Tetanus Shots Can Help Fight Brain Cancer

I'm sure you've heard plenty about the vaccine controversy. Critics have challenged the effectiveness of vaccines and highlighted their dangers for years.

This post is on Healthwise

19 April 2105

Cancer Research Surprise:
Tetanus Shots Can Help Fight Brain Cancer

I’m sure you’ve heard plenty about the vaccine controversy. Critics have challenged the effectiveness of vaccines and highlighted their dangers for years.

But recent research suggests at least one vaccine may have a valuable application no one ever imagined. Researchers looking into better ways to protect the brain have discovered a surprising new life-saving use for a vaccine that has been around since the 1920s.

Their work shows that a tetanus shot can boost survival rates among people battling a type of brain cancer that’s been considered a sure death sentence until now. Keep reading, it’s a remarkable story. . .

This variety of brain cancer, glioblastoma, is diagnosed in 20,000 Americans a year. It’s the brain cancer that killed Senator Ted Kennedy.

This difficult-to-treat cancer kills most victims in about twelve months. It’s usually inoperable and often attacks a part of the brain where radiation treatment is difficult, adjacent to neurons involved in memory and motor skills.

Calling on the Immune System

Your risk for this disease increases as you age. In the latest round of research about how to treat glioblastoma, the most promising treatment is proving to be immunotherapy, a technique that ramps up the immune system’s arsenal against cancer cells.

When cancer strikes, the cells in tumors often suppress the immune response, allowing malignant cells to escape attack by the body’s defenses. During immunotherapy, injections are given to people who are already stricken with cancer, in an effort to reawaken the immune response.

In the case of glioblastoma, studies show that the cancer cells are home to an activated form of cytomegalovirus (CMV), something that is not present in normal cells. Consequently, researchers have tried to boost the immune response to CMV in an effort to wipe out tumors.

To do this, scientists first take a blood sample from patients and culture what are called dendritic cells. Dendritic cells are immune cells that function like tiny detectives. Their job is to locate and identify viruses the body should be attacking and then convey an immunological “wanted poster” to cells called T cells.

Once T cells get the message, they form an immune cell posse that tracks down and kills the designated pathogens. (The type of wanted poster communicated by dendritic cells doesn’t say “Wanted: Dead or Alive;” it’s more like “Wanted: Dead and more Dead.”)

In the initial immunotherapy research, the mean survival time for cancer patients receiving the treatment was only about a year. But when a tetanus shot was added to the treatment, the patients generally lived from four to eight years.

“Patients with glioblastoma usually survive for little more than one year. However, in patients who received the immunotherapy (with the tetanus shot), half lived nearly five years or longer from their diagnosis, so the findings are promising and significant,” says researcher John Sampson, chief of the Division of Neurosurgery at Duke University Medical Center.

The reasons remain mysterious

Many of the details of exactly why the tetanus shot helps improve the immune response to cancer remain unknown. In lab tests, scientists did uncover the fact that the tetanus shot increases the production of a protein called CCL3 that apparently sends more of the injected dendritic cells into the body’s lymph nodes. When more of those cells get into the lymph nodes, they can interact more abundantly with T cells, sending them to attack cancer cells that contain CMV.

As you grow older, your risk for glioblastoma grows. But this new use for a tetanus shot means your chances of surviving this disease are growing, too.

I haven’t had a tetanus shot in years, and I don’t plan to get one. The disease is so rare it’s not worth worrying about. But I believe I WOULD get a tetanus shot if I had glioblastoma brain cancer and was planning to received immunotherapy.

http://www.cancerdefeated.com/cancer-research-surprise-tetanus-shots-can-help-fight-brain-cancer/3168/

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A newer approach to cancer treatment

Sunday November 9, 2014

This post is on Healthwise

Dendritic cells prime the immune system to fight infections. – Filepic

Human Initiated Therapeutic Vaccine (HITV) is a form of cancer immunotherapy that is showing some encouraging results.

HOSPITAL Universiti Kebangsaan Malaysia (HUKM) is currently carrying out a small trial utilising a form of immunotherapy called Human Initiated Therapeutic Vaccine (HITV).

In the trial, HITV is used in combination with modulated radiotherapy to treat advanced stage (metastatic) cancers.

HITV is pioneered by Hasumi International Research Foundation’s Dr Kenichiro Hasumi.

It involves the use of dendritic cells to stimulate an immune system response to cancer.

The dendritic cells are harvested from the patient and cultured in a laboratory.

They are then reintroduced back into the patient, along with activated T cells.

Dendritic cells are part of the immune system, and are basically cells that detect foreign or harmful substances.

Upon detection of such potentially harmful cells, other components in the immune system are activated to initiate an appropriate response.

Although there are over 100 types of cancer, they all start with uncontrolled and abnormal cell growth.

Unfortunately, cancer treatment has been slow to develop over the years, especially if compared with other diseases.

But there have been promising developments in recent years.

Different types of therapy

Surgery was the first form of cancer treatment.

In its earliest incarnation, it was a crude and primitive way of dealing with cancer, saddled with many problems and complications.

Dr Kenichiro Hasumi developed the Human Initiated Therapeutic  Vaccine. – Filepic

However, advances in the late 19th and early 20th centuries saw major improvements in treatment outcomes.

Today, surgery continues to be a mainstay of cancer treatment, especially in early-stage cancers.

Chemotherapy refers to the cocktail of drugs used to treat cancer.

Basically, it targets rapidly dividing cells, i.e. cancer cells, interfering with cell division, and ultimately, leading to cell death.

However, this also means that normal cells that rapidly divide, e.g. bone marrow cells, immune cells and hair follicle cells, are also affected. Hence, the often unpleasant side-effects of chemotherapy like nausea, hair loss and vomiting, among others.

One of the most common cancer treatments, radiation therapy, involves targeting high-energy waves at cancer cells to kill them.

Targeted therapy is one of the newer treatment methods, where either drugs or other cancer-killing substances are specifically targeted at cancer cells.

The aim of such treatment is also to avoid killing normal cells.

Stem cell transplants involve the use of stem cells (e.g. bone marrow, peripheral blood stem cells and umbilical cord blood) to treat cancer.

Meanwhile, immunotherapy primes the body’s own immune system to help fight cancer.

Immunotherapy in cancer

The immune system is a biological work of art, comprising many different organs, cells and substances that have specific roles to play in protecting the body against the multitude of assaults it faces daily from different microbes.

