited treatment options is the antibiotic daptomycin, yet 1 in 3 of all infections remains resistant to this treatment. The research at Imperial College London, and published in Nature Microbiology, has elucidated the mechanism behind this resistance.

MRSA releases decoy molecu5927204872_5a6d669faf_o-1les that mimic the fatty surface layer of the cell. Daptomycin binds to the cell surface and drills a hole, killing the bacterium. However, when decoy molecules are released, lead author Dr Andrew Edwards, explains, “The antibiotic mistakenly targets the decoys, allowing the bacteria to evade destruction. This is the first time this decoy system has been seen in MRSA.” The fact that only some MRSA bacteria exhibit this decoy system may explain why 30% of all infections are not cured.

In the resistant infections, the communication system used by MRSA bacteria to ‘talk’ among each other is silenced, and with it the ability to release toxins that damage human cells. A similar decoy system was previously observed in E.coli, indicating that this mechanism conferring antibiotic-resistance may be severely underappreciated. Strikingly, targeting MRSA with the penicillin-like antibiotic, oxacillin, partially helps prevent the release of decoys. Furthermore, a next generation antibiotic in clinical trials stops production of the fatty decoys, providing another potential treatment option for MRSA.

Read the press release

Read the full article: Pader et al. 2016 Nature Microbiology doi:10.1038/nmicrobiol.2016.194

Image credits: Eczema on hand – Traza/Shutterstock; Glucometer – Andrey_Popov/Shutterstock; MRSA bacteria – NIAID/Flickr CC BY 2.0.

Immunology update – September 2016

Welcome to our fifth installment of our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Novel targets identified for cancer and inflammatory diseases

t-cellExciting new research from the Francis Crick Institute and King’s College London suggests novel targets for cancer and inflammatory diseases. Residing in the epithelial cells that line our skin and gut are specialised T cell compartments that run tight immune surveillance on local tissues. Stimulation of these T cells is mediated by key proteins identified in this study: butyrophilin-like molecules.

Identification of all members of this protein family should help form the foundation for determining how these molecules might be altered during gut development, cancerous transformation, infection, and inflammation to activate epithelial-bound T cells. Understanding the mechanisms could sensitise the system to eliminate tumours, or suppress the system to treat inflammatory diseases such as colitis or dermatitis.

Published in Cell, BSI member Professor Adrian Hayday explains the value of his study: “We need to know how such tissue-resident immune cells sense the status of the body surface in which they sit. How do the cells know when things are not normal and that they need to respond?  And how do they know what responses to make?  Answering these questions could provide major clues to how the immune system monitors cancer and contributes to skin and gut inflammation.”

Read the press release

Read the full article: Di Marco Barras et al. 2016 Cell doi: 10.1016/j.cell.2016.08.030


Dying tumour cells release potassium ions to impede T cell effector functions

t-cells-attacking-cancer-cells

The tumour microenvironment contains rapidly dividing rogue cells that compete for limited resources. As a consequence, dense regions of dying cells accumulate, releasing high concentrations of potassium into the extracellular milieu as they rupture. As researchers from the Babraham Institute and the US-based National Cancer Institute discovered, this localised increase in potassium concentration subdues the anti-tumour activity of T cells.

Other ions, including calcium, magnesium and sodium, have previously been associated with diminished human T cell function but, as lead researcher Dr Rahul Roychoudhuri explains, “While ions such as calcium are known to play critical roles in the activation of T cells when they encounter foreign invaders and cancer cells, very little was known about how extracellular potassium might affect this. Surprisingly, we found that high levels of potassium, which was released by dying cells in tumours, had very little effect on calcium but blocked activation of a cellular signalling pathway called the PI3K pathway when T cells encountered tumour antigens”.

To reverse the attenuating effects of potassium on T cell effector function, the team genetically engineered tumour-specific T cells to express additional molecular pumps that specifically remove surplus potassium from the cell. As such, these T cells exhibited improved anti-tumour functionality. This research, published in Nature, also exposes new mechanisms for cancer immunotherapies.

