Archive for July, 2013
Monash University researchers have gained new insight into the early stages of our immune response, providing novel pathways to develop treatments for diseases from multiple sclerosis to cancer.
In a study published today in Nature Immunology, a team of researchers led by Professor Paul Hertzog, of the Monash Institute of Medical Research (MIMR) and Professor Jamie Rossjohn, of the School of Biomedical Sciences, have characterised for the first time how interferon beta (IFNβ) proteins bind to cells and activate an immune response.
Produced when viral and bacterial infections are detected, interferon proteins are vital to the body’s defences. They activate immune cells, such as macrophages, can interfere with virus replication, and can boost cells’ resilience to infection. They also enhance later immune responses to cancers and other stresses.
There are at least 20 subtypes of interferons that are produced at different stages of the immune response. They appear to have different functions, but these functions and their triggers are generally not well understood. The mapping of INFβ — cell interaction is a breakthrough in the field.
Professor Hertzog of MIMR’s Centre for Innate Immunity and Infectious Diseases said interferon function was vital for developing and refining therapies for incurable diseases such as lupus and multiple sclerosis.
“Interferon therapy is useful in treating a number of diseases; however these treatments have dose-limiting side effects. Further, interferons appear to drive some autoimmune diseases, raising the prospect of interferon blockers as treatment,” Professor Hertzog said.
“The more refined our understanding of interferon function, the more we can tailor treatments to optimise effectiveness — whether by boosting or blocking their actions.”
Lead author on the paper, Dr Nicole de Weerd, also of the Centre for Innate Immunity and Infectious Diseases, said the research provided new pathways for rational drug design.
“We found that when IFNβ binds to a cell, it transmits an unusual signal that seems linked to some of the toxic side effects of interferon therapy, like sepsis. This provides a promising avenue to pursue more selective activation of interferon action,” Dr de Weerd said.
Professor Rossjohn and Julian Vivian from the Department of Biochemistry and Molecular Biology collaborated closely on determining the IFNβ interactions at the molecular level.
“During this seven-year study, we have had great support from the Australian Synchrotron,” Professor Rossjohn said.
Multiple sclerosis treatments that repair damage to the brain could be developed thanks to new research.
A study has shed light on how cells are able to regenerate protective sheaths around nerve fibres in the brain.
These sheaths, made up of a substance called myelin, are critical for the quick transmission of nerve signals, enabling vision, sensation and movement, but break down in patients with multiple sclerosis (MS).
The study, by the Universities of Edinburgh and Cambridge, found that immune cells, known as macrophages, help trigger the regeneration of myelin.
Researchers found that following loss of or damage to myelin, macrophages can release a compound called activin-A, which activates production of more myelin.
Dr Veronique Miron, of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh, said: “In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.
“Approved therapies for multiple sclerosis work by reducing the initial myelin injury — they do not promote myelin regeneration. This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.”
The study, which looked at myelin regeneration in human tissue samples and in mice, is published in Nature Neuroscience and was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.
Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.
Dr Susan Kohlhaas, Head of Biomedical Research at the MS Society, said: “We urgently need therapies that can help slow the progression of MS and so we’re delighted researchers have identified a new, potential way to repair damage to myelin. We look forward to seeing this research develop further.”
Dr Karen Lee, Vice-President, Research at the MS Society of Canada, said: “We are pleased to fund MS research that may lead to treatment benefits for people living with MS. We look forward to advances in treatments that address repair specifically, so that people with MS may be able to manage the unpredictable symptoms of the disease.”
The first large non-commercial clinical study to investigate whether the main active constituent of cannabis (tetrahydrocannabinol or THC) is effective in slowing the course of progressive multiple sclerosis (MS), shows that there is no evidence to suggest this; although benefits were noted for those at the lower end of the disability scale.
The study is published in The Lancet Neurology.
The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study was carried out by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry. The study was funded by the Medical Research Council (MRC), the Multiple Sclerosis Society and the Multiple Sclerosis Trust, and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.
CUPID enrolled nearly 500 people with MS from 27 centres around the UK, and has taken eight years to complete. People with progressive MS were randomised to receive either THC capsules or identical placebo capsules for three years, and were carefully followed to see how their MS changed over this period. The two main outcomes of the trial were a disability scale administered by neurologists (the Expanded Disability Status Scale), and a patient report scale of the impact of MS on people with the condition (the Multiple Sclerosis Impact Scale 29).
Overall the study found no evidence to support an effect of THC on MS progression in either of the main outcomes. However, there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of enrolment but, as the benefit was only found in a small group of people rather than the whole population, further studies will be needed to assess the robustness of this finding.
One of the other findings of the trial was that MS in the study population as a whole progressed slowly, more slowly than expected. This makes it more challenging to find a treatment effect when the aim of the treatment is to slow progression.
As well as evaluating the potential neuroprotective effects and safety of THC over the long-term, one of the aims of the CUPID study was to improve the way that clinical trial research is done, by exploring newer methods of measuring MS and using the latest statistical methods to make the most of every piece of information collected. This analysis continued for several months and has provided important information about conducting further large scale clinical trials in MS.
Professor John Zajicek, Professor of Clinical Neuroscience at Plymouth University Peninsula Schools of Medicine and Dentistry, said: “To put this study into context: current treatments for MS are limited, either being targeted at the immune system in the early stages of the disease or aimed at easing specific symptoms such as muscle spasms, fatigue or bladder problems. At present there is no treatment available to slow MS when it becomes progressive. Progression of MS is thought to be due to death of nerve cells, and researchers around the world are desperately searching for treatments that may be ‘neuroprotective’. Laboratory experiments have suggested that certain cannabis derivatives may be neuroprotective.”
He added: “Overall our research has not supported laboratory based findings and shown that, although there is a suggestion of benefit to those at the lower end of the disability scale when they joined CUPID, there is little evidence to suggest that THC has a long term impact on the slowing of progressive MS.”