Bacteria, viruses and parasites all have certain proteins called antigens on their surfaces.

The immune system detects such antigens, and initiates a series of actions to neutralise such threats.

If the response is inadequate, we fall ill.

Compared to foreign microorganisms, cancer cells are not that different from normal cells, which is why the immune system faces such difficulties identifying them as a threat.

This is why healthy people with normal immune systems can develop cancer.

But what if the immune system could be primed to recognise cancer cells?

Would that enable the body to fight cancer cells on its own?

These are questions researchers have been asking for some time, and have resulted in the field of immunotherapy.

Although relatively new, researchers have made huge strides in this area of cancer therapy.

Here’s a short list of what’s being currently looked at:

•  Monoclonal antibodies

These are already being used as part of the treatment for many cancers.

They are designed to recognise and attach to specific antigens on the surface of cells.

There are three main types, which work in differing ways, i.e. triggering the immune system to attack cancer cells, blocking cancer cell division, and carrying drugs or radiation directly to cancer cells to kill them.

•  T-cell activation

This type of immunotherapy uses the T cells of the immune system to fight cancer cells.

One example is chimeric antigen receptor (CAR) T-cell therapy.

Here, T cells are extracted and altered with chimeric antigen receptors, which can latch on to the surface of cancer cells.

These are then injected into the body to initiate an immune response against the cancer cells.

Such therapy has shown encouraging results in trials, especially against leukaemias and lymphomas.

• Cancer vaccines

Although not a mainstay of cancer treatment, efforts have been ongoing for decades to develop vaccines for cancer.

While the road has been fraught with difficulties, scientists and researchers are continuing their efforts.

The various types of cancer vaccines in development include:

Tumour cell vaccines - Made from the patient’s own cancer cells, it involves altering the cells and injecting them back into the patient.

The cells are altered to make them more likely to be attacked by the body’s immune system.

Antigen vaccines - These are made using parts of the cancer cells, rather than the whole cancer cell.

Dendritic cell vaccines: Dendri-tic cells essentially function as the immune system’s “spotters”.

They spot cancer cells, then mobilise other types of immune cells to destroy them.

In this vaccine, the patient’s dendritic cells are extracted and exposed to cancer cells in the lab.

They are then injected back into the body to provoke a generalised immune response to the cancer cells.

These vaccines are showing the most promising results when it comes to treatment success.

Sipuleucel-T (Provenge), used for advanced prostate cancer, is an example of a dendritic cell vaccine.

Drugs that target the immune system

Why doesn’t the immune system attack normal cells in the body?

The simple explanation is the presence of “checkpoints” that verify whether cells are native or foreign.

In fact, some cancers are able to circumvent such checkpoints, disguising themselves as natives and thus, avoiding attack from the immune system.

In a similar manner, researchers have developed drugs that use such checkpoints to intensify attacks on cancer cells.

CTLA-4: This checkpoint molecule is found on T cells and can be blocked.

An example of a drug that does this is ipilimumab.

Blocking this checkpoint puts the immune system in heightened readiness, which helps the body attack cancer cells.

Unfortunately, it also exposes normal cells to attack, resulting in serious side effects.

PD-1/PD-L1: There has been some serious buzz on these drugs in recent times.

The PD-1 checkpoint is also found on T cells.

Drugs that target PD-1 or PD-L1, like ipilimumab, also boost the immune system, but for some reason, are more specific and less likely to affect normal cells.

Early clinical trials have found that anti-PD-1 drugs, such as pembrolizumab, shrink advanced melanomas in about 25% of test subjects.

Pembrolizumab was recently approved to treat advanced melanoma, and is being tested against other types of cancer as well.

Nivolumab, another anti-PD-1 drug, has been shown to help with some melanomas, kidney cancers and certain lung cancers.

Larger clinical trials are now underway, both using the drug alone and in combination with other cancer therapies.

HITV in cancer

HITV is actually very similar to dendritic cell vaccines.

The difference is that in HITV, the dendritic cells extracted from the patient are injected directly into the tumour mass, while for dendritic cell vaccines, the dendritic cells undergo tweaks in the laboratory before being injected back into the body.

The trial in HUKM has two arms – one lymphoma and the other, breast cancer – involving about 30 patients.

The lymphoma arm started last year, while the breast cancer component commenced recently.

There are various inclusion and exclusion criteria, but all patients in the trial have one thing in common: they are at the advanced stages of cancer, and have little hope with other treatments.

Basically, the protocol involves the following:

1. Evaluation and extraction of dendritic cells from the patient.

2. Injection of dendritic cells into the patient’s tumours, followed by an injection of activated T cells the next day.

3. Radiation therapy eight to 12 days later.

4. Another course of dendritic cells on day 19 of treatment, followed by an injection of activated T cells the next day.

5. Evaluation of the patient, including progress of treatment, during weeks four to six of treatment.

6. Regular review of patient, with HITV treatment administered when required.

This method of treating cancer has been successfully implemented in Japan by Dr Hasumi.

He has reported very encouraging results, with improved quality and duration of life, especially in view of the fact that the treatment is currently being given to very ill, end-stage cancer patients who would otherwise have no hope of reprieve from other treatments.

The HUKM trial might still be in its infancy, but its results would provide us with more data about the effectiveness of this therapy, and how we can progress from here in the effort to find more effective treatments for cancer.

http://www.thestar.com.my/Lifestyle/Health/2014/11/09/A-newer-approach-to-cancer-treatment/

• Dr R Steinman - Nobel Peace Prize in Medicine
• Dr R Steinman - The Man behind Dendritic Cell Canc...
• Dr R Steinman - Dendritic Cell Cancer Treatment
• HITV - New Cancer Treatment
• HITV Therapy: Cancer cure is now in Malaysia

Go to Healthwise for more articles

Human guinea pigs

Published: Tuesday October 15, 2013 MYT 12:00:00 AM
Updated: Tuesday October 15, 2013 MYT 7:59:33 AM

ALTHOUGH nearly 85% of Nobel Prizes in physiology or medicine have relied upon animal research, a few laureates have used themselves as guinea pigs. Below, the organisation Understanding Animal Research details some of these self-experimenters, who each took a risky step for their own reasons – bravery, desperation and hope.


Werner Forssmann (1956)

In the 23 years preceding winning the Nobel Prize, Werner Forssmann had worked as a urologist, served as a Major in the German Army and was captured as a prisoner of war. But none of that concerned the Nobel committee, who were honouring Forssmann for his work as a young surgical intern when he first demonstrated cardiac catheterisation in a human: himself.

