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Immune cells adjust their function like a radio dial, not an on/off light switch; a discovery that hints at how autoimmune disease may develop late in life.

A St. Jude Children’s Research Hospital study shows that T cells, the body’s master immune regulators, do not use simple on/off switches to govern the cellular machinery that regulates their development and function. Rather, they possess sophisticated molecular controls that enable them to adjust their function with exquisite precision. Such subtle adjustment enables T cells to modulate their development and function, including avoiding autoimmunity.

In autoimmune disease, rather than attacking invading microbes, the immune system attacks the body’s own organs, tissues or cells. Some 80 autoimmune diseases are known, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis and lupus.

“Among the many mysteries surrounding autoimmune diseases is why they can sometimes take decades to manifest themselves,” said Dario Vignali, Ph.D., associate member in the St. Jude Department of Immunology. “Our findings hint that this delayed onset could be explained by subtle defects in the molecular controls on T cells.” Such T cells are white blood cells whose duties include shutting down the immune system when it has done its job and suppressing T cells that can attack the body.

Vignali is the senior author of a report on this work that appears in the advance online publication of the journal “Nature Immunology.”

The researchers explored the function of T cell receptors, proteins that span the cell membrane of T cells. These receptors receive outside signals that instruct T cells to develop, proliferate and transmit those signals into the cell. The St. Jude investigators sought to understand why T cell receptors need many copies of switch-like components called immunoreceptor tyrosine-based activation motifs (ITAMS). ITAMs are components of the CD3 adaptor proteins that attach to the T cell receptor and help transmit the control signals from the T cell receptor into the cell.

“The ITAMs we studied are little molecular tags inside the cell by which the T cell receptor communicates to the rest of the cell,” Vignali said. “The mystery we wanted to address was why the T cell receptor needs 10 ITAMs to do its job. Why not just have a simple on/off switch?”

To explore the role of multiple ITAMs, Jeff Holst, Ph.D., the paper’s first author and a St. Jude postdoctoral scientist, used a technique developed in the Vignali lab to produce mice whose T cells have variations in the number and type of functional ITAMs. The technique involved using a virus as a genetic cargo-carrier to transport genes for different combinations of normal and mutant non-functional ITAMs into the mouse cells.

The researchers found that reducing the number of normal ITAMs caused the mice to develop autoimmune disease. However, the investigators also found that some mice with fewer than normal functional ITAMs did not become sick with autoimmune disease. Vignali said this finding suggests that it is not just the number of ITAMs, but also their type that may influence T cell function.

“We theorized that there were two possibilities why the immune system needs so many ITAMs,” he said. “One is that the requirement was purely quantitative, and that the ITAMs were there for signal amplification. The second possibility is that different ITAMs do slightly different things–they do have slightly different structures, so maybe they bind to some signaling molecules better than others; and their positions in the T cell receptor are different. So, while our primary observation is that quantity is more important than ITAM type, we also found that type has some influence.”

The researchers’ analyses of the immune systems of the altered mice indicated that reducing the number of normal ITAMs crippled a process called “negative selection.” In this process, the immune system rids itself of immature T cells that might attack the body’s own cells, causing autoimmune disease. Vignali said that these findings might provide insight into how autoimmune diseases start.

“One implication of our findings is that a relatively small defect in the efficiency of signal transduction through the T cell receptor could give rise to a subtle failing in negative selection, which gives rise over a long period of time to a few overly active T cells that might initiate autoimmunity,” Vignali said. “Clearly from our studies there is the possibility that you don’t really need a very big reduction in T cell receptor signal strength to have a defect in negative selection.”

The study also showed that different T cell functions required different numbers of functional ITAMs. “We were surprised to find that many ITAMs were required to make T cells divide and expand, but only one or two was required to make T cells secrete cytokines,” Vignali said. Cytokines are soluble proteins used by cells of the immune system to communicate and send messages to one another. Vignali said these basic findings represent only the beginning of more detailed studies of the role of ITAMs in T cell function.

“We believe this idea that T cell signaling acts more like a rheostat than an on/off switch offers significant new insights into how T cell development and function is controlled,” Vignali said.

Other authors include Haopeng Wang, Kelly Durick Eder, Creg Workman, Kelli Boyd, Zachary Baquet, Karen Forbes and Richard Smeyne (St. Jude); Harvir Singh, Andrzej Chruscinski and Paul Utz (Stanford University School of Medicine, Stanford, Calif.); and Nicolai van Oers (The University of Texas Southwestern Medical Center, Dallas).

