'Flu update

It's that time of year again. Doctors are planning their 'flu vaccine clinics and posters are appearing reminding us to get our annual dose. Since last year there have been several interesting new developments in ‘flu research.

Over a hundred cases of H7N9 'flu in humans, probably contracted from poultry, have been seen in China. The high death rate emphasises the importance of influenza research. It's a race against time before a variant emerges that can easily be transmitted between humans. When it does it could cause a lethal pandemic with catastrophic death rates.

Even the usual winter 'flu sometimes causes serious illness and up to half a million people die of it, every year.

Some of this year's new information is based on analysis of existing data.

A systematic review of a large number of studies highlighted that new mums (but not pregnant ones) and obese individuals seem to be at an increased risk of dying of the complications of 'flu. These two risk groups have not been previously identified. Good quality research in this area is rather thin and more is needed so vaccination programmes can be targeted appropriately.

Another analysis found that in the 2009 outbreak of swine 'flu, pregnant women who had been vaccinated were less likely to go into premature labour than the non-vaccinated. It seems then that 'flu vaccines during pregnancy may protect both babies, from the dangers of being born too soon and mums from becoming seriously ill with 'flu, or even dying, in the month following delivery.

An Australian study looked at links between heart attacks and 'flu, using data on middle-aged people admitted to hospital. It found that having a 'flu vaccination seemed to have a protective effect against heart attacks. If other research confirmed this result it would, again, lead to a change in the recommendations for priority groups.

One of the most interesting, and surprising, findings of the year is that 'flu vaccines are not as specific as everyone thought. Immunology theory is clear - that the immune system develops antibodies, one virus at a time. So every variant of the virus requires a vaccine to match it. Each year the vaccine is a cocktail of the three types that are currently most common worldwide. This new study found that the vaccine gives significant protection against types of 'flu that are not included as well as those that are. This highlights the fact that there is a lot more to the immune system than just antibodies - and that there is still a great deal to learn about how it works.

Finally, for the needle-shy, there is hope on the horizon. Nasal spray 'flu vaccines are being introduced, (initially for use with children in the UK) and research on mice has revealed that a micro-needle patch can deliver 'flu vaccine effectively. I imagine this would be a bit like pressing a bit of Velcro or sandpaper against your skin.

In the UK the 'flu vaccine is free to priority groups and the rest of us have to pay. I always think that £10 spent on a 'flu jab is fantastically good value if it means I can get through another winter without a bout of this debilitating illness.

New risk groups

http://bit.ly/15ZLtuK

Vaccine in pregnancy

http://bit.ly/14PbZpK

Heart attacks

http://bit.ly/19e7dz6

Wider protection

http://bit.ly/158W4my

Micro patches

http://bit.ly/1geayRr

Border Security in the Gut

A couple of weeks ago, when I was returning to the UK, I chose the electronic passport queue, instead of the normal one. You put your "biometric" passport into a machine and stare into a camera. The computer checks whether your travel-weary features match the ones in the passport. It was extremely slow compared to the human immigration officers in the adjacent queue, who were whipping through British passport holders many times faster. To pass the time, I thought about a comparable process that happens in the gut, in which the immune system checks the identity of passing microbes.

The immune system in the gut is very powerful and there are two reasons. Firstly, the gut is such an inviting, food-rich niche. Millions of microbes have evolved to move in and either live in partnership with us or cause unpleasant intestinal diseases. Also the gut wall has a large, vulnerable surface area that microbes can use as a route to infect other regions of the body - typhoid and polio are examples.

All along the gut lining, defence forces are lined up, ready to repel invaders. Huge numbers of immune cells patrol and antibodies are present in vast quantities. Specialised patches of cells take samples of everything that passes, shuffling their catch of the day inwards for scrutiny. 

This facet of the immune system may remind us of immigration control but it's a lot more complex. The billions of molecules scrutinised daily are much more numerous and varied than human faces. They include:

·      Harmless food molecules

·      New, dangerous microbes encountered for the first time

·      Dangerous microbes that have been previously encountered, for which an antibody has already been manufactured

·      Harmless microbes both familiar and unfamiliar

·      Cells belonging to your own body (cheek cells for instance)

This is a monumental task. Far more demanding than devising an immigration system that could  identify every person on the planet without holding up the queue.