Generally thought to be impossible without causing severe damage to the heart, cardiac catheters require inserting a catheter into a vein and threading it through until it reaches the heart.

This would allow clinicians to measure the pressure in the heart and determine if a defect needs to be operated on.

Inspired by researchers who had achieved this in a horse in 1861, Forssmann saw the potential this technique could have.

2005 Nobel Prize laureate Prof Barry Marshall (above) drank a broth of bacteria from the lab to prove that it was a bacterium that caused stomach ulcers while the late Dr Ralph Steinman’s work on dendritic cells helped prolong his life after he was diagnosed with advanced pancreatic cancer. — File picture

Refused permission to experiment on patients, Forssmann set out to test the technique on himself. First he had to convince the operating room nurse to give him access to surgical instruments.

She relented on the condition that Forssmann would place the catheter in her instead, which he accepted. However, once he had strapped the nurse down onto the operating table,

Forssmann quickly anaesthetised his own arm, made an incision and inserted the catheter 30cm along his veins.

He then walked up two flights of stairs to the X-ray room before extending the catheter the full 60cm to enter his heart and capturing the image.

Forssmann’s reckless bravery generated much annoyance and excitement.

The annoyance eventually won out and Forssmann was forced to withdraw from his residency.

Although he moved out of research, Forssmann’s paper on his work was read many years later by André Frédéric Cournand and Dickinson W. Richards who built on the technique and shared the Nobel Prize with him.

On hearing news of the prize, Forssmann said: “I feel like a village parson who has just learned that he has been made bishop.”


Barry Marshall (2005)

Marshall must be the poster boy for self-experimenters everywhere. He drank a heady broth of bacteria from the lab to prove to his peers that the bacterium Helicobacter pylori was the cause of stomach ulcers.

Stomach ulcers were long thought to be due to stress, with the only treatments being rest, antacids and surgery in extreme cases. But in 1979, pathologist Robin Warren noticed inflammation in regions of stomach biopsies that were colonised by small, curved bacteria.

Marshall, intrigued by his findings, contacted Warren and the pair began a survey of 100 patients and biopsies.

For them, it became clear that the bacteria, which they named H. pylori, were the cause of stomach ulcers and gastritis.



The culprit: The H. pylori bacterium, which Marshall proved caused
stomach ulcers – by testing his theory on himself! — Understanding Animal Research

This discovery was a radical departure from medical opinion at the time, and many researchers and doctors were sceptical. The presence of the bacteria and inflammation did not prove cause and effect.

With no suitable animal model susceptible to the bacteria (this was before the Mongolian gerbil had been found to model the human condition), Marshall decided to demonstrate the role of bacteria using himself as a guinea pig.

Five days after drinking the broth, he began to experience loss of appetite before then vomiting regularly each morning. An endoscopy revealed the truth: Marshall had given himself gastritis. Under orders from his wife, Marshall began taking antibiotics and the symptoms subsided.

This proved that peptic ulcers and gastritis could be cured, saved thousands of lives and rendered the billion-dollar industry of previous treatments obsolete.


Ralph Steinman (2011)

When Steinman was announced as one of the winners of the Nobel Prize in 2011 friends, colleagues and journalists were quick to try to contact him. Outside of his family, no one knew that he had died just three days earlier.

Along with Bruce Beutler and Jules Hoffmann, Steinman was being honoured for his work on the immune system.

He had discovered a new type of cell, which he named dendritic cells because of their tree-like structure, that activate T-cells to fight off an infection.

The immune system is primed to attack foreign and unusual cells in the body, but some cancer cells can slip past its defences.

Being able to control the dendritic cells would allow researchers to train them to target camouflaged cancer cells.

This was a new approach, highly experimental and likely to take decades before it could be available to the public.

So when Steinman was diagnosed with advanced pancreatic cancer in 2007, he saw the opportunity to start a human trial and potentially buy himself more time.

He had little to lose, with less than a 5% chance of surviving a year.

Dozens of his colleagues and collaborators came forward with ideas and techniques for improving his “experiment”.

They worked to grow portions of the tumour in mice, test the effects of different drugs, sequence the cancer’s DNA and extracted proteins from the surface of the cells. In addition, Steinman received three different, personalised vaccines that were based on his work on dendritic cells. Steinman received eight experimental treatments, in addition to conventional chemotherapy.

Despite the range of these treatments, Steinman still succumbed to the cancer, but he had survived four and a half years – far longer than expected.

Although he never learned that he had won the Nobel Prize, he was sure that his work had prolonged his own life and may one day extend many more.

Article courtesy of Understanding Animal Research, a not-for-profit organisation based in Britain that aims to achieve broad understanding and acceptance of the humane use of animals in biomedical research to advance science and medicine. Website: http://www.understandinganimalresearch.org.uk/

• Dr R Steinman - Nobel Peace Prize in Medicine
• Dr R Steinman - The Man behind Dendritic Cell Canc...
• Dr R Steinman - Dendritic Cell Cancer Treatment
• HITV - New Cancer Treatment
• HITV Therapy: Cancer cure is now in Malaysia

http://www.thestar.com.my/Lifestyle/Features/2013/10/15/Human-guinea-pigs.aspx

Dr R Steinman - unlocking secrets of the body's immune system

Nobel medicine prize honours work on body's defences

Posted on 3 October 2011 - 09:26pm
Last updated on 4 October 2011 - 07:52am





STOCKHOLM (Oct 3, 2011): Three scientists who unlocked secrets of the body's immune system, opening doors to new vaccines and cancer treatments, won the 2011 Nobel prize for medicine today.

American Bruce Beutler and French biologist Jules Hoffmann, who studied the first stages of immune responses to attack, share the US$1.5 million award with Canadian-born Ralph Steinman, whose discovery of dendritic cells in the 1970s is key to understanding the body's next line of defence against disease.

"This year's Nobel laureates have revolutionised our understanding of the immune system by discovering key principles for its activation," the award panel at Sweden's Karolinska Institute said in a statement in Stockholm.

Lars Klareskog, who chairs the prize-giving Nobel Assembly, told Reuters: "I am very excited about what these discoveries mean. I think that we will have new, better vaccines against microbes and that is very much needed now with the increased resistance against antibiotics."

Beutler, 53, is based at the Scripps Research Institute in La Jolla, California. Luxembourg-born Hoffmann, 70, conducted much of his work in Strasbourg.

