A researcher at Arizona State University's Biodesign Institute in Tempe received
$7.5 million from the U.S. Department of Defense to develop a cancer vaccine.
Stephen Albert Johnston, director of the institute's Center for Innovations in
Medicine, will focus his research project on breast cancer. He is one of only
two recipients in the nation to receive a five-year, $7.5 million grant from the
DoD's Innovator Award, funded through its Breast Cancer Research Program.
The money will be used to pay for preclinical tests using mice and human tumor
tissue samples from Mayo Clinic to make sure his idea will work, Johnston said.
Once he gets past that point, he would collaborate with Mayo Clinic in
Scottsdale to test the vaccine on people in phase one clinical trials. These
most likely would be healthy people who are predisposed for having cancer, and
would test for any reactions, such as autoimmune responses like lupus.
Johnston said the most frustrating part about his work is that it normal
cells are more complicated than he expected. "It's harder to find the difference
between tumor and normal cells than we thought it would be," he said. "Nobody
knew normal cells were as complicated as they are. It's a good basic discovery,
but from a practical point of view, it seems we're going to have to work
harder."
Cancer is the second leading cause of death in the United States, with an
estimated 1.45 million cases of cancer diagnosed this year. More than 559,000
people will die from the disease this year. Breast cancer is the second leading
cause of death in women.
The DoD is using appropriations from a congressionally directed medical research
program to eradicate breast cancer.
Johnston's goal is to make a vaccine that could be given to all adult women to
prevent the occurrence of breast cancer in the same way vaccines have been
created against infectious diseases.
Cancer isn't only a national problem, he said, but is rampant in Third World
countries, where people don't have the technologies and finances to fight the
devastating disease, he said.
"Most of the people who die of cancer are not in the industrialized world,"
Johnston said, estimating that 70 percent of the cancers are in the developing
world.
He said the average expense for the first year of cancer treatment is about
$17,000.
Johnston, who was recruited from University of Texas Southwestern Medical Center
in Dallas, cautions he has a long way to go.
"This is a high risk deal," he said. "We have yet to see whether the basic idea
will work. We're just glad some people thought it was worth exploring."
Flu-jab alert prompts study to see if vaccines could harm unborn babies
David Rose
Scientists are to investigate how vaccinations given to pregnant women might
affect the health of their unborn child, after research suggested that babies’
immune systems develop much earlier than thought. A study published in the US
Journal of Clinical Investigation yesterday found that the children of mothers
who were given vaccinations against influenza started producing immune cells to
combat the illness while still in the womb.
It is unclear whether such early production of antibodies has adverse or
positive effects on an infant’s health.
Some researchers have suggested that exposure to vaccines, pollens and other
agents during pregnancy may increase a child’s chances of developing allergies
later in life. Such a hypothesis has been cited as the reason for rising rates
of asthma and related illnesses. Vaccinating pregnant women against flu is
currently considered safe and the Department of Health is considering whether to
implement recommendations made in December, by the Joint Committee on Vaccines
and Immunisation (JCVI), the official watchdog, that all pregnant women be given
the jabs when elderly and vulnerable patients are vaccinated during the winter
flu season.
A team of researchers from Columbia University, New York, studied 126 women who
were given flu vaccinations, which are already recommended for all mothers-to-be
in the United States.
Specific antibodies found in the umbilical cord of their babies suggest that
proteins contained in the jabs passed from mother to foetus, and stimulated
production of immune cells in the developing child. Antibodies were found in
approximately 40 per cent of the cord blood samples, suggesting that the
infants’ immune systems were capable of responding to agents passed from mother
to child.
Previously, babies were thought to derive antibodies to protect them against
illness from their mothers, via the placenta, not developing their own immune
responses until some weeks after birth. “These results have important
implications for determining when immune responses to environmental exposures
begin,” Rachel Miller, the lead author of the paper, said. “More research now
needs to be done on what the effect to the child in later life is.”
Professor Miller said: “It is possible that the early stimulation of a child’s
immune system might lead to the child developing asthma, eczema or other
illnesses, but it is also possible that the beneficial effect of the vaccine
might be conferred from mother to child, and protect the baby in early life.”
