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Fall 2009
Inside…
Leukemia Cells Flash
Fake Protein ‘ID’ to Dupe
the Immune System
Scientific American...................2
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The Dana Foundation’s
IMMUNOLOGY
IN THE
Killer Parasites’ Genes Decoded
BBC News................................3
How the Humble Hydrangea
Shrub Could Hold the
Key to Curing MS,
Diabetes and Arthritis
The Daily Mail (London).............4
Professor Jean Dausset
The Daily Telegraph (London).....4
FROM THE UNIVERSITIES:
Immune System Key
Discovered
Monash University..............5
FROM THE JOURNALS:
A Protein Supports
Interferons’ Protective
Function
Immunity...........................5
Receptor Helps Us Fight
Respiratory Virus Infection
Nature Immunology.............6
Immunology
in the News
Vol. 9, No. 3
NEWS
Swine Flu Vaccine Works with One Shot
Protection occurs
in 10 days, study finds.
By Rob Stein
The Washington Post
September 11, 2009
The swine flu vaccine appears to work for adults with
just one shot and within 10 days, a major boost to the
widespread immunization campaign that officials are planning to protect people against the first influenza pandemic
in 41 years, researchers reported Thursday [Sept. 10].
Preliminary data from an Australian study found that a
single standard dose could produce an immune response
in more than 96 percent of recipients, and U.S. studies
indicate that the protection occurs in eight to 10 days, scientists reported. The vaccine also appeared safe.
The eagerly awaited findings mark the first results from
a flurry of studies that scientists have been rushing to conduct to develop a swine flu vaccine. The findings indicate
that plans to inoculate millions of Americans—the most
ambitious vaccine campaign in U.S. history—and others
worldwide could occur much more quickly and require far
less vaccine than officials had feared.
“This is good news,” said Anthony S. Fauci of the
National Institutes of Health, which is leading the U.S.
efforts to develop the vaccine. “This is very good news. If
you needed two doses, that would be a major strain on vaccine supplies nationally and globally.”
The Department of Health and Human Services plans to
release preliminary results Friday [Sept. 11] of its vaccine
studies. Fauci would not disclose any details except to say
“This is very good news. If you needed
two doses, that would be a major
strain on vaccine supplies nationally
and globally.”
—Anthony S. Fauci, director, National
Institute of Allergy and Infectious Diseases
that the findings are consistent with the Australian study
involving 240 patients and that they show the response
occurs even more quickly—eight to 10 days—than the 21
days that study found.
“The NIH clinical trials results verify and corroborate
the exciting results” from the Australian study, Fauci said,
adding that there is no reason to suspect vaccine produced
(See Swine flu vaccine, pg. 2) 4
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Genetic Links to Rare Liver Disease Found
Understanding primary biliary
cirrhosis may lead to new
treatments, researchers say.
By Steven Reinberg
HealthDay News
June 10, 2009
Scientists have found genetic variations that appear to
increase the risk of developing primary biliary cirrhosis, a
baffling disease that can destroy the liver.
Primary biliary cirrhosis is an autoimmune disorder
that blocks the bile ducts in the liver. It is a condition
that mostly affects women, striking about one in 2,500
Americans. The current treatment works in about half of
patients. The other half will need a liver transplant at some
time in the course of the disease, according to researchers, but the condition has been known to return even
after transplantation.
“We have known virtually nothing about what causes
primary biliary cirrhosis,” said lead researcher Dr. Katherine
Siminovitch, a senior investigator at the Samuel Lunenfeld
Research Institute of Mount Sinai Hospital in Toronto.
“What we have found are some of the major genetic causes
of the disease,” she said.
“About half the patients will respond to that treatment, but half won’t. Of the half that won’t, some will
be OK, but many won’t and they will have to have a liver
transplant,” she explained. “So, we urgently need a new
medical therapy.”
Siminovitch thinks the findings indicate that drugs
already being used to treat other autoimmune diseases
might work for primary biliary cirrhosis. “This is terrific
for us, because we can now begin to do early trials to see if
it will change the outcome of this disease,” she said.
It is also possible new, more targeted drugs could be
made to treat the disease, she said.
In addition, the findings may also make it possible to
predict who is likely to develop the disease and possibly
prevent it, Siminovitch said.
The report is published in the June 11 issue of the New
England Journal of Medicine.
For the study, Siminovitch’s team analyzed blood samples from patients with primary biliary cirrhosis as well as
samples from people who did not have the condition.
In the first phase of the study, researchers did a genomewide analysis, comparing the genotypes of 536 patients
with primary biliary cirrhosis with 1,536 people who did
not have the disease. In the next phase, researchers conducted genetic mapping to confirm the initial results and
to identify genetic variations closely associated with primary biliary cirrhosis.
“I don’t think this is going to translate
to a significant change in therapy in
the near term. But it opens the door
to scientific investigation of other
therapies.”
—Scott L. Friedman, chief, division of liver
diseases, Mount Sinai School of Medicine
Siminovitch’s group found variants of two genes, interleukin 12A (IL12A) and interleukin 12RB2 (IL12RB2), that
were strongly linked with the disease. In addition, they
confirmed that the human leukocyte antigen (HLA) area
of the genome is associated with primary biliary cirrhosis,
a link that had been identified before.
Dr. Scott L. Friedman, chief of the division of liver diseases at Mount Sinai School of Medicine in New York City
and president of the American Association for the Study of
Liver Diseases, said the discoveries are an important step
in understanding this disease, but the interaction between
(See Liver Disease Genes, pg. 2) 4
Immunology in the News
Fall 2009
1
(Swine flu vaccine, from pg. 1) 4
by any of the five companies making supplies for
the United States would be different.