They will share half the 10 million Swedish crowns (US$1.46 million) of prize-money. The rest goes to Steinman, 68, from Rockefeller University in New York.

However, the prize giving committee and Rockefeller University reported that Steinman died just last Friday at the age of 68, succumbing to his battle with pancreatic cancer.

An official at the Nobel committee of the Karolinska Institute, Anna Dumanski confirmed his death but said she could not give any more details.

The New York based Rockefeller University said in a statement, posted on its website that Steinman, 68, was diagnosed with pancreatic cancer four years ago, and his life was extended using a dendritic-cell based immunotherapy of his own design.

The work of the three scientists has been pivotal to the development of improved types of vaccines against infectious diseases and novel approaches to fighting cancer.

The research has helped lay the foundations for a new wave of "therapeutic vaccines" that stimulate the immune system to attack tumours.

Better understanding of the complexities of the immune system has also given clues for treating inflammatory diseases, such as rheumatoid arthritis, where the components of the self-defence system end up attacking the body's own tissues.

Beutler and Hoffmann discovered in the 1990s that receptor proteins act as a first line of defence, innate immunity, by recognising bacteria and other microorganisms.

Steinman's work, explained how, if required, dendritic cells in the next phase, adaptive immunity, kill off infections that break through.

Understanding dendritic cells led to the launch of the first therapeutic cancer vaccine last year, Dendreon's Provenge, which treats men with advanced prostate cancer.

"We live in a dangerous world. Pathogenic microorganisms threaten us continuously," the Nobel panel said, describing the work over the decades in understanding our defences.

"The first line of defense, innate immunity, can destroy invading microorganisms and trigger inflammation ... If microorganisms break through this defense line, adaptive immunity is called into action ... It produces antibodies and killer cells that destroy infected cells ... These two defense lines ... provide good protection against infections, but they also pose a risk ...: inflammatory disease may follow."

Medicine, or physiology, is usually the first of the Nobel prizes awarded each year. Prizes for achievements in science, literature and peace were first awarded in 1901 accordance with the will of dynamite inventor and businessman Alfred Nobel.

The award citation noted that the world's scientists had long been searching for the "gatekeepers" of immune response.

Hoffmann's pioneering research was conducted on fruit flies, highlighting how key elements of modern human biology have been conserved through evolution.

The immune system exists primarily to protect against infections but it can also protect against some cancers by targeting rogue cells before they proliferate.

Sometimes, however, the immune system goes into overdrive and attacks healthy tissue, leading to autoimmune inflammatory diseases, such as type 1 diabetes and multiple sclerosis, as well as rheumatoid arthritis. The effect is often compared to "friendly fire", when troops hit their own comrades in combat. – Reuters

http://www.thesundaily.my/news/164569

Dr R Steinman - Dendritic Cell Noble Peace Prize Winner

One of 3 Chosen for Nobel in Medicine Died Days Ago

By LAWRENCE K. ALTMAN and NICHOLAS WADE
Published: October 3, 2011

When a representative of the Nobel Foundation could not reach Dr. Ralph M. Steinman by telephone Monday to deliver the thrilling news that he had been awarded a Nobel Prize in Medicine for his breakthrough work in immunology, he sent him an e-mail about the honor.

Stan Honda/Agence France-Presse — Getty Images
The family of the late Dr. Ralph M.
Steinman, pictured on the screen,
on Monday after he was announced
as a Nobel Prize winner. 

But Dr. Steinman would never see the message nor learn of the prize. He died of pancreatic cancer on Friday, three days before the phone call from the Nobel committee. He had been battling the highly deadly disease for four years, using a treatment he devised to try to prolong his life, essentially turning his body into an extension of his research.

However, Nobel Prizes cannot be awarded posthumously. And so the Nobel committee, which had believed Dr. Steinman to be alive, faced a quandary.
      

Carlos Barria/Reuters
Dr Jules A. Hoffmann, above, and Dr
Bruce A. Beutler, both immunologists,
 shared this year's Nobel Prize in Medicine
with Dr. Ralph M. Steinman, who died of
pancreatic cancer on Friday before
learning of their selection.

On Monday morning, one of Dr. Steinman’s daughters, Alexis, saw the e-mail from the Nobel Foundation and contacted Rockefeller University in New York, where her father had worked. The president of the university, Marc Tessier-Lavigne, immediately called the chairman of the Nobel Prize committee to inform him.

Then the committee, at the Karolinska Institute in Stockholm, scrambled to figure out what to do. As heartless as it might seem, would the prize for Dr. Steinman have to be revoked?

“This is a unique situation — Steinman died hours before the decision was made,” Goran Hansson, secretary of the Nobel committee for physiology and medicine, told Swedish Radio News after the situation came to light. “News of his death was not  made public. We had no idea, nor did they know at his place of work.”

Mike Groll/Associated Press
Dr. Bruce A. Beutler

The foundation’s nine-member board of directors met Monday afternoon and consulted lawyers concerning the interpretation of the statutes of the Nobel Foundation issued in 1974. The statutes hold that the Nobel Prize is not to be given posthumously. But if a person who is announced as a prize winner dies before receiving it at the Nobel ceremonies on Dec. 10 — the anniversary of the death of Alfred Nobel, the Swedish industrialist who endowed the prizes — the award remains valid.

       

Because Dr. Steinman’s award was made in good faith on the assumption that he was alive at the time of his election, he should receive it, the directors decided.
      

The drama seemed to overshadow the fact that Dr. Steinman was awarded one-half of the prize, and that two other immunologists shared the other half. They were Dr. Bruce A. Beutler of the University of Texas Southwestern Medical Center in Dallas and the Scripps Research Institute in San Diego, and Dr. Jules A. Hoffmann of France. All three scientists were honored for discoveries of essential steps in the immune system’s response to infection.

       

But it was Dr. Steinman who actually used his discoveries in the laboratory to try to save his own life. His career-long quest had been to develop a vaccine against cancer for humans, having shown 20 years ago that such a treatment could be effective in mice.

Four and a half years ago, after he was found to be jaundiced from a spreading pancreatic cancer, he began tailoring an experimental vaccine against his own tumor. The idea was to use the principles learned in the experiments on mice and in the laboratory to produce immune cells derived from his dendritic cells, a class of cells that he discovered in 1973.

