A study led by investigators from the Ragon Institute of MGH, MIT and Harvard finds evidence that antibody protection may help control infection with the bacteria that causes tuberculosis (TB). In their study the research team describes finding consistent differences in both the structure and function of antibodies targeting the TB bacteria between individuals with active TB disease and those with latent TB, which neither produces symptoms nor can be transmitted. The findings may lead to better ways of distinguishing between active and latent disease and to a more effective vaccine against a disease that kills more than 1.5 million people each year.

‘Ending tuberculosis by 2030 is one of the targets of the World Health Organization’s newly adopted Sustainable Developmental Goals,’ says Lenette Lu, MD, PhD, of the Ragon Institute and the Massachusetts General Hospital (MGH) Department of Medicine. ‘A more effective vaccine against TB could substantially contribute towards that goal, impacting the nearly one in three people worldwide who are infected and addressing the leading killer of individuals infected with HIV.’

The only currently available preventive against infection with the TB bacteria – the BCG vaccine – has been available since the 1920s; but its effectiveness against pulmonary TB, the most common form of the disease, has always been uncertain. BCG is believed to work by stimulating cellular immunity, which is carried out by specialized immune cells including T cells and the macrophages that are directly infected by TB bacteria. Previous investigations into a possible role for antibodies in the immune response to TB have had conflicting results, but the Ragon team – led by Galit Alter, PhD, of MGH Department of Medicine and Sarah Fortune, MD, of the Harvard T.H. Chan School of Public Health – used a novel approach.

In addition to binding to their target pathogens and marking them for destruction by the immune system, antibodies also directly stimulate pathogen-killing cells of the innate immune system by binding to a cell-surface protein called the Fc receptor. The Ragon team profiled TB-specific antibodies from 22 individuals with latent TB and 20 with active TB for 70 different features associated with Fc-mediated antibody function. They first identified nine characteristics that differentiated between antibodies of the two groups of participants, and further investigation identified the biomarker that best distinguished between them.

A key regulator of Fc-mediated immune function is the addition to antibodies of compounds called glycans, made up of sugar molecules; and distinct differences in glycosylation patterns were found to clearly distinguish latent TB antibodies from active TB antibodies. To confirm these results in the initial group of participants, who were from South Africa, the team conducted a similar analysis of antibodies from 20 individuals from Texas and Mexico – half with latent and half with active TB – and had the same results. Further experiments revealed that application of latent TB antibodies to TB-infected human macrophages not only increased the activation of several antimicrobial processes but also reduced the survival of the TB bacteria.

Co-lead author Amy Chung, PhD, now at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia – a joint venture between The University of Melbourne and The Royal Melbourne Hospital – explains, ‘This is a completely new area of immune research in tuberculosis, since these antibodies don’t just recognize the infection, they also recruit immune cells to target it. People with latent infection have inactive disease for a reason, and if antibodies are playing a role in controlling the infection, the mechanism they use could be harnessed for future vaccine development.’

Alter, an associate professor of Medicine at Harvard Medical School, adds, ‘The diagnostic potential of these findings should not be overlooked. The detection of Fc-related modifications of TB-specific antibodies could be easily translated into a rapid, inexpensive point-of-care diagnostic that could have enormous public health impact, particularly in those parts of the globe where TB is endemic.’

Massachusetts General Hospitalwww.massgeneral.org/about/pressrelease.aspx?id=1992

It’s a Catch-22 with potentially deadly consequences: People trying to overcome addiction can’t get treatment for their pain, because the most powerful pain medicines also carry an addiction risk.
And so their pain continues to get in the way of their addiction recovery – or they seek pain relief in the same addictive substances they’re trying to avoid.

But a new study shows the potential for patients to break out of that cycle through a non-drug approach that combines behavioural therapy and social support to help them manage their pain. The low-cost approach, grounded in psychological theories of pain, could help address the nation’s epidemic of addictions to opioid painkillers and illicit drugs.

Veterans who received this pain-focused care while also being treated for addiction found that the intensity of their pain decreased, their ability to function increased, and their alcohol use went down, compared to veterans who received a less-focused approach. However, the two groups had similar rates of drug use.