“They are really the same. The seed virus is the
same. They are made the same way,” said Fauci, who
heads the NIH’s National Institute of Allergy and
Infectious Diseases. “Even though they are from
different companies, you don’t usually see differences from one company to another.”
Results from additional studies will be needed to
see whether children and other special groups need
one or two doses, he added. Young children usually
need two seasonal flu shots because they have not
been exposed to the virus before.
The National Institutes of Health is conducting a series of studies testing the swine flu vaccine
on 4,600 volunteers, including adults, children and
pregnant women.
“We will hopefully get some information
about kids from our trial in a couple of weeks,”
Fauci said.
The results from CSL Ltd. in Australia will be
published in the New England Journal of Medicine
but were released online Thursday because of their
urgency. The study involved a standard dose of 15
micrograms of vaccine and found that the vaccine
produced a strong immune response in more than
96 percent of the subjects.
“The concern that people had was that because
this was a new virus that this would require two
doses for everyone. That would have created a
problem of supply,” Fauci said. “This greatly alleviates the problem.”
The findings also mean that adults will not
have to return for a booster shot, which would
(Liver Disease Genes, from pg. 1) 4
genes and environmental triggers is complicated.
“I don’t think this is going to translate to a significant change in therapy in the near term,” Friedman
said. “But it opens the door to scientific investigation of other therapies.”
Dr. Nathan M. Bass, medical director of the
liver transplant service for adults at University of
California, San Francisco, noted that the study was
have greatly complicated the already daunting
vaccine effort.
The results were welcomed by officials at the
World Health Organization, which has been particularly concerned about providing enough vaccine to poorer countries.
“If this is true, this is quite encouraging,” said
Gregory Hartl, a WHO spokesman. “If you only
need one shot instead of two, the vaccine will go
twice as far. Twice as many people will be able to
get the vaccine.”
The Australian findings were released with a second study from the University of Leicester. In that
study, 175 British volunteers ages 18 to 50 received
another version of the vaccine made by Novartis
Corp.—either 7.5 or 15 micrograms of vaccine, along
with a substance known as an adjuvant, which can
boost a vaccine’s effectiveness. The study found that
either dose produced adequate immune response
within 14 days. Adjuvants have been used widely in
Europe, which could extend the supplies even further. U.S. officials were considering approving an
adjuvant in this country if supplies ran low.
The strong immune response was somewhat
puzzling, Fauci said, especially given the results of
a third paper, from the federal Centers for Disease
Control and Prevention, that found exposure to the
seasonal flu vaccine offered no protection against
the swine flu.
“The responses you’re seeing suggest that somehow or other there has been some previous exposure to similar viruses or some vaccine that is
responsible,” Fauci said.
The new virus, known as H1N1, emerged last
spring in Mexico and quickly spread around the
world, causing at least 2,837 deaths, including at
least 556 in the United States so far, and prompting WHO to declare the first influenza pandemic
since 1968.
The pandemic has sparked a flurry of emergency planning, including a rushed program to
develop a vaccine. Because the virus is new, experts
thought most people would need one shot followed by a booster several weeks later to produce
sufficient protection.
Because the first batches of vaccine are not
expected until mid-October, that meant the first
Americans would not be protected until after the
outbreak might have peaked.
The federal government has already spent $2 billion to buy 195 million doses of vaccine and plans
to purchase enough to vaccinate every American
if necessary.
Unlike the typical flu, the H1N1 virus has been
affecting children and young adults much more
often than the seasonal flu.
As a result, the top priority for vaccination will
be everyone age 6 months to 24 years and people
who care for children younger than 6 months.
Pregnant women, health-care workers and adults
ages 25 to 64 with health problems that put them
at risk for complications are also being given
high priority.
The results from the H1N1 vaccine trials came
as top U.S. health officials urged Americans to get
vaccinated against the seasonal flu.
the first of its kind in primary biliary cirrhosis “that
appears to shed light on the mechanism of this
uncommon, but puzzling, disease.”
“Primary biliary cirrhosis is a distressing condition that mainly affects women, and which has
eluded our understanding despite many years of
research, although a disorder in immune regulation
has been suspected for some time,” Bass said.
“The findings of this study suggest that the
key problem may rest within the interleukin-12
immunoregulatory signaling pathway, offering a
novel new insight into the pathogenesis of primary
biliary cirrhosis, with the attendant opportunity to
better understand the key mechanisms in the evolution and progression of this disease, and to ultimately develop new therapies based on this understanding,” he said.
From The Washington Post, September 11 © 2009 The
Washington Post All rights reserved. Used by permission
and protected by the Copyright Laws of the United States.
The printing, copying, redistribution of the Material
without express written permission is prohibited.
Copyright 2009 ScoutNews, LLC.
Reprinted by permission.
Leukemia Cells Flash Fake Protein ‘ID’ to Dupe the Immune System
A crucial protein on the surfaces of malignant cells shields them from
destruction, but it could also provide a new way to attack cancer.
By Mandy Kendrick
Scientific American
August 6, 2009
Bone marrow continually makes blood stem
cells, which turn into new blood cells to replace
spent ones, but the process is not perfect: Some
blood stem cells can develop into abnormal versions, although the immune system usually stamps
them out. In acute myeloid leukemia, however, the
immune system seems unable to recognize malformed blood cells, which proliferate quickly and
become cancerous.