Donald Peebles, a consultant from University College London, and spokesman for
the Royal College of Obstetricians and Gynaecologists, said that it was known
that viruses and other agents could pass from mother to a developing baby, but
more research was needed to determine the potential health effects.
“This study shows that the foetus is a good deal more sophisticated in
developing its own immune responses than previously thought,” he said.
Immune System Research Hold Promise For Alzheimer's, Stroke, And
Mental Disorders
Recent discoveries in the field of neuroimmunology, which studies the
interaction between the immune and nervous systems, are offering promising new
leads for the treatment of many devastating neurological disorders, from
Alzheimer's disease to stroke. New research suggests that reducing the
expression of an immune system protein in the brain may help repair neurons
damaged by spinal cord injury and other trauma. Other research has uncovered the
important role that immune molecules perform in the prenatal development of such
diseases as autism and schizophrenia. Additional findings reveal that an
innovative type of immunotherapy assists with the recovery of memory after
stroke.
"The discovery that immune molecules play a crucial role in shaping neuronal
connections and are even expressed on nerve cells important in learning and
memory is opening up a whole range of potential new treatment targets for
diseases in which these connections have gone awry, such as Alzheimer's and
other dementias, autism, amyotrophic lateral sclerosis (ALS), Parkinson's
disease, schizophrenia, and in nerve injury," says Esther Sternberg, MD, of the
National Institutes of Health. "Understanding these neural immune connections at
a molecular and cellular level will shed light on the reasons these
diseases develop and will help provide new ways to prevent or treat them."
Several years ago, researchers at Harvard Medical School made the unexpected
discovery that neurons have major histocompatibility complex (MHC) class I
molecules on their cell surface. MHC class I molecules play a central role in a
healthy, functioning immune system by helping the body recognize and destroy
disease-infected cells.
"We were amazed by this finding," says Carla Shatz, PhD, now at Stanford
University. "Previously it had been thought that neurons were the only cells in
the body that didn't express these molecules." When Shatz and her colleagues
studied mouse models that lack MHC class I, they found another surprise:
greater-than-normal strengthening of the synapses between neurons. This
observation suggests that MHC class I acts as a kind of "molecular brake" on
synaptic plasticity, the ability of brain cells to rewire themselves. Such
plasticity is essential to learning and memory.
In mice, the "brake" for the gene encoding MHC class I appears to be released
twice: during early development and again in old age. Interestingly, late in
life, the gene's neural expression occurs primarily in the hippocampus and other
areas of the brain involved in learning and memory.
"MHC class I neurons may also play a role in age-related neurodegenerative
diseases, such as Alzheimer's and Parkinson's,"says Shatz. "It may
mistakenly signal the immune system to attack brain cells, just as it triggers a
similar attack on the joints in cases of rheumatoid arthritis."
More recently, Shatz and her team have reported that neurons also express an
immune system protein called paired-immunoglobulin-like receptor-B (PirB),
which, over time, gradually inhibits brain plasticity. Mice that lack PirB
exhibit greater synaptic plasticity as they age -- a finding that suggests that
reducing PirB might help reestablish the connections among neurons damaged by
spinal cord injury, stroke, or other trauma.
Together, these studies indicate that immune molecules perform important
functions in the brain, including how much or how quickly our brain changes in
response to new experiences. Researchers at the Karolinska Institute in
Stockholm, Sweden, have found that removal of synapses from damaged neurons
after a motor nerve injury, a process known as "synaptic stripping," is much
stronger in mice who lack functioning MHC class I molecules. They also found
that such mice are less likely to experience a regeneration of their motor
neurons and that their glial cells react differently to the damaged neurons than
do those of mice with functioning MHC class I molecules. "These results provide
a surprising link between neuroscience and immunology," says Staffan Cullheim,
MD, PhD. They also mark the first time a family of molecules has been linked
directly to how the cell body of a neuron reacts after its axon -- the long
projection that conducts electrical signals away from the cell's body -- has
been injured.
In earlier studies, Cullheim and other scientists had reported that MHC class I
molecules can be found in particularly high levels among motor neurons in the
brain stem and the spinal cord, especially after the neurons have been damaged.