Read the press release

Read the full article: Eil et al. 2016 Nature doi: 10.1038/nature19364


Interferon lambda proves to be an effective anti-viral

Positive results for a possible new flu treatment were recently published in EMBO Molecular Medicine. Researchers at the Francis Crick Institute treated influenza-infected mice with either interferon alpha, interferon lambda, or provided no treatment at all. 50% of those without treatment died. 20% died following treatment with interferon alpha, while an impressive 80% survived with interferon lambda. Similar results were observed when the experiment was replicated in human cells.

Interferons are produced naturally by the body in response to viral infection. However, only shutterstock_252860461interferon lambda appears to exert a protective effect. While interferon alpha effectively reduced the number of viral particles in this investigation, it also activated a strong inflammatory response, contributing towards tissue damage in the lungs. In contrast, interferon lambda did not provoke pro-inflammatory effects, thereby inducing a more favourable outcome.

BSI member Dr Andreas Wack is enthusiastic about its potential as a treatment option. “We know interferon lambda has a decent safety profile as it has already been tested for safety in humans. It passed phase 1 and 2 clinical trials as a hepatitis C therapy before better treatment options were found for that disease. If it were to be considered as an influenza treatment, this means the starting point to test it would be relatively advanced.” The team are also hopeful that the therapeutic effects of interferon lambda are not limited to influenza, but could also be used to treat other viruses that cause respiratory disease.

Read the press release

Read the full article: Davidson et al. 2016 EMBO Molecular Medicine doi: 10.15252/emmm.201606413

Image credits: T cell – Shutterstock; T cells attacking cancer cells – Shutterstock; Sick woman with blanket – sheff/Shutterstock.

A Scottish summer crammed with festivals, fun, and lab work!

Each year, the British Society for Immunology (BSI) offers a number of grants through our Medical Elective and Summer Placement Award Scheme (MESPAS) to medical and postgraduate students who are planning to undertake a formal placement for their medical elective or for a summer placement. Here, Radhwan Al-Zidan, a pharmacist from Iraq and one of the 2016 recipients of this grant, discusses his placement and what he gained from the experience.

Radhwan Al-Zidan

Funding from the BSI has allowed me to spend part of my summer involved in exciting and innovative research being carried out at Edinburgh Napier University. In addition to science, it has also allowed me to experience and enjoy the Scottish summer, such as it is! Whilst 12 weeks might not seem like a long period, it has been such an exciting and busy time for me I can barely see how I fitted it all in.

To start here is a glimpse into my story

I am a pharmacist from Iraq; whilst working as a hospital-based pharmacist, I developed an interest in research science. This interest and my belief that bridging the bench-to-bedside gap will require closer integration between biologists and those with a pharmaceutical and clinical background encouraged me to redirect my career path and found me based in the research labs at the College of Pharmacy at Mosul University. Seeking to expand my possibilities, I applied for and was awarded funding from my own government to travel to and study for a Masters in the UK. I chose Edinburgh Napier University because of their unique course in Medical Biotechnology, which has a strong focus on research. This course helped me, as a pharmacist, to find common ground with the biological scientists in the lab.

Finding a passion

During my Masters, I found myself drawn to and engaged by areas of immunology, particularly the evolving field of adoptive cell therapy.  I was excited to have the opportunity of working on a cutting-edge gene therapy-based project under the supervision of Dr Graham Wright. The project involved the transfer of genes aimed to direct and enhance the function of therapeutic regulatory T cells to treat autoimmune disease.  I thoroughly enjoyed the seven weeks I had in Dr Wright’s lab but felt so much more could be achieved with more time. With the encouragement of my supervisor, I applied for funding through the BSI’s MESPAS scheme and was genuinely thrilled when the BSI made it possible for me to spend more time working on a project that fascinated me in a city that I was just starting to understand.

