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Month: October 2016

New immunotherapy-based approach for post-transplant leukaemia relapse

Posted on by Priscille Rivière

An Inserm team from the Mondor Institute for Biomedical Research (IMRB) has just identified a key switch in the immune response, and proposes a new immunotherapy-based approach for combating leukaemia. And maybe other cancers in time. This work is published in the journal Blood.

 

Towards a new immunotherapy for cancer? That may well emerge from the work carried out at Inserm Unit 955, “Mondor Institute for Biomedical Research” (IMRB) by a team led by Prof. José Cohen, Coordinator of the Clinical Investigation Centre – Biotherapy at Henri Mondor Hospital AP-HP, results of which have just been published in Blood. Although it works on the treatment of leukaemias, this team has discovered a key to the regulation of the immune system that makes it possible to stimulate T lymphocyte action, and probably increase the elimination of malignant cells.

It was their work on graft versus host disease, a serious complication in leukaemia patients who receive blood cell transplants, that set them on the track. This complication is due to the recipient’s cells being attacked by overactive T cells present in the transplant. Moreover the researchers found that the presence in the transplant of T regulatory cells (T regs), a specific subpopulation of T lymphocytes, the role of which is to down-regulate the immune response, limited this phenomenon. In a mouse model, when they injected additional T regs during transplantation, they prevented the transplant from attacking the host. They therefore decided to go further, and find out how these T reg cells were controlled.

 

TNFR2, an immune response switch

To do this, they performed different experiments, and finally demonstrated the existence of a closed circuit between conventional T lymphocytes and T reg lymphocytes, involving a key receptor called TNFR2. When conventional T lymphocytes are active, they secrete tumour necrosis factor (TNF), which binds to the TNFR2 receptors present on the surface of T regs. This signal stimulates the latter, which then inhibit the conventional T lymphocyte response. Conversely, when the TNFR2 receptor is blocked, T regs become inactive and T lymphocytes are activated.

“This TNFR2 receptor acts on the immune response just like a real switch. When it is in the ‘on’ position, it inhibits it. When it is in the ‘off’ position, it stimulates it,” explains José Cohen, who supervised this work. Having made this discovery, the researchers now intend to block this TNFR2 receptor in an attempt to improve the immune response against cancer, which will have direct application in immunotherapies. “The role of immunotherapy is to target ‘check-points’ in the immune response in order lift inhibition and allow it to more effectively eliminate malignant cells. The treatments currently available are specific for a population of T lymphocytes known as effectors, while we propose a new target, the regulators. These treatments could therefore be complementary,” adds the researcher.

 

The team has already filed a patent to protect the exploitation of this receptor in the context of post-transplant leukaemia relapse. The idea is now to develop a human anti-TNFR2 antibody to test this therapeutic strategy in a so-called “humanised” mouse model. If the results are conclusive, clinical trials will be conducted. At the same time, this approach is being evaluated for other types of cancers, including solid tumours, by the team led by Dr Benoit Salomon (CIMI-Paris), a co-author of the study.

The gut microbiota to the rescue of chemotherapies

Posted on by Priscille Rivière

inserm_18659

© Inserm/U510

Two species of bacteria present in the gut boost the efficacy of cyclophosphamide-based chemotherapies by optimising the antitumour immunity induced by this drug. This is reported by researchers from Inserm, Gustave Roussy, CNRS, Institut Pasteur Lille, and the Universities of Paris Sud and of Lille in an article published on 4 October in the journal Immunity.

 

Recent studies have shown that certain gut microbes encourage tumours to grow, whereas others contribute to making cancer treatments more effective. It remained necessary to identify the nature and mode of action of the bacterial species capable of optimising the antitumour response induced by chemotherapy.

In this new study, Mathias Chamaillard[1], Laurence Zitvogel[2] and their collaborators showed that two gut bacteria, Enterococcus hirae and Barnesiella intestinihominis, together potentiate the therapeutic effects of cyclophosphamide, a chemotherapeutic agent used to treat many cancers.