In his most recent study, Cullheim found that the presence of MHC class I helps
retain certain inhibitory synapses on the surface of injured motor neurons, thus
reducing the likelihood that the neurons will fire a nerve impulse, or action
potential, to neighboring cells.
MHC class I also has an effect on the action of glial cells, which in turn may
influence neurons in various ways. Although microglia, the "immune cells" of the
central nervous system, responded more weakly in the absence of MHC class I
molecules, other glial cells, known as astrocytes, responded more vigorously. If
-- and how -- these different responses are linked with synaptic stripping is
not yet known.
"The consequences of the effects of MHC class I is still not clear," says
Cullheim, "but it may be linked with the the ability of motor neurons to produce
new axons. Mice with peripheral nerve lesions in their hind limbs exhibit less
axonal bridging on those lesions when their MCH class I function is impaired."
High levels of MHC class I, on the other hand, may pose a danger to neurons in
the same way as is seen for other cell types -- during viral infection, for
example. These high levels may even be involved in the development of
neurodegenerative diseases. Research has shown that motor neurons involved in
ALS and dopaminergic neurons involved in Parkinson's disease express among the
largest amounts of MHC class I molecules in the nervous system. At the
University of California, San Diego, Lisa Boulanger, PhD, and her colleagues
have found that changes in the levels of specific immune molecules, members of
the MHC class I family, are sufficient to cause cellular and behavioral symptoms
of autism and schizophrenia in mice.
One set of preliminary studies from Boulanger's laboratory suggests that normal
levels of MHC class I are needed for proper neuronal signaling by the
neurotransmitter glutamate. The disruption of the glutamate signaling system is
a hallmark of schizophrenia. It's also been recently characterized in patients
with autism. In a second line of research, Boulanger has found that changes in
MHC class I levels cause a striking disruption of the ability to "tune out"
irrelevant sensory information, as measured by a neurological phenomenon known
as prepulse inhibition, or PPI. Scientists have long known that PPI is impaired
in people with schizophrenia, and recent studies suggest that it's also impaired
in people with autism.
"We found in our current study that mice with altered levels of MHC class I
share both abnormal glutamate signaling and this deficit in PPI," Boulanger
says. "These results are exciting because they may provide clues to
understanding the puzzle of why immune abnormalities are frequent among patients
with autism and schizophrenia and their close relatives." Boulanger and her
colleagues are currently investigating whether MHC class I molecules are altered
in people with autism and schizophrenia. They are also using animal models to
determine how immune signaling may affect the earliest events in fetal brain
development. "Human data show that in genetically predisposed individuals, a
maternal viral infection during pregnancy increases the chance of the child
developing either autism or schizophrenia later in life," says Boulanger.
"Recent research in animal models suggests that it's not the infection itself,
but rather an unknown, shared feature of the immune response to a variety of
infectious agents that disrupts fetal brain development and leads to impairments
in PPI."
A leading candidate for this mysterious immune trigger is the release of
cellular signals called cytokines, which are produced during infection and
injury. Cytokine levels are altered in the fetal brain following a maternal
infection -- and in the brains of people with autism. Cytokines can increase the
levels of MHC class I molecules in many types of cells, including neurons.
"We're now trying to determine if changes in MHC class I molecules are the
necessary link between maternal infections and abnormal fetal brain development,"
says Boulanger.
An experimental treatment called anti-NOGO-A immunotherapy has been found to
improve performance on a test of cognitive ability after stroke in aged rats,
according to a new study from a team of researchers led by Gwendolyn Kartje, MD,
PhD, at Loyola University and the Edward Hines VA Hospital in Chicago. This
finding may one day lead to more effective treatments for the millions of people
worldwide who survive a stroke each year and for the millions of others
suffering from Alzheimer's disease and other memory disorders. Anti-NOGO-A
immunotherapy blocks the NOGO-A protein, a molecule found in the brain. The
precise role of this protein is unknown, but it appears to inhibit aberrant
growth. When the brain becomes damaged, however, this inhibitory function turns
harmful, preventing injured cells from regenerating and repairing themselves. It
also prevents uninjured cells from changing to help with the recovery.