Just 10 weekly sessions of the approach, called ImPAT for Improving Pain during Addiction Treatment, had an effect that lasted up to a year in 55 veterans who took part, according to the new results published by a team from the VA Ann Arbor Healthcare System’s Center for Clinical Management Research and University of Michigan Medical School’s Addiction Center.

The researchers have already launched a follow-up study in a larger group of 480 non-veterans in a residential addiction treatment program. And the study’s authors note that the ImPAT approach has the potential to be easily and inexpensively adopted by addiction treatment centers and groups worldwide, through team members trained in standard psychological techniques.

Addiction treatment programs often have patients who suffer from chronic pain, but offer few options to treat them, Ilgen says.’These results highlight the need for addiction treatment programs to offer a multifaceted approach that doesn’t only address substance use but also the other factors that might be driving substance use, including pain,’ says Mark Ilgen, Ph.D., the study’s lead author and a VA and U-M psychologist specializing in addiction research. ‘We’ve shown that it’s possible to improve pain outcomes in people with addiction, and even have some spillover effects on their substance use.’

To make matters worse, ‘Past studies of psychosocial approaches for pain have often excluded people with drug or alcohol problems, addiction treatment programs do not usually have providers trained in pain care, and many pain specialists will not treat people who also have addiction. So patients are caught in the middle.’

All 129 patients in the study, most of them men in their 40s and 50s, were receiving outpatient addiction treatment in a CBT-based, non-abstinence setting at the Ann Arbor VA. Half were randomly assigned to ImPAT sessions, the other half to support groups of peers, led by a therapist, where pain and addiction could be discussed.

ImPAT combines elements of cognitive behavioural therapy with another psychosocial approach called acceptance and commitment therapy.

While the two approaches aren’t usually used together, they are often used in pain treatment settings – but those clinics and programs don’t often accept people who also acknowledge they have addiction issues. Ilgen and his colleagues hope their results will help bring the techniques into addiction treatment settings, where the cognitive behavioural therapy approach is often used.

The ImPAT technique seeks to use integrated approaches both to help patients focus less on their pain and more on other aspects of life. This includes techniques to help people adapt to their pain, find ways to distract themselves from their pain, and think of ways to function in the face of pain.

‘We want to take the focus off pain and put it onto functioning, and finding pleasurable ways to spend time,’ Ilgen says. ‘There’s also a strong link between depression and pain. Pain is responsive to mood, and mood is responsive to social support.’

University of Michigan www.uofmhealth.org/news/archive/201607/treating-pain-without-feeding-addiction-study-shows-promise

Important steps in planning tumour surgery include identifying borders between tumour and healthy tissue and assessing the tumour stiffness, e.g. hard and calcified or soft and pliant. For decades, tumours near the surface of the body have been evaluated for stiffness by simple palpation-the physician pressing on the tissue. Because tumours within the skull cannot be palpated, researchers used Magnetic Resonance Elastography (MRE) to assess pituitary tumour stiffness by measuring waves transmitted through the skull into pituitary macroadenomas (PMAs). MRE reliably identified tumours that were soft enough for removal with a minimally-invasive suction technique versus harder tumours requiring more invasive surgery.
‘The group developed brain MRE several years ago and is now successfully applying it to clinical diagnosis and treatment,’ explained Guoying Liu, Ph.D., Director of the NIBIB Program in Magnetic Resonance Imaging. ‘This development of a new imaging technique followed by its practical application in surgical planning for better patient outcomes is an outstanding example of one of the main objectives of NIBIB-funded research.’
MRE is a special magnetic resonance imaging technique that captures snapshots of shear waves that move through the tissue and create elastograms-images that show tissue stiffness. John Huston III, M.D., Professor of Radiology at the Mayo Clinic in Rochester, MN, and senior author of the study, explains how MRE works. ‘MRE is similar to a drop of water hitting a still pond to create the ripples that move out in all directions. We generate tiny, harmless ripples, or shear waves, that travel through the brain of the patient. Our instruments measure how the ripples change as they move through the brain and those changes give us an extremely accurate measure–and a coloUr-coded picture–of the stiffness of the tissue.’
Ninety percent of PMAs are soft-nearly the consistency of toothpaste. Therefore, without MRE, surgeons would routinely plan for a procedure called transphenoidal resection that employs very thin instruments that are threaded through the nasal cavity to the pituitary gland at the base of the skull, where suction is used to remove the tumour. However, in about 10percent of the cases, the surgeon will encounter a hard tumour. At that point an attempt is made to break-up the tumour-essentially chipping away at it with sharp instruments. If that is not successful, the surgeon must perform a fully-invasive craniotomy that involves removing a piece of the skull bone in order to fully expose the tumour.
The more extensive procedure means added risk and discomfort for patients, and up to a week-long recovery in the hospital compared to the transphenoidal approach that allows patients to leave the hospital in a day or two. Using MRE, hard PMAs can be identified and the more extensive craniotomy can be planned before starting the surgery, which makes the more invasive procedure less taxing for both the surgeon and patient. Similarly, MRE showing a soft PMA gives surgeons confidence that the nasal entry and removal by suction will be successful-eliminating the likelihood that the surgeon may need to perform a second fully-invasive craniotomy.