It is very important that the gut does not over-react to the millions of friendly bacteria, because such a reaction could cause inflammation. When there is good cause, inflammation is literally a life-saver, reacting rapidly to bacterial invasion of wounds. Longer-term inflammation, on the other hand, is harmful because the powerful chemicals released cause tissue damage.

It has long been suspected that some kind of imbalance in the way the immune system reacts to friendly bacteria lies behind inflammatory diseases of the gut. Immunologists in the University of Pennsylvania have made an important discovery about how the delicate immune balance in the gut can be disturbed. It seems that some very specialised immune cells known as ILCs are needed to keep other immune cells - T cells - under control in the gut, and prevent them from causing inflammation. When ILCs in mice were disabled, inflammation of the gut developed. It seems that ILCs are the ones that can determine the difference between dangerous and harmless bacteria. So under-performing ILCs may be an important cause of gut inflammation.

Work like this furthers our understanding of inflammation in the gut and may eventually lead to new treatments for a range of chronic inflammatory diseases. Or it may not. Tinkering with one aspect of a complex system like the immune system is fraught with difficulty. However it is undoubtedly another intriguing jigsaw piece that contributes to our understanding of how the immune system does its work.

http://bit.ly/10ouz0l

T Cell Therapy for Leukaemia - Why is this news?

In a recent report in The New England Journal of Medicine, the authors explain how two child patients were treated with a new technique. In both, their leukaemia was cleared and one of them remains in remission. The technique has previously had some success on a small group of adults.

News of medical research does not usually cover successes in just one or two patients - so why did the researchers go public on this?

In solid cancers you can never be sure that there are no cancer cells left in the body but in leukaemia you can be much more certain. It is no longer a case of looking at slides through a microscope - the latest techniques and equipment can scrutinise large numbers of blood cells and detect the presence - or absence - of cancerous cells.

There are many different kinds of leukaemia, each relating to a particular kind of blood cell. The nursery for blood cells is the red bone marrow and it is here that leukaemia cells are produced before they are released into the circulation. This red bone marrow is essential to life. It not only replaces red blood cells but all the white blood cells that make up the immune system. Without it, fatal anaemia and infection are inevitable.

Doctors can categorise the various leukaemias very accurately these days. For some patients the prognosis is good. For others, the only hope is a stem cell (bone marrow) transplant. These two young patients were suffering from relapsed Acute Lymphoblastic Leukaemia (ALL).

A stem cell transplant is usually the treatment of last resort. It uses brutal chemotherapy to kill all the red bone marrow, diseased and healthy. Then there is an infusion of blood stem cells, gathered from a closely matched donor. These then set up home in the bone marrow cavities and rebuild the blood producing tissue. It is a risky and arduous process. For some it fails to work and for others the treatment itself proves fatal.

Medical researchers sometimes use what they call translational research, which they also refer to as "bench to bedside research". Scientific advances in the lab are tried out on small groups of volunteers. These are patients who have little to lose - maybe a stem cell transplant has already failed - and they are willing to take the risk of acting as guinea pigs.

Translational research is quite different to a controlled trial - it is, literally, trying out something that they think should work to see what happens. This paper is an example of translational research - hence the tiny numbers. The progress of research like this is slow. Suitable patients are rare. By publishing this early success, researchers can share knowledge and perhaps find other patients who would benefit.

 We have long had the tantalising knowledge that immune cells known as T cells (or T lymphocytes) can destroy cancer cells in the lab - but often fail to do so in the body. One of the reasons for this failure is that the immune cells cannot recognise the cancer cells as something alien to the body. Store detectives deal with a similar problem: shoplifters tend to look like honest shoppers.

In the experimental treatment two child patients were treated with a kind of gene therapy in which T cells were genetically altered in the lab and put into the patient's body. The technique teaches the T cells the exact molecular pattern they need to attack and harnesses their killing power. It's like giving store detectives a photograph of a professional shoplifter.

There was a serious reaction to the treatment - the children's immune systems reacted violently to the rapid dying-off of cancer cells (tumour lysis syndrome). But both went into remission with no trace of the ALL cells. One of them subsequently started producing a slightly different kind of leukaemia cell but the other seemed to be remaining clear.