How? Chemotherapy has secondary effects that include increased permeability of the intestinal barrier and, consequently, the entry of the bacteria constituting the microbiota into the bloodstream. To combat this abnormal entry of bacteria into the bloodstream, an immune response is initiated. Against all expectations, this response is beneficial for patients, since it can also lead to the destruction of the tumour cells. The tumour is therefore attacked directly by cyclophosphamide and indirectly by this “booster” effect of the bacteria.

Several preclinical models enabled the researchers to demonstrate that the antitumour immune response induced by cyclophosphamide is optimised after oral administration of E. hirae. Treatment by oral administration of B. intestinihominis enabled a similar effect to be obtained.

The researchers then analysed the immune profile of the blood lymphocytes from 38 patients with advanced stage cancer of the lung or ovary, and treated by chemoimmunotherapy. They discovered that the presence of T memory lymphocytes specific for E. hirae and B. intestinihominis makes it possible to predict the period for which a patient lives with a cancer without it getting worse, during and after a treatment.

“The efficacy of a cancer drug relies on a complex interaction between the patient’s microbiome and his/her ability to mount an effective immune response against certain bacteria of the gut microbiota,” explains one of the main authors of the study, Mathias Chamaillard, Inserm Research Director.

“These results allow us to consider increasing the efficacy of these treatments by optimising the use of antibiotics, but also by supplementing the numbers of certain bacteria, known as oncobiotics (or their active substances), which are able to enhance the effect of cancer drugs.”

The researchers have planned to identify, in future studies, the specific parts of the bacteria responsible for enhancing the effects of cyclophosphamide. “If we succeed in answering this question, we can perhaps find a way of improving the survival of the patients treated using this chemotherapy by giving them drugs derived from these bacteria,” concludes Mathias Chamaillard.

[1] Unit 1019, “Center for Infection and Immunity of Lille” (Inserm/CNRS/University of Lille/Institut Pasteur Lille)

[2] Unit 1015, “Immunology of Tumours and Immunotherapy” (Inserm/Gustave Roussy Institute/Paris-Sud University)

Eating well to grow well: discovery of a missing link

Posted on by Priscille Rivière

Rénald Delanoue, Inserm Researcher, and his colleagues at the Institute of Biology Valrose in Nice (Inserm-CNRS-Université Côte d’Azur) have identified the missing links in the process that regulates the size of an organism based on the richness of its diet. Their research was conducted on Drosophila, an insect that seems very distant from humans, but the study of which has nonetheless enabled many advances in biomedical research. This work is published in the 30 September 2016 issue of the journal Science.

 

The size of an organism depends on its nutrient intake during development. In the event of a nutrient deficiency during this period, animals modify their growth and become adults of small size, while retaining the correct proportions. This coupling between nutrition and growth involves hormones from the insulin family and IGFs (insulin growth factors); however, the molecular mechanisms that govern this regulation are still not well understood.

Work done by Inserm researchers at the Institute of Biology Valrose (Inserm-CNRS-UCA) has enabled the identification of the substances on which this coupling is based at molecular level in the fruit fly (Drosophila melanogaster). Despite 700 million years of evolutionary divergence, this insect is a relevant model for biomedical research, because it possesses the same physiological processes as mammals.

For example, it is interesting to know that the fat body in Drosophila fulfils the same roles as the liver and adipose tissues in humans. The neurosecretory insulin producing cells (IPCs) are located in the larval brain of the insect, and correspond functionally to the pancreatic β-cells in humans.

Using the Drosophila model, these researchers have already shown that the coupling of nutrition and growth requires communication between these two organs (ndlr fat body and IPCs). Depending on the quantity of amino acids available in the diet, the fat body sends different signals to the brain. The IPCs are able to interpret these, and to secrete the appropriate amount of insulin. A low level of amino acids induces a reduction in insulin secretion and a slowing in growth, and vice versa.