My time in the lab

With all the postdocs and PhD students working in one place, the labs at Edinburgh Napier are a hive of activity around the clock. Making the most of my time, I spent long hours in the lab; this helped me to fit in quickly and get to know my colleagues well. Edinburgh Napier is a fascinating place to work; unlike larger institutes the disparate areas of biological science are grouped together, giving me a good insight into a broad range of interesting and diverse projects. Despite spending long hours in the lab, I took the opportunity to visit my favourite spots in Edinburgh such as Edinburgh Castle, Arthur’s Seat, and the National Museum of Scotland, as well as Portobello beach – on occasional sunny days! Edinburgh has been a home away from home for me and bears many similarities to my home city of Mosul. Whilst Mosul now faces different challenges, at different times it is a vibrant and exciting city, just like Edinburgh. Similar to Edinburgh it is also steeped in history and beauty, with famous historical sites that are more than 5,000 years old and beautiful landscapes surrounding the Tigris River.

What did I get from the summer placement?

Having been excited by the potential of retroviral gene transfer as a therapeutic, it has been a fascinating opportunity to get to grips with the various processes in the lab; particularly more recently when I have spent time working independently to optimise the process in various cell subsets. After a series of experiments, I was thrilled to be able to show that my optimisations achieved significantly higher gene transfer efficiency.

In addition to making a lasting contribution to the research taking place in Dr Wright’s lab, I also had the opportunity to gain familiarity with a number of exciting experimental techniques through shadowing other lab members. I have learned techniques from flow cytometry to the state-of-the-art confocal microscopy, as well as many other essential cellular and molecular immunology techniques. I have also gained a better feel for the daily work of a lab scientist, from planning experiments to troubleshooting problems. I believe the personal and technical experience I have gained during this placement will boost my chances to achieve my next goal of doing the PhD in the increasingly important field of immunotherapy.

Finally, as a new member of the BSI, I would like to wish a happy 60th anniversary to our fabulous society.

Radhwan Al-Zidan, Edinburgh Napier University, UK

 

Image credit: (C) Radhwan Al-Zidan

A new tool to help everyone understand and evaluate health research

Healthcare concept vector image [Converted]

Understanding Health Research is a new online tool designed to help the public and patients understand and assess research papers.  In this guest blog, Dr Amy Nimegeer and Chris Patterson from the project team tell us more about the website and how they hope it will help people make better informed decisions on health.

Every day we are hit with a barrage of health information from many different sources – friends, social media, newspapers, TV, magazines, and radio. A lot of this information seems to be based on scientific research but is contradictory, with scientists seeming to say, for example, coffee will give us cancer one week and coffee will keep us healthy the next. Not only can these mixed messages make it difficult for us to make healthy choices, it can also undermine public confidence in the usefulness of science.

Some of these contradictions are down to genuine disagreement between scientists, and some are down to research being poorly reported in the media. More fundamentally, we might not have these problems if more people had been taught to critically appraise research evidence. Scientific papers can be dense and unfriendly, but having the skills to read a piece of research and judge its quality and usefulness can help us all to be more critical of the health claims we come across, and allow us to make better informed decisions for ourselves and others. Unfortunately, evidence suggests that many of us lack the confidence and skills to critically access health information . After all, if healthcare professionals struggle to evaluate health research, what chance does everyone else have?

Help is at hand

To help tackle this problem, we have developed a free online tool called Understanding Health Research, launched this month to support non-scientists through the process of understanding and interpreting health research papers. The tool was a collaboration between researchers at the University of Glasgow, University of Oxford, University of Cambridge and the London School of Hygiene & Tropical Medicine, and was funded by the Medical Research Council’s Population Health Science Research Network.

So what does Understanding Health Research actually do? The tool is an online resource that walks the user through a series of questions designed to highlight key aspects of research. First a set of general questions examines vital issues including whether the paper was peer reviewed and who funded the research. Next, the user is helped through the process of determining what type of research it is, and answers a series of questions specific to the methods being used. This is crucial, because, just as different research methods are used to answer different research questions, different questions are relevant to assessing the quality of different methods.