Such new forms of treatment may in time prove to be less dangerous and more effective than the current approach, which involves strong chemotherapy drugs. For sick children and their parents in particular, a shorter and less arduous course of treatment would be a great step forward.

Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia," New England Journal of Medicine, Online March 25, 2013. To appear in print April 18, 2013.

Science Daily article: http://bit.ly/ZoAuE6

Placebos? Over-excitement can be a side effect

Placebos are in the news lately. Doctors are confessing to prescribing inert medicines. New and intriguing research is published indicating that placebos may work, even when the patients know they are inert. And a pharmaceutical company has patented a new, and questionable, way of conducting placebo-controlled trials (see links below).

Doctors may approve of the placebo effect because the patient’s symptoms may improve without the need for expensive drugs.

Alternative practitioners usually approve because the benefits of their methods seem to rely heavily on the placebo effect.

Psychologists love them because, well, they are intrinsically fascinating. Why should pills of different colours induce different degrees of placebo effect? Such phenomena are fascinating in the extreme.

Drug companies are not so keen on them, because all too often their shiny new products fail to work significantly better than the placebos used in trials.

And the rest of us may think they are a “good thing” because, lets face it, we’d all like to think that positive thinking of one kind or another can bring about miraculous cures.

But the existence of the placebo effect is no reason to get carried away. And completely carried away some folks do seem to be when they argue thus:

1.    The placebo effect exists, therefore your mind can control your body.

2.    The placebo effect is a kind of positive thinking

3.     Therefore my kind of positive thinking can cure cancer, AIDS and other serious diseases.

Fortunes have been made selling books and conducting lectures along these lines but there are a few flaws in the argument, lurking beneath that therefore like ants, teeming beneath a stone.

Firstly, not everyone is susceptible to the placebo effect. In any controlled experiment, some subjects who have received a placebo will report they feel much better. While others report no improvement. It is not a consistent or predictable effect – not in the least.

Secondly, the placebo effect may alleviate symptoms, but nothing more. It may bring about less pain, less nausea, better mood, that kind of thing. These are symptoms, not diseases. It does not work as a method of shrinking cancers, curing for AIDS or repairing damaged heart muscle.

If you read the “miracle cure” literature it is sprinkled with “case studies” – or rather, anecdotes, in which people claim that their methods have cured serious illnesses. But they offer no research to back these claims.

So we should not get over-excited about the placebo effect. It may have its uses in the control of symptoms, but panacea it is not.

http://www.bbc.co.uk/news/health-21834440

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015591

http://asserttrue.blogspot.co.uk/2013/03/new-patents-aim-to-reduce-placebo-effect.html

Undercover Inflammation?

There is increasing mention of the word inflammation these days - in relation to diabetes for instance. Put the word into Google and you get 66 million hits. Many of them will be talking in alarmist terms, claiming that inflammation causes nearly every worrying disease you can think of. They go on to recommend anti-inflammatory diets or supplements. It's a typical sales pitch: create concern; convince customers they have a need and then offer a solution.

But scientists also seem interested in chronic inflammation, so what is behind this increasing interest?

Inflammation is the emergency response of the immune system. If you scratch your hand in the garden, within 24 hours it will be red and swollen. Around the scratch, tissues are flooded with fluid. This contains a potent mix of immune chemicals whose main role is to disable bacteria by attaching themselves, in a kind of chemical rugby tackle. They will also send out an alarm call to millions of immune cells (white blood cells). When they arrive on site they destroy the immobilised bacteria. Within a couple of days the redness and swelling is subsiding and the inflammation starts to disappear as the immune system stands down. Inflammation is nature's way of protecting the body against bacterial invasion and it saves lives on a routine basis.

The problem comes when there is inflammation without any invading bacteria.

Unwanted inflammation can cause damage to healthy tissues. In the absence of an enemy, the troops (the immune cells and chemicals) start picking a fight with the civilians. A vivid demonstration of this is seen in rheumatoid arthritis in which inflammation gradually causes permanent damage to a joint. 