In earlier studies, Kartje and her colleagues showed that anti-NOGO-A
immunotherapy led to the recovery of forepaw and arm movement after induced
stroke in aged rats. The new study found that the therapy also improved
cognitive recovery when testing performance on a spatial memory task. "This
suggests that the NOGO-A protein limits the recovery of memory after stroke and
that by blocking the protein, more recovery may occur," Kartje says. Her
laboratory next plans to look for structural changes in the brain that underlie
the recovery process.
Adapted from materials provided by Society For Neuroscience.
Vaccines have drawn an intense spotlight in recent years, and a study
published last week raised a new question in the debate: Do Americans
overvaccinate?
Scientists writing in the New England Journal of Medicine found that immunity
lasts far longer than previously believed, suggesting that fewer booster shots
may be warranted in adults. Still other doctors are wondering whether new
vaccine approaches would better aid children.
At least one doctor would like to see childhood vaccinations spread out over a
longer period of time.
Dr. Mark Slifka, an associate scientist with the Vaccine and Gene Therapy
Institute in Oregon, wanted to know how long immunity lasts after vaccination
or infection. He and his colleagues went into the study with a lot of strong
hypotheses and "expected to see long-lived immunity following a viral
infection and relatively short-lived immunity after vaccination." Those
notions, Slifka and his team said, are the reasoning for booster shots.
To his surprise, the research revealed that the immunity the body marshals
after vaccination with tetanus and diphtheria lasted far longer than
scientists had once believed. Immunity that arose after certain viral
infections, Slifka and collaborators discovered, were essentially maintained
for life. Although it is important for the country to abide by vaccination as
a vital public health tool, Slifka reported in the journal, it also is
important to understand that boosters are not always necessary. "We also need
to mention that overvaccinating the population poses no health or safety
concerns," he said, adding "it may just be unnecessary under certain
circumstances."
Dr. Len Horovitz, a pulmonary physician at Lenox Hill Hospital in Manhattan,
said while the concept of overvaccination may sound radical and new, doctors
have had the power for years to test a person's immunity after initial
vaccination. Horovitz says he always tests students who come to see him prior
to their first year of college. If they need a booster, he gives it. "It is
possible to prevent this phenomenon," Horovitz said, referring to
overvaccination, "by testing for antibodies." These immune-system proteins
develop in the aftermath of vaccination. Antibodies are stimulated in the
presence of a key protein called an antigen, a protein introduced by
vaccination or infection.
The body "remembers" antigens through highly specialized, all-knowing
constituents of the immune system: B cells, whose role is never to forget.
When that memory fails, it can be reactivated with a booster shot. "To
determine whether an MMR booster is needed," Horovitz said of the
mumps-measles-rubella shot, "antibody testing for each antigen can be done so
that an unnecessary vaccine is not administered.
"A lot of doctors do not test to see if a patient is still immune. When kids
go to college, the university wants a kid to get a booster. It's very possible
that a booster isn't needed - and you can test to get an answer. But there are
a lot of doctors who'll say, 'Let's just give the kid a booster.'" Dr. Robert
W. Sears, a vaccine expert and author of "The Vaccine Book," said parents of
young children also use the term "overvaccination," but in a different way.
They want to know whether vaccinations can be spread out to avoid a child's
receiving so many shots at once.
"This is the single most important topic that I am most passionate about,"
Sears said. "Parents are concerned that simultaneous vaccines given to babies
at an early age may be overwhelming to the infants' systems."
Just as Slifka sees no need for unnecessary boosters, Sears says it is
possible to spread out vaccinations for children and still provide them with
the same level of vital immunity to communicable diseases. "Vaccination is
definitely important," Sears said. "Vaccines have played a tremendous role in
eliminating or at least limiting certain diseases in our population."
But he adds that spreading out the shots is far less traumatic and does not
compromise the benefit of immunization.