Finally, the tool gives the user a summary of the answers they gave and what those answers might mean. Rather than giving a definitive judgement about whether the research is good or bad, the tool is designed to highlight the important aspects of the research in question and empower the user to make up their own mind. In truth, research is rarely completely good or completely bad – every study has limitations, and nearly every study has some merit. The key to using research effectively is to weigh up those strengths and weaknesses, as well as considering how relevant the research is to the specific circumstances that you are interested in.

Building knowledge

Older woman at computerAs well as the main critical appraisal tool, the Understanding Health Research website is full of useful information and background reading. We offer a guide to the essential step of learning how to read a scientific paper, as well as introductions to complex, but important, scientific concepts such as the difference between correlation and causation. As well as providing our own resources, we recognise that Understanding Health Research is just one part of a larger puzzle of health literacy, and we encourage our users to make use of other excellent resources, such as NHS Choices Behind the Headlines and Sense about Science’s Ask for Evidence campaign.

Understanding Health Research was made with input from a broad range of people with an interest in using health evidence, ranging from members of the public to academics. We designed our tool to be useful to as many different types of people as possible. Reading scientific research can be difficult, and scientific concepts can be complex, but we believe that by taking it step-by-step, everyone can understand health science. To find out how effective the tool is, we plan to carry out a formal evaluation, and to keep improving it in response to feedback from users. If you have any thoughts about Understanding Health Research, please do not hesitate to contact us, and together we can help to demystify scientific research for everyone.

Dr Amy Nimegeer & Chris Patterson

Amy and Chris are researchers at the MRC/CSO Social and Public Health Sciences Unit, University of Glasgow.

Images credits: Healthcare vector – Shutterstock/Hilch; Woman at computer – Shutterstock/Mik Lav

Immunology update – August 2016

Welcome to the next installment of our regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Potential mechanism to reboot immune system after bone marrow transplant

ViSNE plot of immature T-cells in thymus
A ViSNE plot of immature T-cells in the thymus. Highlighted in red is a population of T-cell progenitors that colonise the thymus and give rise to all T-cells.

The populations of some immune cell types, in particular T cells, are slow to recover following bone marrow transplant, but the reason for this is not known.  Using murine models, researchers at the University of Birmingham have discovered a new in vivo mechanism involving the thymus that could help to explain this phenomenon.

They found that Lymphotoxin β receptor, a cell surface molecule, controls the entry of T-cell progenitors to the thymus, both in a healthy state and during immune recovery following bone-marrow transplantation. Importantly, the team also found that, in mice, antibody-mediated stimulation of this receptor following a bone marrow transplant increased the number of donor-derived T-cells and boosted initial thymus recovery.

Writing in Journal of Immunology, lead author and BSI member, Professor Graham Anderson explains, “Post-transplantation, T-cell progenitors derived from the bone marrow transplant can struggle to enter the thymus, as if the doorway to the thymus is closed. Identifying molecular regulators that can ‘prop open’ the door and allow these cells to enter and mature, could well be a means to help reboot the immune system.” The team now hope to expand their studies to see if the same molecular mechanism functions in humans.

Read the press release

Read the full article: Lucas et al. 2016 Journal of Immunology doi:10.4049/jimmunol.1601189


What scales the T-cell response?

One question that has baffled immunologists is how the immune system manages to proportionally scale its response in relation to any threat it encounters. In this thought-provoking article, published in Trends in Immunology, Professor Michael Dustin and Dr Viveka Mayya from the University of Oxford set out their hypothesis for how this occurs.

BSI member Professor Michael Dustin, explains, “While an overwhelming T-cell response might on the face of it sound effective, it brings risks of immunopathology, where an over-active immune system destroys healthy human tissue, not just the invading disease-causing pathogen.  Scaling the immune response is therefore a safer option, and we know that is what happens. Until now, however, no one had suggested how the body does that.”

They hypothesise that the scale of the T-cell response to an infection could be mediated through their interactions with dendritic cells. Several studies have shown that T-cells slow down and accumulate around dendritic cells when an infection is severe, i.e. their interaction length is prolonged.  The authors discuss the reasons why they think this interaction length may be the key factor in determining immune response severity.