NIBIB http://tinyurl.com/gu285fb

Acute myeloid leukaemia (AML) is an aggressive cancer known for drug resistance and relapse. In an effort to uncover new treatment strategies, researchers at University of California San Diego School of Medicine and Moores Cancer Center discovered that a cell surface molecule known as CD98 promotes AML. The study also shows that inhibiting CD98 with the therapeutic antibody IGN523 blocks AML growth in patient-derived cells and mouse models.
‘To improve therapeutic strategies for this disease, we need to look not just at the cancer cells themselves, but also at their interactions with surrounding cells, tissues, molecules and blood vessels in the body,’ said co-senior author Tannishtha Reya, PhD, professor of pharmacology at UC San Diego School of Medicine and Moores Cancer Center. ‘In this study, we identified CD98 as a critical molecule driving AML growth. We showed that blocking CD98 can effectively reduce leukaemia burden and improve survival by preventing cancer cells from receiving support from the surrounding environment.’

Reya led the study together with Mark Ginsberg, MD, professor of medicine at UC San Diego School of Medicine and Moores Cancer Center. Co-author Edward van der Horst, PhD, senior director at Igenica Biotherapeutics Inc., provided the anti-CD98 antibody IGN523.
AML is a type of cancer in which the bone marrow makes abnormal white blood cells, red blood cells or platelets. Reya’s team and others have previously shown that leukaemia cells interact with their surroundings in the body via molecules on their cell surfaces, and that these interactions can help the cancer cells divide, replicate and metastasize.

CD98 is a molecule found on the surface of cells, where it controls how cells stick to one another. CD98 is known to play a role in the proliferation and activation of certain immune cells. CD98 levels are also known to be elevated in some solid tumours, and linked to poor prognosis.

To determine CD98’s role in AML, in this latest study Reya’s team engineered mouse models that lack the molecule. They found that the loss of CD98 blocked AML growth and improved survival. CD98 loss largely spared normal blood cells, which the researchers said indicates a potential therapeutic window. Further experiments revealed that leukaemia cells lacking CD98 had fewer stable interactions with the lining of blood vessels – interactions that were needed to fuel AML growth.

Next, the researchers wanted to see what would happen if they blocked CD98 in AML with a deliverable inhibitor. In 2015, Igenica Biotherapeutics Inc. tested IGN523, a humanized antibody that specifically binds and inhibits CD98, in a phase 1 clinical trial at Moores Cancer Center and elsewhere. The trial’s goal was to determine a safe dose for IGN523 administration in AML patients. In this study, Reya and team tested IGN523 in their own AML models.

The researchers found that IGN523 blocks CD98’s AML-promoting activity in both mouse models of AML and human cells in the laboratory. They also transplanted human patient-derived AML cells into mice and treated the recipients soon after with either IGN523, the anti-CD98 antibody, or with a control antibody. Anti-CD98-treatment effectively eliminated AML cells. In contrast, AML in control mice expanded more than 100-fold.