Scientists discover a direct route from the brain to the
immune system
– It used to be dogma that the brain was shut away from the actions of the
immune system, shielded from the outside forces of nature. But that’s not how it
is at all. In fact, thanks to the scientific detective work of Kevin Tracey, MD,
it turns out that the brain talks directly to the immune system, sending
commands that control the body’s inflammatory response to infection and
autoimmune diseases. Understanding the intimate relationship is leading to a
novel way to treat diseases triggered by a dangerous inflammatory response.
Dr. Tracey, director and chief executive of The Feinstein Institute for
Medical Research, will be giving the 2007 Stetten Lecture on Wednesday, Oct. 24,
at the National Institutes of Health in Bethesda, MD. His talk – Physiology and
Immunology of the Cholinergic Anti-inflammatory Pathway – will highlight the
discoveries made in his laboratory and the clinical trials underway to test the
theory that stimulation of the vagus nerve could block a rogue inflammatory
response and treat a number of diseases, including life-threatening sepsis.
With this new understanding of the vagus nerve’s role in regulating
inflammation, scientists believe that they can tap into the body’s natural
healing defenses and calm the sepsis storm before it wipes out its victims. Each
year, 750,000 people in the United States develop severe sepsis, and 215,000
will die no matter how hard doctors fight to save them. Sepsis is triggered by
the body’s own overpowering immune response to a systemic infection, and
hospitals are the battlegrounds for these potentially lethal conditions.
The vagus nerve is located in the brainstem and snakes down from the brain to
the heart and on through to the abdomen. Dr. Tracey and others are now studying
ways of altering the brain’s response or targeting the immune system itself as a
way to control diseases.
Dr. Tracey is a neurosurgeon who came into research through the back door of
the operating room. More than two decades ago, he was treating a young girl
whose body had been accidentally scorched by boiling water and she was fighting
for her life to overcome sepsis. She didn’t make it. Dr. Tracey headed into the
laboratory to figure out why the body makes its own cells that can do fatal
damage. Dr. Tracey discovered that the vagus nerve speaks directly to the immune
system through a neurochemical called acetylcholine. And stimulating the vagus
nerve sent commands to the immune system to stop pumping out toxic inflammatory
markers. “This was so surprising to us,” said Dr. Tracey, who immediately saw
the potential to use vagus stimulation as a way to shut off abnormal immune
system responses. He calls this network “the inflammatory reflex.”
Research is now underway to see whether tweaking the brain's acetylcholine
system could be a natural way to control the inflammatory response. Inflammation
is key to many diseases - from autoimmune conditions like Crohn's disease and
rheumatoid arthritis to Alzheimer's, where scientists have identified a strong
inflammatory component.
Dr. Tracey has presented his work to the Dalai Lama, who has shown a great
interest in the neurosciences and the mind-body connection. He has also written
a book called “Fatal Sequence,” about the double-edge sword of the immune
system.
About The Feinstein Institute for Medical Research
Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research
is home to international scientific leaders in Parkinson's disease, Alzheimer’s
disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis,
inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma,
neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the
North Shore-LIJ Health System, ranks in the top 6th percentile of all National
Institutes of Health grants awarded to research centers. Feinstein researchers
are developing new drugs and drug targets, and producing results where science
meets the patient. For more information, please visit
www.FeinsteinInstitute.org or
http://feinsteininstitute.typepad.com/feinsteinweblog/
http://sciencenow.sciencemag.org/cgi/content/full/2008/521/4
Vaccine Booster's Secret Revealed
By Martin Enserink
ScienceNOW Daily News
21 May 2008
For decades, scientists have known that they can make vaccines much more
efficacious by adding aluminum compounds, but they never knew why. Now, a
study reveals how, on a molecular level, these helpers spur the production of
antibodies. The finding may help researchers develop better vaccines.
Many vaccines contain adjuvants, nonspecific agents that help jolt the immune
system into action. "Alum," a term referring broadly to aluminum hydroxide and
several aluminum salts, has this effect, as was accidentally discovered in the
1920s. It has been widely used in human vaccines since the 1950s, and it's still
the only adjuvant allowed in the United States. "But we didn't really have a
clue about how it worked," says immunologist Harm HogenEsch of Purdue
University's School of Veterinary Medicine in West Lafayette, Indiana. The
dominant theory held that alum particles bind the antigen--the vaccine's main
ingredient--on their surfaces, presenting them more slowly to the immune system
and thus ensuring a more thorough response.