Read the press release

Read the full article: Mayya & Dustin 2016 Trends in Immunology 37 513–522 doi: http://dx.doi.org/10.1016/j.it.2016.06.005

 

New therapeutic target for autoimmune diseases

New research, published in Scientific Reports, has discovered a potential novel strategy to treat a variety of autoimmune diseases, such as multiple sclerosis or psoriasis. Dimethyl fumarate is a drug that is known to be effective against a variety of autoimmune diseases because of its anti-inflammatory properties.  However, its molecular target and mode of action were not known until now.

Through a combination of in vitro and in vivo studies, researchers from the University of Dundee led by BSI member Dr Simon Arthur found that dimethyl fumarate targets the actions of a particular group of enzymes in the body called E2s, some members of which are active in inducing inflammation. “This suggests that more selective inhibitors of E2s may be well tolerated and validates these enzymes as targets for future drug development,” commented Dr Arthur.

Read the press release

Read the full article: McGuire et al. 2016 Scientific Reports doi: 10.1038/srep31159


Image credits: ViSNE plot of immature T-cells in the thymus – University of Birmingham; T lymphocyte – NIAID

The fight against yellow fever

Yellow fever virusLast week, the World Health Organization (WHO) reported one of its largest emergency vaccination campaigns for the yellow fever virus in Africa – in Angola in southern Africa and its northern neighbour, the Democratic Republic of Congo. The outbreak has already claimed more than 400 lives and sickened thousands more.

This is also the first time such a large outbreak of yellow fever has needed to be controlled in densely populated urban regions. Health workers in the region now have the enormous task of vaccinating more than 17 million people before the rainy season starts in September, which presents ideal breeding conditions for the mosquitoes that spread the virus.

The virus

The yellow fever virus is transmitted by two species of mosquitoes of which the main type, Aedes aegypti, thrives in urban environments. Although most people experience either minor symptoms (such as fever, muscle ache and nausea) or none at all, a small minority of those infected go on to enter a second, more toxic disease stage.  This is marked by serious symptoms such as jaundice (yellowing of the skin and whites of the eyes), kidney failure and bleeding from the mouth, nose, eyes or stomach. Up to half of people that experience these more serious symptoms will die.

Great challenges ahead

During the course of the Zika epidemic in South America, labs arounds the world have been in a race to come with an effective vaccine. Yet for the yellow fever virus, a safe and effective vaccine has been available since the 1930s – a single dose or two can protect an individual for the rest of their lives.  In 1951, the Nobel Prize in Medicine or Physiology was given to Max Theiler for the development of the vaccine and so far this remains the only time that a Prize has been awarded for the development of a vaccine.

Projet Amazone Vaccin fièvre jauneHowever, the current global production of yellow fever vaccine can’t sustain the present rate of vaccination needed to give everyone at risk a single dose. This is partly attributed to a year-long laborious process of manufacturing the vaccines in pathogen-free eggs. Since December 2015, 19 million doses of the vaccine has already been given to people in affected areas, and now the global emergency stockpile is critically low with only 5 million doses remaining. Angola alone has a population over 21 million people. Prior to the report of the first outbreak there in December 2015, the country was not considered at risk so most people are not vaccinated. Therefore, the WHO plan to dilute the vaccine fivefold in the hope that it will provide shorter-term protection for 12 months to as many people as possible.

Aside of the logistics from carrying out such mass immunisation programme, there is an added problem of storing the vaccines. Yellow fever vaccines need to be refrigerated with ice packs due to the lack of reliable electricity and sources of fuels for generators.

Clearly having a safe and effective vaccine is only the first step towards combating mosquito borne diseases. With accelerated urbanisation in Africa and the growing emergence of mosquitoes such as Aedes aegypti that thrive in urban environments, the world needs to develop strategies that allow us to monitor and respond quickly and effectively to such disease outbreaks.