Researchers from Stanford University recently
uncovered a mechanism by which these leukemia
cells elude the immune system. As described in two
papers in Cell, the cancerous pretenders use the
same “ID” that blood stem cells use to travel around
the body. Their findings may not only have implications for the treatment of this form of leukemia but
possibly for other cancers, as well.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. The average
age of sufferers is 67, according to the American
Cancer Society, and the disease has a dismal prognosis: the National Cancer Institute estimates a
five-year survival rate of 22.8 percent.
Crowding out healthy cells
According to Ravindra Majeti, a hematologist
at Stanford School of Medicine and an author on
both studies, the problem is not necessarily the
2
Immunology in the News
Fall 2009
presence of the leukemia cells but how these cells
interfere with blood-making. He notes that a person’s bone marrow makes approximately 100 billion
new blood cells daily. AML cells grow uncontrollably and over time crowd out the progenitor blood
stem cells made by the marrow. “So most of the real
problems,” including death, are a result of the body
“no longer making blood,” Majeti says, and not
because of the cancer cells themselves.
The findings may have implications
not only for the treatment of acute
myeloid leukemia but possibly for
other cancers, as well.
Once made, these cancerous cells express a protein called CD47 on their surfaces. This protein,
which is the same as that shown by normal blood
stem cells, serves as a forged passport of sorts that
it presents to leave the bone marrow. The security
guards of the immune system, the macrophages,
sense the CD47 protein and consequently pass the
cell as “safe.” Once through the checkpoint, the
malignant cells can enter the blood stream and then
can spread throughout the body.
Furthermore, AML cells produce more CD47
than healthy cells do to mask themselves, ensuring
complete protection from the macrophages. And in
previous work the group has shown that the more
CD47 produced, the worse the prognosis.
Exploiting the CD47 protein shield
Although CD47 enables cancerous cells to evade
the immune system, the protein could also lead
to their undoing. In preliminary tests with mice
infected with human AML, the Stanford group
found an antibody that attaches to the CD47 protein, thereby masking this safety signal. As a result,
macrophages attacked and removed the cells. The
antibody does not go after normal blood stem
cells as frequently, because those cells only express
CD47 when they are on the move.
The researchers found a second method by
which they could exploit the excessive amount
of CD47. They were able to separate the cancerous cells from the noncancerous stem cells using
a technique called fluorescence activated cell sorting. To do this, the group added a fluorophore, a
molecule that emits fluorescent light, to the CD47
antibody. The fluorescing CD47 antibody then
attached to any cells that have CD47 present. The
cell sorter could separate cells with more fluorescence (the cancerous cells) from those with less
fluorescence (noncancerous stem cells). The group
hopes that this technique of isolating and removing
the leukemia cells can help improve the results of
autologous stem cell transplant—using a patient’s
own stem cells to restore the blood-producing system after chemotherapy or radiation.
Copyright 2009 Scientific American.
Reprinted by permission.
A Clue in the Multiple Sclerosis Mystery
Ralph Steinman, M.D.
O
ne of the most challenging links between
immunology and the nervous system is
the disease multiple sclerosis (MS). In people
with MS, the immune system attacks myelin,
an important material that insulates our nerves
and helps conduct electrical signals from cell
to cell.
Scientists do not yet understand what triggers the attack on myelin. However, in the last
two years a sea change has occurred in our
understanding of the nature of the “self ” attack
after it begins. This new understanding, many
of us believe, will lead to new therapies for MS.
In this resurging field, a molecule called interleukin-17, or IL-17, is a fulcrum. IL-17 first came on the scene in 1996 in the lab of Jacques Banchereau,
this year’s winner of the American Association of Immunologists–Dana
Foundation Award in Human Immunology Research.
The Banchereau team was not, at the time, focused on MS, but rather
on molecules that drive inflammation more broadly. They reported in the
Journal of Experimental Medicine their discovery of a new molecule—IL-17—
which stimulated the production of phagocytes (white blood cells) to defend
against infection.
Shortly thereafter, Jay Kolls, now at Louisiana State University, began
to identify the helpful roles of IL-17. Kolls was trying to figure out how
the body defends against a difficult pneumonia caused by the organism
Klebsiella pneumoniae. In 2001, Kolls proved that IL-17 was needed to
defend against this bug.
The IL-17 field has taken off in the years since. Scientists identified a major
new pathway in which immune T cells—a subtype of white blood cells—
commit to making IL-17. These “Th17” cells help our bodies resist not only
Klebsiella, but other scourges such as Staphylococcus aureus and the fungus
Candida albicans. Th17 cells and IL-17 are important; people with genetic
deficiencies in the Th17 pathway suffer from corresponding infections.
That’s the protective role of IL-17. But what about the downside?
Thanks to more superb immunology from several quarters, we now realize that Th17 cells bring about certain types of autoimmunity, and MS is a
leading example.
Much of current MS research on IL-17 is in a mouse model that has
been vital for the development of most existing therapies for human MS.
In addition, scientists already are looking for Th17 cells in samples from
MS patients.
Notably, immunologists quickly figured out some key molecules that
teach T cells to become Th17 in nature. They identified other interleukins,
such as IL-6 and IL-23, that drive the Th17 cells.
Furthermore, the intricate genetic program of the Th17 cell is being illuminated. This program allows Th17 cells to make many products in addition
to IL-17 whose relevance was previously obscure. Now there is great potential to develop agents to block the elements of the newly discovered Th17
pathway in people with MS and other forms of autoimmunity.
A sea change has occurred in our understanding
of the nature of the “self” attack after it begins.
This new understanding, many of us believe, will
lead to new therapies for MS.