It remained necessary to identify the nature of these remotely acting signals, and the IPC molecule capable of interpreting them to determine the quantity of insulin to be secreted. To do this, the researchers inhibited, one by one, the known receptors on IPCs, and identified the Methuselah receptor, inhibition of which blocks insulin secretion.

The Stunted protein, which binds to this receptor, was known, but had not been linked to the regulation of insulin secretion. And for a reason! This protein is usually found mainly inside the cells, and plays a role in ATP synthesis. It was therefore surprising to find it freely circulating in the haemolymph of the insect (the equivalent of the bloodstream). The researchers showed that the level of circulating Stunted varies with the quantity of amino acids present in the diet. Its suppression disrupts insulin secretion, and gives rise to adults of small size. Finally, they also demonstrated that this “signalling” function of Stunted in communication between two organs is a novel one, and independent of its function in ATP synthesis.

 

These results, although very fundamental, could nonetheless guide the study of the molecular circuits of certain diseases such as diabetes, obesity or some forms of cancer that depend on hormones and receptors from the same family as those described in Drosophila. Stunted proteins, which have been found on the surface of many cell types, could also play a signalling role in humans.

Drosophile2

The fluorescent protein GFP (green) is expressed in insulin producing neurons, IPCs (dotted white lines). Secretion of Drosophila insulins (Dilp2, in red) is regulated in these specialised neurons by the presence of the Methuselah receptor. The absence of this membrane protein in Mth- IPCs leads to blocking of insulin (Dilp2) secretion and its accumulation in IPCs (bottom row), compared with the control (top row).

(c) Rénald Delanoue/Inserm

1 in 2 French people suffers from joint pain

Posted on by Priscille Rivière

According to the results of an IFOP survey, “Les Français et les Rhumatismes” (Rheumatic Diseases and the French), conducted by Inserm and “Ensemble Contre les Rhumatismes” (Together Against Rheumatic Diseases), 93% of French people report having already suffered from joint pain[1] and one in two were suffering from it at the time of responding to the survey. This joint pain strongly affects their daily life. Quality of sleep and the ability to perform leisure activities are the two aspects of daily life that are most affected, ahead of working life and family life.

The results of this survey emphasise the need to continue to conduct ambitious research programmes to find new treatments, and encourage the French to act from the earliest age possible to retain their “joint capital.”

 

This press file has been prepared to mark World Arthritis Day and the French initiative “Ensemble Contre les Rhumatismes” (ECR, Together Against Rheumatic Diseases) which will take place on 12 October next.

ECR brings together the 3 most important contributors to research on joint diseases in France. Created at the initiative of the National Alliance for Life Sciences and Health (Inserm-AVIESAN), Fondation Arthritis and the French Society for Rheumatology (SFR), Ensemble Contre les Rhumatismes (ECR, Together Against Rheumatic Diseases) has the mission of promoting research in Rheumatology in order to prevent, relieve and cure diseases of the bones and joints, which affect one quarter of the European population.

Rheumatic diseases

Rheumatic diseases comprise all diseases of the musculoskeletal system (bones / cartilages / muscles tendons / ligaments).

Osteoarthritis and Arthritis are multigenerational diseases that affect the young and less young.

Rheumatoid Arthritis and Ankylosing Spondylitis are the most common inflammatory rheumatic diseases.

12-13 million French people suffer from rheumatic diseases including:

9-10 million from osteoarthritis

600,000 from chronic inflammatory rheumatic diseases (rheumatoid arthritis, spondylitis)

4,000 children suffer from idiopathic juvenile arthritis, a serious form of juvenile arthritis

 

True / False

Joint pain affects only a small part of the population / FALSE

More than 1 in 2 French people presently suffer from joint or bone pain
1/3 of 18-24 year olds presently suffer from joint pain*

WHO has declared lumbago to be the leading cause of disability worldwide? In France nearly 4,000 children suffer from inflammatory rheumatic diseases, nearly 600,000 adults suffer from the same diseases, and nearly 10 million French people suffer from osteoarthritis. These diseases are therefore clearly not only due to the ageing population.