This work was supported by the National Institutes of Health, a Cancer Center Support CORE grant and ALSAC.

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U.S. researchers say the treatment allowed an 82-year- old sufferer to recognise his wife for the first time in years.

In the UK, specialists believe the claims should be properly tested as only a few patients have been treated so far.

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* Blood test that gives ‘a six-year early warning’ of Alzheimer’s

The treatment involves injecting a drug called Enbrel – which is normally used to treat arthritis – into the spine at the neck.

Patients are then tilted to encourage blood flow into the brain where the drug is designed to block a chemical responsible for inflammation. At least one Alzheimer’s patient had his symptoms reversed “in minutes” while others have shown some continuing improvement in problems such as forgetfulness and confusion after weekly injections.

They needed less help from carers during treatment, which appears to reach a plateau at three months.

Around 50 people are being treated by the Institute of Neurological Research, a private clinic in California, with some having had injections for three years.

In one case, the clinic has video evidence of Marvin Miller, 82, which showed he was unable to answer basic questions by a nurse, or identify-everyday objects like a bracelet and a pencil.

Shortly afterwards he is injected with the drug and it is claimed that five minutes later he could greet his shocked wife, who said he had not recognised her for years.

The experiment follows the discovery that levels of TNF (tumour necrosis factor) can be up to 25 times higher in the fluid surrounding the brain in sufferers of Alzheimer’s disease.

Enbrel, a biologic treatment licensed for rheumatoid arthritis, binds to excess TNF in the body and makes it inactivate.

When used by arthritis sufferers, the drug is self-administered by injection and researchers had to develop a way of injecting the drug into the spine in order to get an effect in brain cells.

Enbrel is not approved for treating Alzheimer’s in the U.S. or in the UK and is regarded at this stage as a highly experimental therapy.

Professor Edward Tobinick, of the University of California Los Angeles and director of the Institute for Neurological Research, is leading the research.

He said the latest report was an in-depth account of one patient’s response to treatment.

He said: “It makes practical changes that are significant and perceptible, making a difference to his ability to do activities of daily living such as getting around, accomplishing things and conversing.”

He added: “Some patients have been able to start driving again. They don’t come back to normal but the change is good enough for patients to want to continue treatment, and some have been doing so for three years.

“We are working with several universities and larger trials are getting under way.”

Dr Susanne Sorensen, head of research at the Alzheimer’s Society, said: “On the surface these results are exciting but we need to treat the study with caution.

“There are large gaps in the research, which only involved a small pilot group and we cannot draw any conclusions until a controlled trial is carried out.”

Rebecca Wood, chief executive of the Alzheimer’s Research Trust, said: “It is too early to speak of a miracle cure and we need to do more research into this.”

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The drug is to be developed for the US military to protect troops and is already undergoing tests to help improve cancer treatments.

The new drug protects animals’ bone marrow and gut cells from being destroyed by radiation therapy, without reducing radiation’s effectiveness against tumour cells, say today’s studies.

Although radiation is an important weapon used by doctors to blast cancers, drugs that limit radiation’s devastating effects on healthy cells are needed to reduce the potentially severe side effects.

Radiation induces damage in healthy tissues not by directly killing cells but by prompting them to commit “suicide” through a process called apoptosis.

The new drug, called “Protectan CBLB502, tested in mice and monkeys, protects radiation-blasted tissues by shutting down this cell death programme, which the body normally turns on in cells with damaged DNA to keep them from multiplying. The feat is reported by Dr Lyudmila Burdelya, who worked with Drs Vadim Krivokrysenko and Andrei Gudkov at the Roswell Park Cancer Institute and colleagues at the company Cleveland BioLabs, also in Buffalo, New York.

Today in the journal Science they describe how a single injection of the drug given to animals shortly before receiving radiation therapy significantly reduced radiation damage to bone marrow and gut cells and prolonged the animals’ survival.

In one of the experiments, the treated mice were all alive when the controls had all died after 10 days. “We reported complete rescue and monitored these mice up to six months after control animals were all dead,” says Dr Gudkov, Cleveland Biolabs chief scientific officer, lead author and inventor.

One concern was that the drug could also protect the tumour cells targetted by the treatment, since cancers also turn off apoptosis to thrive, but the long term risk of cancer was not raised by the drug. “We showed directly that tumour cells are not protected while normal cell are – tumour cells already used this mechanism and our drug simply imitates tumour trick,” says Dr Gudkov.

Even when the drug was injected after a radiation dose it enhanced survival and, to underline its relevance to humans, it helped protect lethally irradiated rhesus monkeys, so 90 per cent survived after three weeks, compared with 20 per cent controls.