But what about the enigma? How does this Th17 pathway get triggered
in the first place, especially to focus on the brain? Federica Sallusto and her
colleagues identified a major clue in findings they published in the May
Nature Immunology.
This Swiss team knew that Th17 cells had a special receptor called CCR6
that guides the cells’ movement to wherever an attracting molecule, CCL20,
is made. Normally, CCR6 and CCL20 work together to direct Th17 cells
to body surfaces to fight infections such as K. pneumoniae, S. aureus and
C. albicans.
The downside is that parts of the brain, particularly the choroid plexus,
are rich in CCL20 and thus also attract Th17 cells. The Nature Immunology
research showed that if a mouse has Th17 cells, but these cells cannot get
into the choroid plexus, MS is blocked. The step that enables Th17 to enter
the brain looks like a pivotal one for figuring out how the autoimmune
attack in the brain begins.
Clearly the research community is making significant discoveries in its
longstanding commitment to figure out MS and to identify new treatments—
beginning with steps toward understanding, once and for all, how it starts.
Ralph Steinman, M.D., is professor and senior physician at The Rockefeller
University in New York City, and is the recipient of the 2007 Albert Lasker
Award for Basic Medical Research. He serves as scientific consultant for the
Dana Foundation and scientific advisor for Immunology in the News.
Killer Parasites’ Genes Decoded
BBC News
July 16, 2009
Scientists have decoded the genetic blueprint of
two parasitic flatworms responsible for thousands of
deaths worldwide every year.
Schistosoma mansoni and Schistosoma japonicum both cause the debilitating disease schistosomiasis, otherwise known as Bilharzia.
“This genome sequence catapults
schistosomiasis research into a
new era. It provides a foundation
for understanding aspects of the
parasite’s complex biology as well
as a vehicle to immediately identify
new targets for drug treatment.”
—Matthew Berriman, researcher,
Wellcome Trust Sanger Institute
The work has already uncovered targets for
new treatments for the disease, which causes fever
and fatigue.
The international study features in the
journal Nature.
Schistosomiasis cases top 200 million every year,
with 20 million people seriously disabled by severe
anemia, chronic diarrhea, internal bleeding and
organ damage caused by the worms and their eggs,
or the immune system reactions they provoke.
In sub-Saharan Africa alone it kills 280,000 people each year.
Dr. Anthony Fauci, director of the U.S. National
Institute of Allergy and Infectious Diseases, said:
“Chronic infection with Schistosoma parasites makes
life miserable for millions of people in tropical countries around the globe, and can lead to death.
“New drugs and other interventions are badly
needed to reduce the impact of a disease that lowers
quality of life and slows economic development.”
Since the 1980s, a cheap drug, praziquantel, has
been widely distributed to areas where the disease
is common.
However, although the drug is effective, it does
not prevent a person becoming re-infected. There
is also a risk that the parasites will become resistant
to it.
Therefore, developing new drug targets
is important.
Enzyme targets
Researchers working on the genetic blueprint of
S. mansoni, the most widespread of the schistosomiasis parasites, found that it was made up of 11,809
genes—about 10 times the size of the malaria parasite genome.
In particular, they identified a large number of genes that produce enzymes that break
down proteins, giving the parasite its ability bore
through tissue.
Subsequent analysis revealed 120 enzymes that
could potentially be targeted with drugs to disrupt
the worm’s metabolism.
The researchers also identified 66 drugs
already on the market that might also be effective
against schistosomiasis.
The analysis also found that S. mansoni lacks
a key enzyme needed to make essential fats and
must rely on its host to provide these—revealing a
potential Achilles’ heel that could be exploited for
CDC.gov
In S. mansoni, the smaller female parasite lives inside
the thicker male.
drug development.
Researcher Dr. Matthew Berriman, of the
Wellcome Trust Sanger Institute, said: “This genome
sequence catapults schistosomiasis research into a
new era.
“It provides a foundation for understanding
aspects of the parasite’s complex biology as well as a
vehicle to immediately identify new targets for drug
treatment.”
Fellow researcher Dr. Najib El-Sayed, of the
University of Maryland, said: “The genome sequence
has given us, for the first time, a comprehensive view
of the engines that drive the parasite, the strategies
that allow it to survive in us, its human host.
“It is a catalogue of opportunities.”
In a separate study, scientists discovered that S.
japonicum, which is largely confined to Asia, had
even more genes.
Copyright 2009 BBC News, http://news.bbc.co.uk.
Reprinted by permission.
Immunology in the News
Fall 2009
3
How the Humble Hydrangea Shrub
Could Hold the Key to Curing
MS, Diabetes and Arthritis
Fiona MacRae
The Daily Mail (London)
June 5, 2009
Its bright and beautiful flowers bring a splash of
color to gardens all over Britain.
But it seems the hydrangea is more than just a
pretty bloom.
A drug made from its roots could be used to
treat a raft of common diseases, researchers say.
“Halofuginone may herald a
revolution in the treatment of
certain types of autoimmune and
inflammatory diseases.”
—Anjana Rao, Children’s
Hospital, Boston
The colorful shrub—a staple of Chinese medicine—has the power to “revolutionize” the treatment
of multiple sclerosis, psoriasis and some forms of
diabetes and arthritis, scientists claimed yesterday.
These diseases occur when the immune system
attacks the body.
Existing treatments are expensive, have to be
injected, and do not address the biological cause of
the problem.
Powerful drugs that suppress the immune system can be used as a last resort but leave patients at
risk of infections and other serious side effects.