Joint diseases are not serious / FALSE

65% of French people have had their sleep affected by joint pain.
Of those under 25 years of age, more than 1 in 2 young people consider rheumatism to have had an impact on their social and family life*

Joint diseases have a major impact on quality of life and sleep, but also on mortality. They are the main reason for sick leave. Rheumatic diseases are the leading cause of chronic pain. They have a direct impact on mobility and an indirect impact by increasing the risk of cardiovascular disease and cancer because of the inactivity they generate.

One should remain as still as possible / FALSE

On the contrary, physical activity, which is impeded by mobility problems in people affected by these diseases, is also a remedy for maintaining one’s bone and joint capital.

 

What should be remembered from the IFOP survey:

How common rheumatic diseases are

A large majority of respondents (93%) have already had joint pain at least once in their lifetime. 8 out of 10 French people have even experienced it several times.

1 in 2 French people and 1 in 3 young people (18-24 years) are presently suffering (at the time of responding to the survey) from joint pain.

These figures, when compared to those for the prevalence of rheumatic diseases in Europe (one in four people has rheumatic disease), may suggest that the French are “patients” without knowing it. Most of them do not associate their bone and joint pain with the possibility of being treated for rheumatic disease.

The researchers therefore recommend speaking more and more to French people about “osteoarticular/bone and joint diseases” rather than “rheumatism.” First, because the word “diseases” gets away from the concept of being destined to have this pain. Second, because the words “osteoarticular” or “bone and joint” specifically describe the location of the problems (bones and joints), in the same manner as “cardiovascular disease” or “lung disease.”

Received ideas

8 out of 10 French people wrongly believe that rheumatic diseases are never fatal. In reality, due to the resulting inactivity, mortality is increased by 50% when walking is limited by these diseases.

The majority of respondents believe that rheumatic diseases are age-related, and cannot affect children. In reality, 4,000 children in France suffer from idiopathic juvenile arthritis.

Impact on daily life

Joint pain strongly affects the daily life of people who suffer from it. Three quarters of them mention at least one impact on the following activities: sleep, leisure activities, working life, family life, and life with spouse/partner.

These diseases have a particular impact on quality of sleep and the inability to take part in a leisure activity.

 

What about research?

Medical research is a major asset in combating rheumatic diseases, the leading cause of disability worldwide, and which affect more than one quarter of the European population.

Some twenty years ago, for example, collaboration between basic and clinical research enabled the discovery of innovative drugs. These are biotherapies such as anti-TNF agents, which specifically target inflammatory molecules. These discoveries revolutionised the treatment of patients with rheumatoid arthritis or spondylitis.

Also through research, some years ago a blood test to diagnose rheumatoid arthritis, anti-CCP, enabled physicians to diagnose the condition early, thereby allowing them to initiate treatment before the joints become damaged.

Many other bone and joint diseases have not yet benefited from advances in research. Inserm researchers are working to try to find new treatments. In France, highly ambitious projects are supported by the 3 bodies involved in the ECR initiative.

MIRIAD PROJECT

“MIcrobiome Research Initiative on spondyloArthritis and Dysbiosis”

THE MIRIAD project, led by Prof. Maxime Bréban, a researcher at Inserm Unit 1173, “Infection and Inflammation,” and a physician at Ambroise-Paré Hospital, Paris (AP-HP), in collaboration with INRA and the Flanders Institute of Biotechnology, Ghent (Belgium), will study the influence of environment on inflammatory rheumatic diseases and has the following specific objectives: 1) To identify a diagnostic marker, 2) To test a new therapeutic strategy that involves restoring the equilibrium of the microbiota in patients with spondylitis by administering a healthy microbiota.

ROAD PROJECT

“Research on Osteoarthritis Diseases”

The ROAD project, led by Jérôme Guicheux, Inserm Research Director in Nantes (Inserm Unit 791, “Laboratory of Osteoarticular and Dental Tissue Engineering:” LIOAD), is the first networked research project on osteoarthritis in France, bringing together the 7 best academic and clinical laboratories. It has the following objectives: 1) To classify the different types of osteoarthritis in mice, 2) To classify the types of osteoarthritis of the knee in humans, and to create the first National Bank of human osteoarthritic tissues, 3) To identify new biomarkers and specific targets, in order to develop innovative therapeutic strategies.