Dr Gudkov says, “We consider this paper a breakthrough for the study of radioprotection, since it provides a long awaited example of single agent anti-radiation therapy with significant survival benefits at a single dose. “

The US Department of Defence recently awarded Cleveland BioLabs a contract valued at up to $8.9 million to turn the drug into a treatment for radiation injury following exposure to radiation from nuclear or radiological weapons.

The drug is a derivative – so it does not trigger immune attack – in the flagella (whiplike tails) of a Salmonella bacterium protein found in the body that the bug uses to coexist in the human gut. Says Dr Gudkov: “The remarkably strong radioprotective abilities of Protectan CBLB502 are the result of a combination of several mechanisms of action, each of which is substantially effective on its own.”

The drug not only reduces damage caused by radiation by inhibiting of programmed cell death but also cuts damage caused by highly reactive chemical intermediates, called free radicals, generated by radiation, and also stimulates the manufacture of immune system factors, called cytokines, that help repair damage.

The company plans to have its first Phase I human safety study in the next few weeks, and to use the drug to help protect head and neck cancer patients to see if it can cut the side effects of radiation and chemotherapy. In particular, they want to limit mucositis, painful sores, cracking and swelling of the mucosa in the mouth and throat/digestive tract that make chewing and swallowing difficult.

In February, the company announced results of a study demonstrating the drug’s ability to reduce the side effects of a chemotherapy drug, cisplatinum (Ciplatin, Platinol) broadly used for treatment of ovarian, endometrial, head and neck, lung, stomach and other types of cancer.

Dr Michael Fonstein, president and chief executive officer of Cleveland BioLabs, says, “We are very excited by these results. The prospect of increasing patients’ tolerance to chemotherapeutic drugs and optimizing treatment regiments would be a significant paradigm shift in cancer treatment.”

It is estimated that approximately 40 per cent of the spending on cancer treatment concerns supportive care addressing side effects of various treatments, including chemotherapy. The team hopes the drug can help improve quality of life by cutting side effects caused by chemotherapy and radiotherapy, aiding recovery. It may also allow more aggressive treatments.

Dr Richard Kolesnick of the Memorial Sloan-Kettering Cancer Centre in New York City tells Science that the work is “a breakthrough.”

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According to the American Red Cross:

* Being positive for the AIDS or hepatitis viruses rules one out as a blood donor.
* Individuals who have had ear, tongue, or other body part piercing are allowed to donate blood as long as the needle used in the piercing was sterile. If it was not or if this is unknown, the potential donor must wait 12 months from the time of the piercing.
* Being imprisoned rules one out as a blood donor.
* Being in the US military and serving in Iraq or Afghanistan rules one out as a blood donor for one year.
* A person with diabetes is allowed to donate blood. Insulin dependent diabetics are allowed to donate blood as long as their insulin syringe, if reused, is used only by them.
* Being deferred from travel to the UK and Western Europe due to concerns about Mad Cow Disease rules one out as a blood donor.
* Physically small people are not acceptable as blood donors as they have lower blood volumes and may not be able to safely lose a full pint of blood.
* One may not donate blood while one has the flu. But one can donate blood after exposure to someone with the flu provided the potential donor feels and has no symptoms.
* A minimum age limit exists as to how old a person must be in order to donate blood (usually age 17). There is no maximum age limit.
* Pregnancy and recent childbirth rule one out as a blood donor. The safety of donating blood during and shortly after pregnancy has not been fully established. There may be medical risks to the mother and baby during this time.
* Having high or low cholesterol does not exclude a person from donating blood.
* Potential blood donors may be temporarily prevented from donating if they have a low level of iron (hematocrit) in their blood. This requirement is for the safety of the donor in order to ensure that their blood iron level remains within the normal range for a healthy adult.
* For almost all cancers (such as breast, brain, prostate, and lung), a person may donate blood five years after diagnosis or date of the last surgery, last chemotherapy or last radiation treatment.
* For blood cancers (such as leukemia or lymphoma), a person is not allowed to donate blood.
* For non-melanoma skin cancer or a localised cancer that has not spread elsewhere, a person may give blood if the tumour has been removed and healing is complete.
* If a potential donor has had malaria they cannot donate blood for 12 months. This is because the parasite that causes malaria can lay dormant in a person’s system for as long as a year.
* A person cannot donate blood while they are on antibiotics. This is not because of the antibiotic, but due to the presence of the illness or infection requiring the antibiotic – it may be transmitted through the blood.

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