After a piece of Dr. Steinman’s cancer was removed, a colleague, Dr. Michel Nussenzweig, grew it in the laboratory to produce enough material to send to at least 20 researchers at Rockefeller University and at least five other laboratories around the world. Dr. Steinman organized the work among the researchers who developed the experimental vaccine.

Dr. Steinman received standard chemotherapy for his cancer as well as the experimental vaccine, which other doctors at Rockefeller University injected under his skin, Dr. Nussenzweig said Monday in a telephone interview. Rockefeller University’s institutional review board approved the experiment.

“Ralph believed strongly that it would work,” Dr. Nussenzweig said. “Obviously, it did not work or he would be here now, but possibly it prolonged his life.” The research, he added, will continue.

Pancreatic cancer is among the most aggressive malignancies, in part because it arises in a gland deep in the abdomen that is hard for doctors to feel with their hands and because usually it produces symptoms only after it has become advanced. About 20 percent of patients with pancreatic cancer survive one year after detection and 4 percent after five years, according to the American Cancer Society.

Dr. Nussenzweig and other doctors said it was impossible to determine whether Dr. Steinman would have survived as long without his self-tailored experimental treatment.

At the time of his death, Dr. Steinman was working to develop a general method for making a vaccine that would not need to be tailored to each patient and that could be used against cancer and certain infections. Other vaccines based on dendritic cells are being tested in patients, researchers said.

Provenge, a vaccine against advanced prostate cancer, was based on Dr. Steinman’s work with dendritic cells. It was approved by the Food and Drug Administration last year and is sold by the Dendreon Corporation of Seattle. (Dr. Nussenzweig said that neither he nor Dr. Steinman had any connection to Dendreon, financial or otherwise.)

Scientists who knew Dr. Steinman and his work said the Nobel committee had made the right decision.

       

“All I can say is that the work deserved the prize,” said Susumu Tonegawa of the Massachusetts Institute of Technology, who himself won the prize in 1987 for his work on immunology.
       

Honored along with Dr. Steinman were Dr. Hoffmann, who was born in Luxembourg, and Dr. Beutler, an American. In 1996, Dr. Hoffmann discovered the cell receptors in laboratory fruit flies that are activated by pathogenic bacteria or fungi. Two years later, Dr. Beutler identified the cell receptors in mice that respond to a substance in the coat of bacteria and that can set off septic shock if overstimulated. These receptors turned to be made by the same family of genes as those in the fruit fly, known as Toll-like receptor genes.

Mr. Hansson of the Nobel committee said Nobel Prizes had been awarded posthumously twice before: in 1931, for literature, to the poet Erik Axel Karlfeldt, and, 30 years later, to Dag Hammarskjold, for peace.

“The situation was a little different then because the committee was aware that the recipients were dead,” Mr. Hansson told Swedish radio. “The practice now is not to award the prize to someone who is deceased.”

The Nobel committee was not able to make contact with any of the three winners before the announcement was made, Mr. Hansson said, adding that the committee normally makes personal contact with the winners before going public with the news.

Annika Pontikis, a spokeswoman for the Nobel Foundation, said she did not know whether the board had discussed how to check whether future recipients were alive at the time of their election.

Christina Anderson contributed reporting from Stockholm, and Maria V. Elkin from Washington.

 A version of this article appeared in print on October 4, 2011, on page A1 of the New York edition with the headline: Death Doesn’t Rob Recipient Of Nobel Prize.

The above is taken from:
http://www.nytimes.com/2011/10/04/science/04nobel.html?_r=1&ref=science

_______________________________________________________


The excerpt below is taken from:
http://www.rockefeller.edu/research/faculty/labheads/RalphSteinman/




Heads of Laboratories
Ralph M. Steinman, M.D.
Senior Physician
Henry G. Kunkel Professor
Laboratory of Cellular Physiology and Immunology
Ralph.Steinman@rockefeller.edu


Dendritic cells, which were originally codiscovered by Dr. Steinman with Zanvil A. Cohn at Rockefeller, are pivotal to the adaptive and innate branches of the immune system. Dr. Steinman’s research focused on the mechanisms employed by dendritic cells to regulate lymphocyte function in tolerance and immunity, as well as the use of dendritic cells to understand the development of immune-based diseases and the design of new therapies and vaccines.

The immune system contains a system of dendritic cells, which captures, processes and presents antigens and provides additional controls on the development of antigen-specific immunity and tolerance. Because of these functions, dendritic cells (DCs) are providing an important means to monitor and manipulate immune function in several disease states.

Dr. Steinman was the recipient of the 2011 Nobel Prize in Physiology or Medicine, the A.H. Heineken Prize for Medicine in 2010, the Albany Medical Center Prize in Medicine and Biomedical Research in 2009 and the Albert Lasker Basic Medical Research Award in 2007. He received the Debrecen Prize in Molecular Medicine in 2006, the New York City Mayor’s Award for Excellence in Science and Technology in 2004, the Novartis Prize in Immunology in 2004 and the Gairdner Foundation International Award in 2003. He was a member of the National Academy of Sciences and the Institute of Medicine.

For more, see  http://www.rockefeller.edu/research/faculty/labheads/RalphSteinman/

Dr R Steinman - Nobel Peace Prize in Medicine

Ralph M. Steinman, a Nobel Recipient for Research on Immunology, Dies at 68

By WILLIAM GRIMES

Published: October 3, 2011

Dr. Ralph M. Steinman, a cell biologist who was named one of three winners of the Nobel Prize in Medicine on Monday for his work on the human immune response, died Friday in Manhattan, a fact unknown to the prize committee when it made its announcement. He was 68.

Rockefeller University, via Getty Images
Dr. Ralph M. Steinman died three days
before the Nobel Committee announced that
he was a winner of this year's prize in medicine

                     

The cause was pancreatic cancer, his daughter Lesley said.

Dr. Steinman, the director of the Laboratory of Cellular Physiology and Immunology at Rockefeller University and a senior physician at the Rockefeller University Hospital, shared the award with Bruce A. Beutler, of the University of Texas Southwestern Medical Center in Dallas and the Scripps Research Center in San Diego, and Jules A. Hoffmann, a former research director of the National Center for Scientific Research in Strasbourg, France. The three scientists were honored for discovering the essential steps in the immune system’s response to infection.

In 1973, Dr. Steinman and Dr. Zanvil A. Cohn discovered a new class of cells, known as dendritic cells, that play a critical role in activating the body’s adaptive immune system, and his subsequent research led to a new understanding of how they function.