These two projects constitute pioneering initiatives in Europe. Microbiota and ageing are, moreover, two of the three priority cross-disciplinary research programmes in Inserm’s 2016-2020 strategic plan.

ESPOIR AND DESIR (Hope and Desire) COHORTS

Two national multicentre cohorts for rheumatoid arthritis (ESPOIR cohort) and spondylitis (DESIR cohort), in which several Inserm teams are participating, have already given rise to many discoveries regarding the risk factors for these diseases, such as smoking or poor oral hygiene. Prof. Xavier Mariette (Inserm Unit 1084) is coordinating a clinical trial in the ESPOIR cohort aimed at improving the oral status of patients suffering from rheumatoid arthritis.

 

Can rheumatic diseases be prevented?

In the absence of treatment, it is possible to conduct preventive action on rheumatic diseases. Developing the notion of “Joint Capital,” the capital that must be maintained for life at any cost, and particularly from childhood, is vital. This capital is essential, since once it is affected by one or other of these diseases, loss of this capital ends in inactivity, with known harmful consequences for the heart and blood vessels, among other things.

This “Bone and Joint Capital” relies on:

  • Specific physical activity, that needs to be tailored for patients with a bone or joint disease.
  • A balanced diet, to avoid both overweight, a major risk factor for rheumatic disease, and deficiency in calcium and vitamin D, which increases the risk of osteoporosis and hence of fracture.
  • Smoking cessation and good oral hygiene, to eliminate 2 demonstrated risk factors for the initiation and aggravation of rheumatoid arthritis.
  • Trauma prevention programmes, from childhood/adolescence:
    • Writing textbooks (junior and senior secondary school level, in Life and Earth Sciences) explaining the physiological functioning of the musculoskeletal system, and the environmental risk factors for the main bone and joint diseases, to help incorporate the concept of “Bone and Joint Capital”
    • Training sports coaches in the consequences of trauma for the bones and joints (targeted warm-ups, strengthening the muscles to stabilise the joints, appropriate interruption of sports in the event of trauma, etc.)
  • In older people, prevention of falls, which cause fractures in patients with osteoporosis.

 

A day to talk about it

World Arthritis Day (WAD) takes place on 12 October every year. On this day Inserm, Aviesan (National Alliance for Life Sciences and Health), Fondation Arthritis and the French Society for Rheumatology (SFR), 3 major bodies that fund rheumatology research in France, have joined forces to organise the
ECR 2016 (Ensemble Contre les Rhumatismes) day. Its objective will be to speak with one voice to the public and relevant politicians about the importance of supporting research on rheumatic diseases.

It will be held at the Daunou building from 10 am to 4 pm, in the form of round table discussions broadcast live on the Web and in 2 French cities.

Each theme of the “ECR 2016” day will be successively presented by a researcher and by a representative of a patient association, and followed by a discussion to enable the exchange of points of view between researchers, physicians and patients.

The programme has been prepared in very close collaboration with the patient associations, which were invited to a first meeting at Inserm to propose and select themes and speakers to meet their needs.

Further information: www.ensemblecontrelesrhumatismes.org

Email: gro.semsitamuhrselertnocelbmesne@ofni

gro.semsitamuhrselertnocelbmesne@muabnerebsicnarf

[1] Rheumatic diseases comprise all diseases of the musculoskeletal system (bones / cartilages / muscles / tendons / ligaments)

Nobel Prize in medicine 2016

Posted on by Priscille Rivière

The Nobel Prize in Physiology or Medicine 2016 is awarded to Yoshinori Ohsumi for his discoveries of mechanisms for autophagy.

jap

Yoshinori Ohsumi. Ill. Niklas Elmehed.

© Nobel Media 2016.

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