But the situation is more complicated than that. Last year, HogenEsch's team and
a group led by Fabio Re at the University of Tennessee Health Science Center in
Memphis showed that in macrophages--white blood cells that gobble up pathogens
and cellular detritus--alum triggers the production of interleukin 1β and
interleukin 18, two key signaling molecules, or cytokines, known to stimulate
the production of antibodies. Researchers knew that this duo is often released
after the activation of so-called NOD-like receptors. "So then the race was on,"
says Re, to pinpoint which NOD-like receptor was involved.
That race was won by a team led by Richard Flavell of Yale University. In this
week's issue of Nature, Flavell's group reports that aluminum adjuvants trigger
a NOD-like receptor called the Nalp3 inflammasome--an intracellular protein
structure that plays a key role in immune activation. When the group injected
mice lacking Nalp3 with an alum-boosted vaccine, they produced almost no
antibodies; but a vaccine with another adjuvant called Freund's resulted in the
usual, vigorous immune response. Re says he will publish the same result in a
paper accepted by the Journal of Immunology, which also shows that two other
adjuvants--QuilA and chitosan--work in the same way.
The Nalp3 inflammasome is known to be activated by compounds of microbial origin
and also by molecules that appear when cells die, such as uric acid. So
researchers think that Nalp3 is like a "danger sensor," says Yale immunologist
Stephanie Eisenbarth, the first author on the Nature paper. Alum-containing
vaccines may simply "hijack" that response.
Knowing how alum works its magic may help researchers design more specific
adjuvants that are more effective or have fewer side effects, HogenEsch says.
Alum, for instance, is known to kill muscle cells when injected into muscles, as
many vaccines are.
Yale Researchers Describe How Vaccine Adjuvant Jump-Starts Immune System
New Haven, Conn. - Yale University researchers have determined how a key
component of many vaccines activates an immune system response, a finding that
opens up promising new avenues of research on better ways to prevent infections.
A team of scientists led by Stephanie C. Eisenbarth and Richard A. Flavell of
the departments of immunobiology and laboratory medicine at the Yale School of
Medicine describe one way aluminum hydroxide th a key adjuvant used in many of
the world's vaccines th helps fight off pathogens in a paper published Wednesday
in the online edition of the journal Nature.
(Media-Newswire.com) - New Haven, Conn. — Yale University researchers have
determined how a key component of many vaccines activates an immune system
response, a finding that opens up promising new avenues of research on better
ways to prevent infections.
A team of scientists led by Stephanie C. Eisenbarth and Richard A. Flavell of
the departments of immunobiology and laboratory medicine at the Yale School of
Medicine describe one way aluminum hydroxide – a key adjuvant used in many of
the world’s vaccines – helps fight off pathogens in a paper published Wednesday
in the online edition of the journal Nature.
Yale University scientists helped spur a revolution in immunology a decade ago
by describing the key role played by Toll-like receptors, or TLRs, in triggering
inflammatory responses. TLRs are a key receptor in the evolutionarily older and
more generalized innate immune system that senses the presence of foreign
invaders. TLRs must be activated before the younger adaptive immune system, -
which can respond to specific pathogens and has long-term memory - can begin to
fight infections in people.
However, scientists have found that the aluminum hydroxide, or alum, used in
vaccines does not require that TLRs be activated to trigger an immune response,
and the molecular mechanisms that explain its efficacy remained a mystery.
Eisenbarth and Flavell found that a crucial player in the process is a part of
another weapon in the immune system’s arsenal called Nod-like receptors,
specifically a protein complex called the Nalp3 inflammasome that is located
within cells. They found that alum adjuvant activated the Nalp3 inflammasome,
which is also triggered when cells come under stress. They also showed that when
Nalp3 inflammasome was removed from cells they failed to produce cytokines known
as interleukins, part of the immune system response usually triggered by the
adjuvant. Also, antibody and T Cell responses were reduced in mice lacking parts
of the inflammasome.
For vaccinologists, the paper is important because it describes at least one
molecular basis for how an adjuvant like alum activates the immune system.