Yeping Lu, Communications Intern, British Society for Immunology

Image credits: Yellow fever virus – Sanofi Pasteur/Flickr (CC BY-NC-ND 2.0) ; Yellow fever manufacturing facility in France – Sanofi Pasteur/Flickr (CC BY-NC-ND 2.0)

Immunology update – July 2016

Welcome to the third installment of our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Genetic link to flu transmission in chickens

ChickenNew work, published in the journal Scientific Reports, shows that some chickens may have genes that significantly reduce their susceptibility to spreading and catching flu. Researchers at the Pirbright Institute, along with colleagues from Francis Crick Institute and University of Oxford, examined two genetically distinct lines of chickens that differ in their susceptibility to catching flu. They found that, within the resistant line, any bird that did catch flu only shed the virus through its respiratory tract for a short period. In comparison susceptible birds shed the virus through their respiratory tract for longer as well as shedding virus through their faeces, a key transmission route for spreading the flu virus within bird populations.

BSI member and lead researcher Dr Colin Butter said, “It is important for us to understand how different genetic lines of birds react to influenza viruses, so that we can begin to understand the spread of the disease. Our results are valuable in emphasising the important role a ‘host’ plays in the spread of avian flu, and also in highlighting a number of factors relating to the chain of infection and control mechanisms which are affected by the route of infection.” The team hope these findings will pave the way for more research into the precise biological mechanisms behind genetic resistance, which may have major implications for poultry breeding, as well as human flu treatments, in the future.

Read the press release

Read the full article: Ruiz-Hernandez et al. 2016 Scientific Reports doi: 10.1038/srep26787


Markers of neutrophil activity may help sepsis diagnosis in severe burn patients

B0004153 White blood cell - polymorphonuclear leuc

The rapid diagnosis of sepsis remains a major challenge in patients with severe burns whose injury may mask many of the classic diagnostic biomarkers.  It is vital that sepsis is diagnosed as quickly as possible as any delay can significantly increase the risk of death. Researchers from the University of Birmingham set out to determine if biomarkers of neutrophil function may be accurate in predicting which patients will go on to develop sepsis.  Writing in the Annals of Surgery, the team studied markers of neutrophil activity and function, a key type of white blood cells which responds to immediate infection threats.  Through studying 62 patients with severe burns, they found that immature granulocyte count, neutrophil phagocytosis and plasma cell free DNA show significant potential as biomarkers.

BSI member and study author Professor Janet Lord said, “Our data showed that immature granulocyte count could accurately discriminate between septic and non-septic patients, even with the complications that systemic inflammatory response syndrome has caused for other potential biomarkers. In addition to this, when we used a combination of two or more of our biomarkers, the discriminatory power was further enhanced.” The team now plan to see if using these markers to decide which patients should receive antibiotics at an earlier stage results in reduced sepsis levels.

Read the press release

Read the full article: Hampson et al. 2016 Annals of Surgery doi: 10.1097/SLA.0000000000001807


How our immune system recognises pathogens

Every antigen receptor is composed of three regions – V (variable), D (diversity) and J (joining) – each of which have multiple versions. The shuffling, or recombination, of these allows the immune system to recognise the vast array of pathogens that it encounters.  Researchers at the Babraham Institute have developed a new technique to study this process called VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products.

Writing in Cell Reports, the team used this technique to take a look at the V gene found in an immune cell type in mice. They found that not all V segments were used with the same frequency, implying the involvement of complex regulatory mechanisms with epigenetic features.

“Understanding the VDJ recombination process is important because it is the first determinant of receptor diversity, said BSI member and study author Professor Anne Corcoran. “Having a precise readout of which V, D and J segments are used advances our understanding of the process of recombination and how this is regulated. These findings have implications for immune disorders and aberrant VDJ recombination in cancer.”

Read the press release

Read the full article: Bolland et al. 2016 Cell Reports DOI: http://dx.doi.org/10.1016/j.celrep.2016.05.020


Image credits: Chicken, credit: Steven Turner/Flickr CC-BY 2.0; Credit: University of Edinburgh, Wellcome Images CC BY-NC-ND 2.0