‘This study suggests that human AML can’t get established without CD98, and that blocking the molecule with anti-CD98 antibodies could be beneficial for the treatment of AML in both adults and children,’ Reya said.

Moving forward, Reya and team are working to further define whether CD98 could be targeted to treat paediatric AML.

UC San Diego Health health.ucsd.edu/news/releases/Pages/2016-10-27-antibody-breaks-leukaemias-hold-new-therapeutic-approach.aspx

Extra-low dose combinat ion of two anticytokines reduces disease activity and cardiovascular events Immunotherapy reduces cardiovascular risk in patients with rheumatoid arthritis, according to research presented by Professor Aida Babaeva, head of the Department of Internal Medicine, Volgograd State Medical University, Volgograd, Russia. The combination of two extralow dose anticytokine drugs reduced rheumatoid arthritis disease activity and cardiovascular events.
‘Rheumatoid arthritis is an autoimmune disease in which cytokines such as tumour necrosis factor (TNF) and interferon (IFN), which normally protect the
body, attack healthy cells,’ said Professor Babaeva. ‘Patients have painful and inflamed joints. They are also at increased cardiovascular risk, particularly if their rheumatoid arthritis is not controlled.’
Professor Babaeva’s previous research showed that treatment with anticytokine drugs can decrease the activity of rheumatoid arthritis. Extra-low dose anti-TNFα reduced levels of inflammatory mediators and cytokines including C-reactive protein (CRP), rheumatoid factor, TNF, interleukin-1 (IL-1), and interleukin-6 (IL-6). The effect was more apparent and developed earlier when patients were treated with a combination of anti-TNFα and anti-IFNγ both at extra-low doses.
The current study investigated the impact of the combination of drugs on cardiovascular events. It included 68 patients who had suffered from active rheumatoid arthritis for at least five years. Patients were randomized to receive the combination of anti-TNFα and anti-IFNγ plus standard disease-modifying therapy (38 patients) or placebo plus standard therapy (30 patients). During the three year follow up period the investigators monitored rheumatoid arthritis disease activity and cardiovascular events.
Patients taking the combination of anticytokines had a lower rheumatoid arthritis disease activity score, as measured by the DAS28,2 and more dramatic decreases in IL-1, IL-6 and TNFα than the group on standard therapy alone.
The incidence of cardiovascular events (unstable angina, severe hypertensive crisis, and deterioration of chronic heart failure) was more than double in the group on conventional disease-modifying drugs alone (37percent) compared to those also taking the combination of anticytokines (13percent).
Professor Babaeva said: ‘Our findings suggest that the decreased  rheumatoid arthritis disease activity with the combination of anticytokines translates into decreased cardiovascular risk. Rheumatoid arthritis promotes the development of cardiovascular disease in a number of ways. Therefore, decreasing disease activity may also reduce cardiovascular risk by slowing down or halting these processes.’
For example, rheumatoid arthritis is associated with dysfunction of the blood  vessel lining (called endothelium), which leads to lipid accumulation in the artery wall, plaque formation and atherosclerosis. Increased disease activity is also linked with a pro-coagulant state in which patients are more prone to blood clots and thrombosis. Patients with active disease have an increase in molecules that promote inflammation, which has been associated with an increased risk of cardiovascular disease.
In patients with hypertension, target blood pressure was reached in 71percent of those taking the combination of anticytokines compared to just 32percent of patients on standard therapy alone.
Professor Babaeva said: ‘This doesn’t mean that the two drugs directly impact on blood pressure. But the combination can improve endothelial function and it could be that blood pressure is more stable when disease activity is low.’
‘We found that the combination of two anticytokines containing extra-low doses of antibodies against TNFα and IFNγ can improve the efficacy of standard rheumatoid arthritis therapy and decrease cardiovascular risk,’ said Professor Babaeva.

European Society of Cardiology http://tinyurl.com/gny3vyg