Researchers hope to harness that knowledge to find new ways to use adjuvants to
bolster immune system responses.
“As a physician, that is the most important thing. We need to know how these
adjuvants actually work.’’ Eisenbarth said. (um yeah duh)
But as a researcher, Eisenbarth said, she is also fascinated by the role
Nod-like receptors like the Nalp3 inflammasome might play in the
fundamental activation of the arm of the immune system that mediates long-term
protection against pathogens. “The paper also adds a new aspect to one of the
most exciting fields in immunology – how the innate, or ancient immune system,
needs to be activated before the more sophisticated adaptive immune system can
do its work,’’ she said.
Other Yale researchers involved in the study are Oscar R. Colegio of the
Departments of Dermatology and Immunobiology, William O’Connor Jr, of the
Department of Immunology and Fayyaz S. Sutterwala, now of the University of
Iowa.
Sci. & Tech.
Scientists discover how common vaccine booster works
In an online paper in the journal Nature, Yale University researchers funded by
the National Institute of Allergy and Infectious Diseases (NIAID), part of the
National Institutes of Health, explain how a common ingredient in many vaccines
stimulates and interacts with the immune system to help provide protection
against infectious diseases.
According to Eurekalert, the news service of the American Association for the
Advancement of Science, vaccines must possess not only the bacterial or viral
components that serve as targets of protective immune responses, but also
ingredients to kick start those immune responses. In many vaccines, the
bacterial or viral components themselves have this capability. For other
vaccines, the immune system requires an added boost. Adjuvants are those
substances added to a vaccine to help stimulate the immune system and make the
vaccine more effective.
Currently the only vaccine adjuvants licensed for general use in the United
States are aluminum hydroxide/phosphate formulations, known as alum. Although
alum has been used to boost the immune responses to vaccines for decades, no one
has known how it worked.
In this paper, the Yale team, led by Richard Flavell, M.D., Ph.D., and Stephanie
Eisenbarth, M.D., Ph.D., examined the immune system pathway and cell receptors
used by alum. Many microbial compounds function as adjuvants by stimulating
Toll-like receptors. These receptors identify microbial invaders and alert the
body to the presence of a disease-causing agent, or pathogen. Alum, however,
does not stimulate Toll-like receptors. The Yale team found that alum stimulates
clusters of proteins called inflammasomes, found inside certain cells.
Inflammasomes respond to stresses such as infection or injury by releasing
immune cell signaling proteins called cytokines. Inflammasomes are a component
of the innate immune system that operates in parallel with, but separate from,
Toll-like receptors, also part of the innate immune system.
To make this determination, Dr. Eisenbarth and her coworkers used mice that had
been genetically engineered to be deficient in various components of a specific
type of inflammasome, characterized by the presence of the protein termed Nalp3.
The team demonstrated that an immune response did not occur in those animals
with the deficient Nalp3 inflammasomes, despite the inclusion of alum, while it
did occur in normal mice. The team’s findings provide the first convincing
evidence that the Nalp3 inflammasome forms the basis for alum’s adjuvant action.
According to the study authors, several unanswered questions remain regarding
how activation of this pathway controls a highly specific and long-lasting
immune response generated by a vaccine. But this new information on the
molecules that alum uses to activate the innate immune system should provide the
keys to better understanding adjuvant function and should facilitate the design
of new vaccine adjuvants.
ScienceDaily (Jun. 1, 2008) — A study funded by the National Institutes of
Health (NIH) has transformed scientists' understanding of Rett syndrome, a
genetic disorder that causes autistic behavior and other disabling symptoms.
Until now, scientists thought that the gene behind Rett syndrome was an "off"
switch, or repressor, for other genes. But the new study, published today in
Science*, shows that it is an "on" switch for a startlingly large number of
genes.
Rett syndrome is caused by a deficiency of the MECP2 gene. It occursalmost
exclusively in girls, robbing them of language, cognitive and fine motor skills
around the time they are learning to walk. Having extra copies of MECP2 can also
cause Rett-like symptoms. By manipulating the number of copies of the ME CP2
gene in mice, the authors of the new study found that it controls thousands of
other genes, suppressing some, but activating most. The research was funded by
the National Institute of Neurological Disorders and Stroke (NINDS) and the
Eunice Kennedy Shriver National Institute of Child Health and Human Development
(NICHD), both part of NIH.