“Ralph’s research has laid the foundation for numerous discoveries in the critically important field of immunology, and it has led to innovative new approaches in how we treat cancer, infectious diseases and disorders of the immune system,” said Marc Tessier-Lavigne, the president of Rockefeller University, in a statement published on the university’s Web site.

       

Dr. Steinman, who had been suffering from pancreatic cancer for four years, had been undergoing treatment using a pioneering immunotherapy based on his own research. Dendritic cells from his body were deployed to mount an assault on his cancer.

“He was very enthusiastic about the possibilities of immunotherapy,” Lesley Steinman said. “As soon as he was diagnosed, he said, ‘I’m going to get right on this with some things I’ve been working on.’ ”

Dr. Steinman’s research extended the insights made possible by Dr. Hoffmann’s discovery, in 1996, of cell receptors in fruit flies that are activated by pathogenic bacteria or fungi, and Dr. Beutler’s identification of cell receptors in mice, genetically similar to the receptors in fruit flies, that can cause septic shock when stimulated.

The receptors studied by Dr. Hoffmann and Dr. Beutler act as a first line of defense in the immune response by recognizing potentially harmful bacteria and other microorganisms. Dr. Steinman focused on the dendritic cells that play a critical role in adaptive immunity, activating T-cells that help the body mount a defense against infections that breach the first line of defense.

       

Dr. Steinman was awarded half the prize, which totals $1.45 million, and the other half was divided between the two other winners, but the award was called into question because the rules governing the Nobel Prize do not allow it to be awarded posthumously unless death occurs after the announcement is made.

Citing this exception, the prize committee announced Monday that the award would stand. “An interpretation of the purpose of this rule leads to the conclusion that Ralph Steinman shall be awarded the 2011 Nobel Prize in Physiology or Medicine,” it said.

Ralph Marvin Steinman was born on Jan. 14, 1943, in Montreal. He received a bachelor of science degree from McGill University in 1963 and a degree from Harvard Medical School in 1968.

After completing an internship and residency at Massachusetts General Hospital, he joined Rockefeller University in 1970 as a postdoctoral fellow in the Laboratory of Cellular Physiology and Immunology. Working with Dr. Cohn, he began researching the primary white cells of the immune system — the large macrophages and the highly specific lymphocytes — which operate in a variety of ways to spot, apprehend and destroy infectious microorganisms and tumor cells.

       

He later concentrated on the role of dendritic cells in the onset of several immune responses, including graft rejection, resistance to tumors, autoimmune diseases and infections, including AIDS. He and Dr. Cohn coined the term, whose Greek root, “dendron,” or “tree,” refers to the branched projections that the cells develop.

Dr. Steinman lived in Westport, Conn. In addition to his daughter Lesley, of Seattle, he is survived by his wife, the former Claudia Hoeffel; his mother, Nettie, of Montreal; a son, Adam, of Brooklyn; another daughter, Alexis, of Los Angeles; two brothers, Seymour, of Montreal, and Mark, of Toronto; a sister, Joni, of Toronto; and three grandchildren.

 A version of this article appeared in print on October 4, 2011, on page A20 of the New York edition with the headline: Ralph M. Steinman, a Nobel Recipient For Research on Immunology, Dies at 68.

See link for Nobel prize announcement:-
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.html#


 This article taken from:-
 http://www.nytimes.com/2011/10/04/science/04steinman.html#h[]

Dr R Steinman - The Man behind Dendritic Cell Cancer Treatment

For his biography, see  http://lab.rockefeller.edu/steinman/drSteinman, copied below, before it is taken down or amended.

Biography of Ralph Steinman

Ralph M. Steinman, Henry G. Kunkel Professor at The Rockefeller University and a senior physician at The Rockefeller University Hospital, is a cell biologist whose research focuses on the immune system, including the human immune system in the setting of several diseases.

The body's immune defense system involves extremely complex interactions of specialized cells and molecules. Steinman's early research, conducted in collaboration with the late Zanvil A. Cohn at Rockefeller, began as an attempt to understand the primary white cells of the immune system — the large "eating" macrophages and the exquisitely specific lymphocytes, which operate in a variety of ways to spot, apprehend and destroy infectious microorganisms and tumor cells.

In the course of their studies, Steinman and Cohn discovered a previously unknown class of immune cells, which they called dendritic cells. Steinman's subsequent research points to dendritic cells as important and unique accessories in the onset of several immune responses, including clinically important situations such as graft rejection, resistance to tumors, autoimmune diseases, and infections including AIDS. In other words, when the immune system is presented with antigens in association with dendritic cells, a vigorous immune response ensues. ("Antigens" are the molecules on the surface of invader cells that are recognized by the body's lymphocytes, which are the cellular mediators of immunity.) Additionally, dendritic cells can be exploited during the development of many immunebased diseases.

Steinman heads the Laboratory of Cellular Physiology and Immunology at The Rockefeller University. His current research address the fundamental mechanisms of immunity and the interface of several disease states with the immune system, including studies aimed at developing vaccines and immune-based therapies for tumors, infections and autoimmune diseases. Steinman's research points to dendritic cells as critical sentinels of the immune system controlling many of their early responses from immune silencing (tolerance) to resistance (immunity).

Steinman was born in Montreal, Canada on January 14, 1943. He received a B.S. degree, with honors, from McGill University in 1963, and an M.D., magna cum laude, from Harvard Medical School in 1968. After completing an internship and residency at Massachusetts General Hospital, he joined The Rockefeller University in 1970 as a postdoctoral fellow in the Laboratory of Cellular Physiology and Immunology headed by Cohn and the late James G. Hirsch. He was appointed an assistant professor in 1972, associate professor in 1976, and professor in 1988. He was named Henry G. Kunkel Professor in 1995, and Director of the Christopher H. Browne Center for Immunology and Immune Diseases in 1998.

Steinman is editor of the Journal of Experimental Medicine and advisory editor of Human Immunology, the Journal of Clinical Immunology, the Journal of Immunological Methods, and the Proceedings of the National Academy of Sciences.

Steinman is a trustee of the Trudeau Institute, in Saranac Lake, NY, and serves as a scientific advisor to several organizations including the Charles A. Dana Foundation; a European consortium on the development of HIV vaccines; the Campbell Family Institute of Breast Cancer Research in Toronto, Canada; the M. D. Anderson Cancer Center for Immunology Research in Houston, TX; the RIKEN Center for Allergy and Immunology Research in Yokohama, Japan; and the CHAVI Center for HIV AIDS Vaccine Immunology, Durham, NC. Steinman is a member of the American Society of Clinical Investigation, the American Society of Cell Biology, the American Association of Immunologists, the Harvey, the Kunkel and Practitioner's Societies and the Society for Leukocyte Biology.