Now it appears that a medicine derived from
Obituary
Professor
Jean Dausset
The Daily Telegraph (London)
June 23, 2009
Professor Jean Dausset, who has died aged
92, was a Nobel Prize-winning immunologist
whose pioneering work helped verify the compatibility of donor and recipient in organ and
bone-marrow transplants; his work on genetics
helped establish the field of “predictive medicine,”
which identifies the predisposition of individuals to
certain diseases.
Dausset won the Nobel Prize for Medicine
in 1980 (shared with George Snell and Baruj
Benacerraf ) for a lifetime’s work, the crowning
achievement of which was his contribution to the
identification of the genetic system known as HLA,
for human leukocyte antigen.
Identifying the HLA system, by which human
tissues belong to compatible and incompatible
groups just as blood cells do, was a crucial step
forward for transplants. Until Dausset’s discovery,
transplants were often marked by organ rejection
and short life expectancy for the patient.
But identifying HLA had an effect well beyond
the already substantial impact on transplants. It
became clear that these were the key genes controlling immunity. Their effects are visible in susceptibility to so-called “autoimmune diseases” such as
multiple sclerosis, rheumatoid arthritis and insulindependent diabetes, to infectious diseases such as
HIV/Aids and to various cancers.
According to Dausset’s colleague Laurent Degos,
the nature of HLA also meant that it enabled the
tracking of genetic heritage in groups of people and
was therefore “a precise tool to understand migration and blood relations.”
It was with this in mind, that, shortly before he
4
Immunology in the News
Fall 2009
the hydrangea’s root could offer an
alternative.
Experiments found that it blocked
the formation of a type of white blood
cell involved in autoimmune disease.
Crucially, the drug does not seem
to affect other kinds of cells vital to
the body’s defenses— meaning it does
not otherwise inhibit the immune system. Mice with a multiple sclerosis-like disease were far less severely
affected when given low doses of the
hydrangea-based drug, which is called
halofuginone, the journal Science
reported.
Halofuginone is already used to
treat a rare autoimmune disease that
affects the skin and internal organs.
Much more research would be
needed for it to be given the green
light to treat other conditions such as
rheumatoid arthritis and diabetes.
However, scientists say it is a promising avenue of research.
Dr. Anjana Rao, of the Children’s
Hospital in Boston in the U.S., said:
“Halofuginone may herald a revoluZuma press
tion in the treatment of certain types
Hydrangea: The common shrub could hold the key to combating common autoimmune diseases.
of autoimmune and inflammatory
diseases.”
Her fellow researcher Dr. Mark Sundrud added:
medicine and is also a traditional medicine of
“This is really the first description of a small moleNorth American Cherokee Indians.
cule that interferes with autoimmune pathology but
An extract of hydrangea leaf is also said to have
is not a general immune suppressant.”
anti-malarial properties.
Hydrangea root has traditionally been used to
Copyright 2009 Daily Mail/ZUMA Press.
relieve inflammation and “cleanse” the joints.
Reprinted by permission.
It is one of the 50 staple herbs of Chinese
retired to live permanently in Majorca in 2007, he
claimed that one of the four realms to which he had
made a significant contribution was “anthropology.”
The other three were: “Transplantation, predictive
medicine and immune response.”
Jean Baptiste Gabriel Joachim Dausset was born
on October 19, 1916, in Toulouse. His father was a
captain in the French army, serving as a doctor, a
career for which Jean was soon marked out. Jean
was brought up in Biarritz, until the Daussets settled in Paris when he was 11. It was with a certain
inevitability that he began medical studies, which
he was completing at the outbreak of war in 1939.
Identifying the HLA system, by
which human tissues belong to
compatible and incompatible
groups just as blood cells do,
was a crucial step forward
for transplants.
He was called up to serve as a doctor in Rennes,
then Autun, from which he retreated on his motorcycle as the Germans invaded in 1940. His unit fell
back to the Alps, and, in the ensuing chaos, Dausset
found himself back in Toulouse, from where he
headed to North Africa. He made it to Algeria
before the French defeat was completed, and he
was demobilized.
Returning to Paris, he began his medical career.
There he met a countess from the Caucasus who
was recruiting volunteers to man ambulances in
Morocco, a country that Dausset had already toured
on his motorcycle before the outbreak of war.
Dausset began his irregular ambulance service in
1942, wearing flowing white silk robes in the Arab
style, which were emblazoned with the countess’s
coat of arms. With the Allied landing in 1942, the
ambulance unit joined regular forces and headed
to the thick of the fighting in Tunisia. Such was the
rivalry between Free French generals Leclerc and
Giraud, Dausset remembered, that a unit attached
to one once loudly played music to drown out the
speech of an officer attached to the other.
Dausset, who spent most of his career in research,
found working on the front line “horrible.”
“The ambulances arrived full of blood,” he
recalled later. “I saw my first casualties: Germans,
Italians, Arabs. Bizarrely, some of the German
wounded refused blood transfusions from Italians,
but didn’t mind it from Jews….”
In 1944, in the middle of the V-1 bombardment,
Dausset got himself transferred to London, where
he was issued a medical kit including a plastic bathtub, a small chair, and (contrary to wartime conventions) a machine gun.
He landed at Arromanches under incessant rain
10 days after D-Day, in charge of a convoy of medical supplies en route for Paris. With half his load
destroyed, he finally arrived—only for his truck
to give up the ghost on the Champs-Elysées, from
where it was towed to its destination with a length
of camouflage netting. Dausset then helped organize blood banks and transfusions for the Allied
assault on Germany.