"This study simultaneously upends prevailing ideas about the disease process in
MECP2-related disorders, and hints at new therapeutic strategies," says NIH
Director Elias Zerhouni, M.D. Rett syndrome occurs predominantly in girls
because the MECP2 gene is located on the X chromosome. In boys, who have only
one X compared to girls' two, a deficiency of MECP2 tends to cause death during
infancy. Girls with Rett syndrome tend to develop normally until about one year
of age, and then regress in their language, cognitive and motor skills. They
lose the words they have learned, as well as their skilled hand movements, which
become replaced by repetitive wringing and clapping. Other common features
include seizures, stunted growth and small brain size, mood disturbances, and
sleep problems.
Duplications of MECP2 have been linked to another syndrome, which can cause Rett-like
symptoms, and sometimes severe mental retardation, in boys. MECP2's dual roles
in gene repression and activation were "a total surprise," says the lead author
of the new study, Huda Zoghbi, M.D., a professor at Baylor College of Medicine
in Houston and an investigator of the Howard Hughes Medical Institute. Dr.
Zoghbi led the team that first linked MECP2 deficiencies to Rett syndrome in
1999, also an NIH-funded effort. Many lines of evidence pointed to the MeCP2
protein as a gene repressor, and that is how experts in the field, including Dr.
Zoghbi, have defined its function for the past 10 years.
Dr. Zoghbi did not intend to question that definition. She was interested in
comparing Rett syndrome and MECP2 duplication syndrome, and in adding to the
list of the few genes known to be regulated by MECP2. Toward that end, she and
her team analyzed gene activity patterns in the brains of mice with a MECP2
deficiency and in mice with a MECP2 duplication (MECP2+). Previous studies had
revealed only subtle differences between the brains of normal and MECP2-mutant
mice, but
those studies measured gene activity throughout the brain. Dr. Zoghbi's group
focused on a brain region called the hypothalamus, which is known to produce
hormones that influence growth, mood, and the sleep-wake cycle -- all of which
typically become derailed in Rett syndrome.
Their analysis revealed nearly 2600 genes that are misregulated in both mouse
models, with opposite patterns. The activity of about 2200 genes dropped in
MECP2-deficient mice and spiked in MECP2+ mice, indicating that MECP2 is an
activator for those genes. About 400 genes showed the reverse pattern,
indicating that MECP2 is a repressor for those genes. In other experiments, the
researchers confirmed that the MeCP2 protein binds directly to several of the
target genes. They also found evidence that MeCP2 collaborates with another
protein known to serve as a gene activator. Among the genes activated by MeCP2,
the
researchers found many that encode neuropeptides, proteins that are secreted by
nerve cells.
All of these results raise a number of challenges and opportunities for future
research, Dr. Zoghbi says. Researchers could design effective therapies for Rett
syndrome and MECP2 duplication syndrome by aiming at MeCP2's target genes, but
first they would have to know which target genes are most relevant to
neurological function. Also, given that the two disorders have opposite gene
activity profiles, they might not respond to the same therapies. The ideal
therapy would aim closer to MECP2 itself, Dr. Zoghbi says. "We know that the
MeCP2 protein is important for orchestrating gene expression in neurons," Dr
Zoghbi says. "To treat the disease, we may need to find a way to re-orchestrate
gene expression. The challenge is to identify the immediate lieutenants of
MeCP2, and co-opt them to
take over when MeCP2 is not working."
Journal reference:
Maria Chahrour, Sung Yun Jung, Chad Shaw, Xiaobo Zhou, Stephen T. C. Wong, Jun
Qin, and Huda Y. Zoghbi. MeCP2, a Key Contributor to Neurological Disease,
Activates and Represses Transcription. Science, 2008; 320 (5880): 1224 DOI:
10.1126/science.1153252 Adapted from materials provided by NIH/National
Institute of Neurological Disorders and Stroke.