Steinman is a recipient of the Freidrich-Sasse, Emil von Behring, and Robert Koch Prizes, the Rudolf Virchow and Coley Medals, the New York City Mayor's Award, the Gairdner Foundation International Award, the Debrecen Award in Molecular Medicine, the Albert Lasker Award for Basic Medical Research and the Albany Medical Center Prize. He has been awarded honorary degrees from the University of Innsbruck, Free University of Brussels, Erlangen University, and the Mount Sinai School of Medicine. He is a corresponding fellow of the Royal Society of Edinburgh and a member of the National Academy of Sciences and its Institute of Medicine.

Steinman, a resident of Westport, Connecticut, is married to the former Claudia Hoeffel. They have three children: Adam, Alexis and Lesley.

October 1, 2009

 http://lab.rockefeller.edu/steinman/drSteinman

Dr R Steinman - Dendritic Cell Cancer Treatment

Sunday October 23, 2011

A cell of a discovery

Research following the discovery of dendritic cells 35 years ago is profoundly changing the science of immunology and its many interfaces with medicine.

DENDRITIC cells were discovered in 1973 by Ralph Steinman and Zanvil A. Cohn at the Rockefeller University. At the time, Steinman and Cohn were studying spleen cells to understand the induction of immune responses in a major lymphoid organ of the mouse.

They were aware from research in other laboratories that the development of immunity by mouse spleen required both lymphocytes and “accessory cells”, which were of uncertain identity and function. The accessory cells were thought to be typical macrophages (a type of white blood cell that engulfs and digests cellular debris and pathogens), but despite extensive laboratory experience with macrophages, Steinman and Cohn encountered a population of cells with unusual shapes and movements that had not been seen before. Because the cells had unusual tree-like or “dendritic” processes, Steinman named them “dendritic cells”
.
When Steinman evaluated this population of cells, they had little, if any, resemblance to the well-known macrophages. Accordingly, these cells were identified as novel cells having distinct properties, and eventually, functions.

Laboratories worldwide have studied dendritic cells and 
demonstrated their potent immune stimulatory functions.

Functional studies revealed their potent stimulatory role in immune function. Subsets of dendritic cells were identified, each having its own surface markers. Dendritic cells were seen in the T-cell areas of organs of the lymph system, the ideal location for initiating immunity. Laboratories worldwide started to study dendritic cells and demonstrate their potent immune stimulatory functions.

Star performers

Dendritic cells exist throughout the body. As seen in the tissues of skin, airway, and lymphoid organs, the cells are shaped like stars.

When isolated and spun onto slides, they display numerous fine branches. When looked at with an electron microscope, these branches are long and thin and can appear spiny or sheet-like. When alive and viewed by phase-contrast microscopy, dendritic cells extend large, delicate, sheet-like processes that can drape around the cell bodies of lymphocytes, which can bind to dendritic cells in large numbers.

The processes of dendritic cells continually form, bend, and retract. The tentacular shape and constant movement of dendritic cells fit precisely with their functions: to snatch invaders, embrace other cells of the immune system, and deliver the antigens and other signals that are needed to initiate vigorous responses.

Dendritic cells are found in lymphoid or immune organs, and at the interfaces between our bodies and the environment. The epidermal layer of the skin has a rich network of dendritic cells, which were first described in 1868 by a medical student in Germany, Paul Langerhans, who thought they were part of the nervous system.

In addition, dendritic cells line the surfaces of the airway and intestine, where they function as sentinels that sample proteins and particulates from the environment. It took until 1973 for Ralph Steinman and Zanvil Cohn to begin the modern era of dendritic cell science by showing that dendritic cells are a new class of white blood cells with a number of distinctive features and functions.

Dendritic cells arise from proliferating progenitors, primarily in the bone marrow, a process driven by chemical messengers, to become precursors such as the monocytes in blood, and these in turn give rise to immature dendritic cells.

The cells develop further or mature as they capture, process antigens, and migrate under the influence of other chemical messengers to tissues such as spleen and lymph nodes. There they attract and stimulate T and B cells to produce strong immune responses.

The dendritic cells die unless they receive signals from the activated T cells to prolong their life span. These previously unknown cells are now recognised as controllers that both create and curtail immunity.

In the steady state, and when the body is challenged by injury and infection, dendritic cells travel from body surfaces to immune or lymphoid tissues, where they home to regions rich in T cells. There, dendritic cells deliver two types of information: they display antigens, the substances that are recognised by T cells, and they alert these lymphocytes to the presence of injury or infection.
This directs the T cells to make an immune response that is matched to the challenge at hand.

Orchestrating immunity

Dendritic cells are a critical, and previously missing, link in the immune system. As sentinels, dendritic cells patrol the body seeking out foreign invaders, whether these are bacteria, viruses, or dangerous toxins.

After capturing the invaders, often termed antigens, dendritic cells convert them into smaller pieces and display the antigenic fragments on their cell surfaces.

The dendritic cells then travel to lymph nodes or the spleen where they stimulate other cells of the immune system to make vigorous responses, in particular, the B cells that make antibodies to neutralise the invaders, and killer T cells that launch specific attacks to destroy them.

New research is showing that dendritic cells are equally responsible for a seemingly opposite role in health called immune tolerance, which silences dangerous immune cells and prevents them from attacking innocuous materials in the body or the body’s own tissues.

The use of dendritic cells in cancer treatment is
an example of the impact of Steinman’s discovery.

 

Given these functions of dendritic cells, it is not surprising that they are the subject of much research in medicine. During infection and cancer, microbes and tumours exploit dendritic cells to evade immunity, but dendritic cells can also capture infection- and tumour-derived protein and lipid antigens and generate resistance, including new strategies for vaccines.

During allergy, autoimmunity and transplantation, dendritic cells instigate unwanted innate and adaptive responses that cause disease, but dendritic cells also can suppress these conditions.
In other words, dendritic cells, because they orchestrate innate and adaptive immune responses, are an unavoidable target in studying disease and in designing treatments.

Studies of immunology and disease have long focused on antigens and lymphocytes (B cells, T cells, NK cells) as the mediators of immune responses. However, accumulating evidence shows that dendritic cells provide vital links between antigens and all types of lymphocytes.