After the war, in tandem with Professor Marcel
Bessis, he began his medical research in earnest,
specializing in the properties of blood cells. “We
were regarded as biologists more than doctors,”
he said. Their work helped improve the efficacy
of transfusions, saving patients, including many
women who had sought illegal abortions.
As part of the Marshall plan, Dausset went to
Boston on a medical exchange program in 1948, but
did not enjoy his time there, blaming his shyness
and poor English. Despite that, he had established
good contacts with British medical researchers—in
particular Robin Coombs at the British Society of
Immunology. Dausset drew on Coombs’s work to
develop the idea that white blood cells could possess
the same quality of “autoimmunity” displayed by red
blood cells. By 1952 he had observed white blood
cells clumping together in response to antibodies, a
process known as leuco-agglutination.
This early research was carried out in antediluvian, dust-filled laboratories in Paris that, he
recalled, “had been abandoned since 1914.”
He was soon working towards HLA. “I understood, and little by little was able to prove, that cells
of all tissues in an organism have a chemical identity which distinguishes them from cells of another
organism of the same species to the point that they
are incompatible one with another,” he explained.
According to Danny Altmann, professor of
immunology at the Department of Infectious
Disease and Immunity, Imperial College, the period
from the mid-1950s to the mid-1960s was one of
intense activity for immunologists and geneticists
as they struggled to understand this enormously
complex aspect of human genetics—HLA being the
most variable family of genes in man. Along with
Dausset, others in the field included Jon van Rood,
Walter Bodmer, Rose Payne and Paul Terasaki.
“A key aspect of Dausset’s contribution was his
insight that one would only unravel the secrets of
such a diverse group of genes by analyzing large
numbers of family ‘pedigrees,’ ” noted Altmann.
The extension of this approach was to lead many
years later to Dausset’s founding of the Centre
d’Etude du Polymorphisme Humain (CEPH), a
major, international resource of family DNA samples. This resource became central to many disease
genetics studies and contributed to efforts to analyze the human genome.
“A key aspect of Dausset’s
contribution was his insight.”
—Danny Altmann, professor of
immunology, Imperial College
Dausset, was, however, not purely a pioneering research doctor. He was also a great organizer, contributing actively to the fundamental
reorganization of France’s medical system in the
late 1950s. For several years he was a government
adviser, work that culminated in a law establishing full-time employment in French hospitals and
encouraging research.
In 1958 he was named assistant professor of
hematology at the Faculty of Medicine in Paris,
then professor of hematology in 1963, before being
appointed head of the immunology department at
the Hôpital Saint-Louis. There he devoted himself
entirely to research, uncovering the HLA system.
He published the results in 1964.
Apart from the Nobel Prize, Jean Dausset was
subsequently honored with dozens of awards and
honorary academic roles. Tall, thin and elegant,
he was discreet but willing staunchly to defend his
ideas.
Outside medicine, he was fond of the plastic arts, collecting examples of work by Surrealist
artists and displaying them at a gallery he ran in
Paris.
Jean Dausset, who died on June 6 in Palma, married, in 1963, Rose Mayoral, with whom he had a
son and a daughter. Until the end of his life he was
determined that his work in genetics should be
used with a strong sense of moral purpose.
He feared what he called the “sorcerer’s apprentices” in his profession, and noted that “the temptations of eugenics are close to the temptations of
totalitarianism. Both can manipulate humans to
create identical beings.”
Copyright 2009 The Daily Telegraph.
Reprinted by permission.
From the Universities
Immune System Key Discovered
Monash University
June 23, 2009
A team of Monash University researchers has
discovered the importance of a protein that could
improve the way the drug interferon is used to
strengthen the human immune system.
Published online in the prestigious journal
Immunity, the findings show that the protein promyelocytic leukemia zinc finger (PLZF) is a key
player in the body’s immune response to disease,
increasing our understanding of the function of the
immune system.
Team leader Professor Bryan Williams, at the
Monash Institute of Medical Research, said the
findings demonstrate a role for PLZF, not previously recognized, that shows the protein is key to
the body’s immunologically important interferon
response.
“We have shown that interferon stimulates an
association between PLZF and co-factors to switch
on a decisive subset of interferon-stimulated genes,
including those involved in protection against viral
infections,” Williams said.
Interferon is a naturally produced substance that
modulates the immune response and provides protection against viral infections and cancer. It has
been developed as a drug over many years and has
been used in the treatment of hepatitis, cancer and
autoimmune diseases, such as multiple sclerosis.
See also the journal article summary by Bryan
R.G. Williams below.
Although much has been learned about the mechanism of action of interferon, the reason that some
patients are more sensitive to treatment with interferon than others has proved difficult to identify.
“The results described in the study provide new
insights into the mechanisms regulating the action
of interferon, and demonstrate that PLZF is an
important factor in the immune response and could
therefore be used as a possible drug target for both
anti-viral and anti-tumor therapy,” Williams said.
Copyright 2009 Monash University.
Reprinted by permission.
From the scientific journals
A Protein Supports Interferons’ Protective Function
Summary by Bryan R. G. Williams
Full text: Immunity
June 2009
Interferons are a family of proteins that play an
important role in protecting our bodies against dangers such as viral infections and cancer. They are
naturally produced by cells in response to an attack,
and are a vital component of the innate immune
system. How they work is not fully understood, but
our recent research solves one piece of the puzzle by
showing that a specific protein is crucial.
Interferons have proved to be useful in the treatment of a range of viral infections, such as hepatitis B and C. They are also an effective treatment
for several cancers, including cancers of the blood
and solid tumors. One member of the family, interferon-beta, is used to treat multiple sclerosis.
