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/
SCIENTIFIC AMERICAN COMMUNITY SCIENTIFIC AMERICAN DIGITAL 60-SECOND
SCIENCE scientific american
Immune System Keeps Your Brain Tidy Too
Researchers have uncovered a link between the the brain's nerve cell network and
the immune system--the same protein that helps gets rid of uninvited bacteria
also eliminates unused neural connections. Karen Hopkin reports.
You might not realize it, but you’re born with more brain cells than you know
what to do with. Or at least more brain-cell connections. As you grow older,
through childhood and adolescence, you get rid of the connections that aren’t
being used to store information or to tell you which tie goes with that jacket.
For years researchers have known about this cellular pruning. But they didn’t
know how it worked. Now scientists from the Stanford University School of
Medicine report that it’s the immune system that carries out this critical brain
maintenance. In fact, the same protein that helps gets rid of uninvited bacteria
also eliminates unused neural connections. The findings appeared in the December
14 issue of the journal Cell.
This routine cellular maintenance is important for normal brain development.
Mice that are missing this pruning protein wind up with disorganized, abnormal
retinas. And mice that are prone to getting glaucoma make too much of the
protein, particularly later in life—so connections in their retinas are
destroyed when they shouldn’t be. Reigning in this overzealous pruning process
could provide a treatment for glaucoma or for other diseases where neural
connections are lost. But it probably won’t help you decide whether to go with
the solid tie or the stripes.
—Karen Hopkin
Early Fine-Tuning of Neural Connections May Turn Destructive
Later in Life Mouse study implicates immune process in brain development as well
as
degenerative diseases
The immune system helps to prune excess connections between neurons in the
developing brains of young mice, according to scientists funded by the National
Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH).
The study, published in the December 14 issue of the journal Cell, sheds
critical new light upon a fundamental process, while hinting at a likely
mechanism behind neurodegenerative diseases like glaucoma and Alzheimer's
disease.
Shortly after birth, the mammalian brain contains vast numbers of connections,
or synapses, between neurons -- many more than will be needed in adulthood.
Scientists have known for years that the developing brain follows a use it or
lose it rule: inactive connections are pruned away during childhood and
adolescence. However, the molecular mechanism underlying this pruning process
has remained one of the biggest mysteries in neurobiology. Now, Dr. Beth Stevens
and Dr. Ben Barres of the Stanford University School of Medicine and their
colleagues report that a protein used by the immune system to destroy
bacteria is also
needed by the young brain to target and destroy unwanted synapses.
"From the fetal period through early adulthood, the developing brain is
constantly fine-tuning its synaptic connections. These results provide new
insight into this vital process," said Dr. Nora Volkow, NIDA director.
"Eventually, research like this, into the fundamental mechanisms of brain
development, will help us understand why a child's brain is so vulnerable to
environmental factors, including addictive drugs." "The immune system's
involvement in sculpting synapses was totally unexpected," added Dr. Barres. The
immune protein C1q is among the body's first responders to injury or infection,
attaching to dead cells or bacteria and triggering their destruction.
Surprisingly, the researchers also found C1q attached to immature synapses in
the brains and retinas of young mice. Unlike normal mice, mice missing C1q were
unable to eliminate extra synapses as they aged, producing disorganized,
abnormal connections in their visual systems.
In collaboration with Dr. Simon John of The Jackson Laboratory, the researchers
asked whether diseases like glaucoma could trick C1q into targeting synapses in
the adult. They found that although C1q is normally turned off in the nervous
systems of mature mice, it reappears during the early stages of glaucoma, when
retinal synapses begin to deteriorate. This discovery offers a tantalizing clue
to how synapses might be lost in neurodegenerative diseases like Alzheimer's
disease and ALS.
"It looks like as soon as something goes wrong, C1q is reactivated," said Dr.
Barres. "In the mouse model of human glaucoma, C1q is the earliest sign of
disease, appearing well before visible damage to synapses and neurons. We hope
that if we block C1q and the immune cascade it triggers, we can block the
disease before neurons start to die."