Migration of dendritic cells

Before dendritic cells can perform their major function – to initiate the immune response – two events typically need to take place, migration and maturation.

Most dendritic cells circulate in the body in an “immature” state and lack many features that lead to a strong T-cell response. Immature dendritic cells are, nonetheless, ideally poised and well equipped to capture microbes and other sources of antigens.

Dendritic cells are stationed at surfaces where antigens gain access to the body. For example, they are positioned in the skin, where they are termed Langerhans cells. There, dendritic cells are involved with two of the body’s most powerful immune responses, organ transplantation and contact allergy.

Dendritic cells are also located in lymphatic vessels, which allow cells to move from peripheral tissues to lymphoid organs. There, they can encounter immune lymphocytes, selecting those cells that specifically recognise the antigens being carried by the dendritic cells.

At this point, the immune response begins. The lymphocytes begin to grow vigorously and they start to produce products that will serve to eliminate infections and other sources of antigens.

Initiating the immune response

Dendritic cells are professional antigen processing cells. They have a number of receptors that enhance the uptake of antigens, and they are specialised to convert these antigens into complexes that can be recognised by lymphocytes.

However, the dendritic cells need to do more than present antigens to T cells. They are also potent accessory cells that directly trigger and control responses by T cells and by all other types of lymphocytes.

Some early studies showed that dendritic cells carry on their surface high levels of major histocompatibility complex (MHC) products, which are critically recognised by T-lymphocytes. The high levels of MHC led Steinman to test these cells in the mixed leukocyte reaction (MLR), a well-known clinical assay for identifying the compatibility of tissue transplants between donors and recipients.

At the time, this assay was known as mixed “lymphocyte” reaction, because it presumed that the B lymphocytes were presenting MHC products from the organ transplant donor to the recipient’s T cells.
Instead, Steinman found that dendritic cells were the major stimulators and were unusually potent. In fact, a dendritic cell to T cell ratio of one to 100 sufficed to initiate vigorous and optimal responses.
Moreover, the dendritic cells directly activated both the subset of helper T cells as well as the killer T cells. Once activated by dendritic cells, the T cells could also interact vigorously with other antigen-presenting B cells and macrophages to produce additional immune responses from these cells.

The term “accessory” has since been replaced by the terms “professional” and “co-stimulatory”, but the basic concept is unchanged. Dendritic cells provide the T cells with needed accessory or co-stimulatory substances, in addition to giving them a signal to begin to grow and function.

Dendritic cells also influence the type or quality of the response. A T cell, for example, has to know whether the enemy is a virus that needs to be resisted with its own interferons and cytolytic molecules, or whether the pathogen is a parasite that requires a different set of protective cells to respond with antibodies.

Therefore, when dendritic cells migrate to the body’s pool of T cells areas in the lymph nodes, they need to orchestrate two fundamental components from the repertoire of lymphocyte functions.

First the dendritic cells select the specific T cells from the assembled repertoire that recognise the specific peptide information the dendritic cells are carrying. Amazingly, only one in 10,000-100,000 of the T cells in that repertoire are able to respond to this information.

Second, the rare T cells that are selected for expansion then differentiate into helper and killer T cells that have the appropriate functions to eliminate the infection or disease-causing stimulus.

After these two decisions have been made, the newly activated T cells leave the lymph node to return to the body surface or peripheral organ to eliminate the antigens.

For orchestrating these various processes efficiently and precisely, the dendritic cells are considered to be “conductors of the immune orchestra”.

Dendritic cells and immune tolerance

Most studies have focused on the dendritic cells’ role in activating T cells to resist foreign antigens, especially infections.

Recent research in Steinman’s laboratory, in close collaboration with other laboratories at Rockefeller, is showing that dendritic cells can also make the immune system tolerate harmless antigens, including those from the body’s own tissues, cells, and proteins. This is necessary to keep the body from making an immune attack on itself.

The dendritic cell system appears to play a pivotal role in two kinds of immune tolerance. Usually, when young T cells are launched from the thymus, the dendritic cells participate in eliminating those cells bearing “self-reactive antigens” before they can harm the body’s own tissues, a mechanism known as central tolerance.

Since some T cells may slip through this process, or other self-antigens do not access the thymus, or still others arise later in life, the dendritic cells also participate in the mechanism known as peripheral tolerance that restrains their activity.

In the absence of infection or inflammation, the dendritic cells are in an immature state, but they are not quiescent. Like perpetual custodians, they clean house and collect trash.

Sweeping non-stop through tissues and into lymphoid organs, the dendritic cells capture all kinds of antigens – the harmless self-antigens, those from dying cells, and the many non-pathogenic antigens encountered from the environment.

Two mechanisms have been identified that allow dendritic cells to induce tolerance. The antigen-loaded immature dendritic cells silence T cells by either deleting them or by inducing regulatory T cells that suppress the reactions of other immune cells.

When the dendritic cells subsequently mature in response to infection, the pre-existing tolerance nullifies any reaction to innocuous antigens and allows the dendritic cells to focus the immune response on the pathogen.

Other current research is providing clues about the dendritic cells’ occasional failures to maintain tolerance. Failure to silence the immune system can lead to autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.

If dendritic cells are too tolerant, this can create a permissive environment for chronic infectious agents, such as HIV. Infections and tumours can exploit the tolerogenic function of dendritic cells, shut down the normal immune defenses, and perpetuate disease.

References:

1. Steinman, R.M., and H. Hemmi. 2006. Dendritic cells: translating innate to adaptive immunity. In Innate Imunity to Imunological Memory. eds Pulendran, B., and R. Ahmed, Current Topics in Microbiology and Immunology. 311, 17-58. (Berlin Heidelberg: Springer-Verlag).
2. Silverstein, S.C., Steinman, R.M., and Cohn, Z.A. Endocytosis (review). Ann. Rev. Biochem. 46: 669-722, 1977.
3. Steinman, R.M., and Nussenzweig, M.C. Dendritic cells: features and functions (review). Immun. Rev. 53: 127-147, 1980.
4. Steinman, R.M. Dendritic cells (review). Transplant. 31: 151-155, 1981.
5. Tew, J.G., Thorbecke, J., and Steinman, R.M. Dendritic cells in the immune response: characteristics and recommended nomenclature. J. Reticuloendothelial Soc. 31: 371-380, 1982.

http://thestar.com.my/health/story.asp?file=/2011/10/23/health/9730368&sec=health