However, some patients are more sensitive to
treatment with interferons than others, and not
all tumors, infections or inflammatory diseases
are responsive to treatment. It is therefore critical
to learn more about the action of interferons and
develop new therapies.
PLZF and interferons
Since its initial discovery a half-century ago, scientists have learned much about how interferons
work: They switch on a large number of interferonstimulated genes (ISGs) through signaling pathways within cells.
Our research has identified a transcription factor that plays an important role in the interferon
response. Transcription factors are proteins that
bind to DNA and can either activate or repress gene
activity, thus either increasing or decreasing the
amount of protein a particular gene encodes. Our
work involves a transcription factor called promyelocytic leukemia zinc finger (PLZF) protein, which
Our discovery of PLZF’s
important role in innate immunity
provides us with new insights
into the way interferons protect
us from diseases.
is known to be involved in sperm formation and
skeletal development as a repressor of gene activity.
However, we have discovered a new function for
PLZF as an activator of a large subset of interferonstimulated genes (ISGs).
We compared the expression of ISGs in two cell
lines derived from patients with renal cancer and
found that the cell line that was more sensitive to
interferon treatment showed a higher expression
of a large subset of these ISGs. This same cell line
expressed higher levels of PLZF.
Appropriately, the subset of ISGs that had a greater
response in this cell line contained binding sites for
PLZF in their promoters. Promoters are regions of
genes that are involved in their activation.
We then looked to see whether PLZF played a
role in the innate immune response. Cells taken from
normal mice and grown in culture with interferon
were protected from infection with a virus called the
Semliki Forest virus, whereas cells from mice that
lacked the gene for PLZF were more susceptible to
infection. We also looked at the effect of interferon
treatment on the survival times of mice infected with
the virus. Normal mice treated with interferon before
exposure to the virus survived significantly longer
than mice lacking the PLZF gene. Thus PLZF is a key
player in the innate immune response.
Supporting actors
However, we found that normal mice and mice
that lacked the PLZF gene still produced the same
amount of interferon when they were infected
with the virus. Therefore, interferon production
alone cannot account for the different responses
in mice with or without the PLZF gene. We found
an answer in the expression of several ISGs known
to be involved in the antiviral response that we
had identified as being regulated by PLZF: Their
expression was reduced in mice that lacked the
PLZF gene. So the antiviral action of interferon
depends on the activation of these genes by PLZF.
PLZF also is important when interferon activates
natural killer cells, another key component of the
innate immune response. This type of white blood
cell can detect and kill cells that are infected with a
virus, as well as tumor cells. After being activated
(See Protein Helps Protect, pg. 6) 4
Immunology in the News
Fall 2009
5
From the scientific journals
(Protein Helps Protect, from pg. 5) 4
by interferon, natural killer cells release proteins
called perforin and granzyme B, which cause the
destruction of damaged or infected cells.
We discovered that natural killer cells from mice
lacking the PLZF gene were deficient in their ability to kill tumor cells in response to interferon.
These cells were impaired in the production of a
chemokine—a type of immune mediator—called
CXCL10, which has previously been associated
with natural killer cell activity and protection from
virus infection. In addition, we found that the production of granzyme B was much lower in natural
killer cells from PLZF-deficient mice.
We have found that a process called phosphorylation, in which a phosphate group is added to
the PLZF protein, is essential to the activation of
selected ISGs by PLZF. We also discovered that two
co-factors, known as HDAC1 and PML, interact
with PLZF and increase the activation of ISGs in
response to interferon. We think interferon stimulates the phosphorylation of PLZF and its interaction with these co-factors to form a complex that
binds to selected ISGs and activates them. These
genes then go on to produce proteins involved in
the immune response against viruses.
Our discovery of PLZF’s important role in innate
immunity provides us with new insights into the
way interferons protect us from diseases. This
knowledge of the role of PLZF may help us to
improve the way interferons are used clinically,
including the design of new therapies for patients
who currently do not respond to interferon treatment. PLZF thus could be an important target in
the development of drugs to treat viral infections
and cancers.
Original article:
“Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity.”
Dakang Xu,1,6 Michelle Holko,2,6,7 Anthony J.
Sadler,1 Bernadette Scott,1 Shigeki Higashiyama,3
Windy Berkofsky-Fessler,4,8 Melanie J. McConnell,4,9
Pier Paolo Pandolfi,5 Jonathan D. Licht,4 and Bryan
R.G. Williams1
1Monash Institute of Medical Research, Monash University,
Melbourne, Australia.
2Department of Preventive Medicine, Northwestern
University, Chicago, IL 60611, USA.
3Department of Biochemistry and Molecular Genetics,
Ehime University Graduate School of Medicine,
Shitsukawa, To-on, Ehime 791-0295, Japan.
4Division of Hematology/Oncology, Department of
Medicine, Northwestern University Feinberg School of
Medicine, 303 E. Superior Street, Lurie 5-123, Chicago, IL
60611, USA.
5Cancer Genetics Program, Beth Israel Deaconess Cancer
Center and Department of Medicine and Pathology, Beth
Israel Deaconess Medical Center, Harvard Medical School,
Boston, MA 02215, USA.
6These authors contributed equally to this work.
7Present address: Gene Expression Omnibus, National
Center for Biotechnology Information, National Institutes
of Health, Bethesda, MD 20892, USA.
8Present address: RNA Therapeutics Department,
Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
9Present address: Malaghan Institute of Medical Research,
Wellington, New Zealand.
(This is a summary by one of the study’s coauthors. Full text appears in Immunity, June 19,
2009, Vol. 30, No. 6, pp. 802-816.)