Recent research has been unpicking the complex links between obesity and raised levels of inflammation chemicals in the body. These chemicals are referred to a “inflammatory markers” in research papers.

When someone gains weight, they don’t grow more fat cells. Instead, their fat cells store more and more fat, like balloons filling with water. When they get to a certain size they start to trigger tiny amounts of inflammation. This may be because they start to leak, or start interacting with immune cells in abnormal ways. Recent research has revealed that they can even start behaving a bit like immune cells when they become over-filled with fat. The net result is that there are more inflammation-related chemicals sloshing around the body than you would want. These chemicals can cause slow and subtle damage to tissues and play their part in chronic diseases. They are a link in the chain between increased body fat and the increased risk of heart disease and diabetes.

There is lots of research going on into the exact mechanisms. This is fascinating for those involved but the immune system is unimaginably complicated and therefore difficult to tweak. Science is unlikely to come up with any miraculous, seise-effect-free drugs that will protect obese people from diabetes and heart disease.

If you are overweight and concerned about your health then pills and potions will not “reduce inflammation”. They will just waste your money and make supplement sellers rich. The solution, I'm afraid is to eat a better diet, lose weight and shrink those fat cells.

"Obesity makes fat cells act like they’re infected." Science Daily article.

http://bit.ly/10aMgRR

Using Regulatory Immune Cells to Control Arthritis

For years now immunologists have been trying to understand auto-immune diseases, which occur when the immune system turns its weapons on the cells of its own body. This is no easy task because the immune system is extremely complex, consisting of many different types of immune cells and a host of complex chemicals. All of these interact and like the musicians in an orchestra they normally they produce a seamless performance. Orchestras need to play faster and more loudly at times but they also need to reverse this so as to play softly or slowly. In an autoimmune disease it’s as if one section of the orchestra is ignoring the conductor and just keeps playing louder and faster. The conductor’s job in the immune system is undertaken by regulatory T cells. These are a type of lymphocyte, also known as Tregs or CD8 cells, that calm things down after a period of inflammation. 

One of the most common autoimmune diseases is rheumatoid arthritis. In arthritis immune cells start attacking joints and the inflammation this causes runs out of control. For some reason the Tregs can't calm things down.

In some recently reported work, researchers injected some of Tregs into mice with arthritis and they worked – reducing the unwanted inflammation in the joints. They also used a technique to increase the number of Tregs produced by the mice and this also worked.

It is no easy task to tweak the workings of the immune system. Conventional drugs such as steroids can blunt more than one aspect of the immune system and cause other serious side effects throughout the body.

Experiments like these are beginning to give hope that one day the mountain of research papers in immunology will pay some real dividends in terms of treatments.

Article in Science Daily 

Immune System Even Cleverer Than We Thought

In any branch of science there are moments when conventional wisdom is overturned. One of those moments has just occurred in immunology as a result of research at Stanford University. Our previous understanding was too simplistic. Things are even more complicated than we thought.

For years now everyone has believed that lymphocytes can learn to recognise specific molecules but that each type of lymphocyte can only learn a single lesson. One kind of lymphocyte can learn to recognise measles virus, another can learn to spot whooping cough bacterium on sight and another can only be activated by a particular protein made by prawns. Once a lymphocyte has had its initial exposure it will produce memory lymphocytes (CD4 cells) that will hang around for the rest of your life, waiting patiently to deal with a second encounter. This is how adaptive immunity and, of course, vaccination works. 

But the one lymphocyte = one lesson theory has just been blown out of the water. It seems that lymphocytes can generalise their learning.

The human brain can generalise easily. Learner drivers are taught to negotiate road junctions. Once the basic skill is there, they will be able tackle all kinds of road junctions. No two junctions are identical but nevertheless the competent driver tackles them all confidently. The learning has been generalised.

Now it seems that memory lymphocytes have some ability to do the same kind of thing. They are even cleverer than we thought. They can recognise not only the microbe that first activated them, but some other types as well.

We knew the immune system was magnificently complicated and now we have to acknowledge the existence of a whole new level of complexity. This new knowledge may shine a light several aspects of how the immune system learns about its environment, such as how benign bacteria help the immune system to develop in childhood.
http://www.sciencedaily.com/releases/2013/02/130207131602.htm