Receptor Helps Us Fight Respiratory Virus Infection
New findings may explain
why some people are more
susceptible to infections
caused by influenza and
respiratory syncytial virus.
Summary by Santanu Bose
Full text: Nature Immunology
August 2009
Respiratory syncytial virus (RSV) and flu are
leading causes of severe and sometimes deadly respiratory diseases among infants, children, the elderly
and people with compromised immune systems.
With the recent emergence of various subtypes of flu
(such as swine flu) and a high mortality rate among
some infants and young children infected with RSV,
it is crucial to understand how our immune systems
protect us against viruses and why they sometimes
fail in that regard.
First it is important to understand how cells in
our lungs recognize respiratory viruses and mount
a defense response to restrict viral spread. The first
line of defense during a microbial infection is called
the innate immune system. This innate defense
mechanism is crucial to diminish the severity of diseases associated with flu and RSV infection, including pneumonia and bronchiolitis.
Our immune cells possess biosensor molecules
called pattern recognition receptors, or PRRs,
that can recognize various components of viruses,
known as pathogen associated molecular patterns,
or PAMPs. Once a pattern recognition receptor
identifies a viral pattern, it relays that information
to cellular defense molecules, which then launch
an anti-viral response to eliminate the virus from
the body.
In our current study, we have identified a novel
pattern recognition receptor called the NOD2
(nucleotide-binding oligomerization domain–2)
protein that can sense both flu and RSV and tell the
body to launch a defensive response to combat infection. NOD2 recognizes the virus’s genetic material, a
type called single-stranded RNA (ssRNA), and activates the immune response by producing an antiviral protein called interferon-beta (IFN).
Findings could affect medicines, vaccines
We already knew that NOD2 could detect bacteria and activate the anti-bacterial response, but
NOD2 never had been shown to detect viruses or
RNA. However, our studies have shown that NOD2
is capable of detecting both viral ssRNA and small
synthetic ssRNA (which might be used in medicine
or with a vaccine) to activate the anti-viral response.
We further demonstrated that NOD2 interacts with
a protein called mitochondrial anti-viral signaling protein to activate the IFN-mediated anti-viral
response against RSV and flu.
We showed how important NOD2 is to the host
defense against respiratory virus infection by using
mice that lacked NOD2 protein. When challenged
with a respiratory virus, mice deficient in NOD2
showed enhanced susceptibility and survived for
only 10 days after infection, compared with normal
mice that survived seven to eight weeks. In addition,
the infected mice that lacked NOD2 showed exaggerated lung disease with severe pneumonia, unlike
the normal animals (please see image at right).
Thus, NOD2 plays a critical role in host defense
against respiratory viruses, by detecting viral ssRNA
genome during early infection. NOD2
bound to ssRNA then interacts with a
mitochondrial protein MAVS, which
activates the anti-viral defense apparatus by producing anti-viral protein
IFN. A schematic showing the role
of NOD2 in host anti-viral defense is
shown at left.
Our study is clinically relevant for
the development of therapeutics against
respiratory viruses. In addition, our
work suggests that screening for the
presence of the NOD2 gene could identify people who are more susceptible to
RSV and flu infections. Because small
Bose laboratory
A schematic demonstrates the anti-viral defense mechanism of the
synthetic ssRNA can activate NOD2
NOD2 receptor. NOD2 recognizes a virus’s genetic material, singleby mimicking the viral ssRNA genome,
stranded RNA (ssRNA), and interacts with the mitochondrial anti-viral
we could utilize synthetic ssRNA (as a
signaling (MAVS) protein. This, in turn, activates a protein called
nasal spray or mist) to boost anti-viral
interferon regulated factor-3 (IRF3) and the interferon-beta (IFN) gene.
response among high-risk individuals,
Interferon-beta protects surrounding cells and tissue from infection.
6
Immunology in the News
Fall 2009
Bose laboratory
Cross-sections of virus-infected mouse lungs illustrate
the critical role of the cellular molecule NOD2 in host
defense. The cross-section on the left is from a normal
mouse with healthy lungs; the one on the right is from a
NOD2-deficient mouse with pneumonia.
or as part of an adjuvant therapy to enhance vaccine
efficiency against the flu. This approach is an attractive method for controlling respiratory virus infection since it does not involve viral components—
viruses can mutate in response to an anti-viral drug
such as Tamiflu.
Apart from therapeutic potential, variations in
the NOD2 gene, which are common in humans, may
explain why some people are more prone to respiratory virus infections. Future studies will explore
whether NOD2 gene variations enhance susceptibility to these infections.
Original article:
“Activation of innate immune anti-viral response
by NOD2.”
Ahmed Sabbah,1 Te Hung Chang,1 Rosalinda
Harnack,1 Victoria Frohlich,2 Kaoru Tominaga,2,3
Peter H Dube,1 Yan Xiang,1 and Santanu Bose1
1Department of Microbiology and Immunology, The
University of Texas Health Science Center at San Antonio,
San Antonio, Texas, USA.
2Department of Cellular and Structural Biology, The
University of Texas Health Science Center at San Antonio,
San Antonio, Texas, USA.
3Sam and Ann Barshop Institute for Longevity and Aging
Studies, The University of Texas Health Science Center at
San Antonio, San Antonio, Texas, USA.
(This is a summary by one of the study’s coauthors. Full text appears in Nature Immunology,
advance online publication, Aug. 23, 2009;
doi:10.1038/ni.1782. http://www.nature.com/
ni/journal/vaop/ncurrent/full/ni.1782.html)