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Rafi Ahmed is curious. Why
does the immune system sometimes fail to eliminate
viruses that cause chronic diseases? Why have vaccines designed to boost
immune response in people with chronic diseases been so unsuccessful?
What he has discovered so far is that once-good memory T cells in charge
of remembering and combating pathogens can become exhausted and ineffective,
allowing viruses to multiply virtually unchecked.
A multi-institutional team of researchers
headed by Ahmed, a Georgia Research Alliance Eminent Scholar and director
of the Emory Vaccine Center, has identified the exhaustion pathway and
developed a new strategy to re-energize exhausted T cells. Published in
Nature, the strategy helps T cells fight aback against the once free-swinging
viral infections.
The landmark research has applications for
multiple millions of patients challenged by chronic viral infections,
including HIV/AIDS and hepatitis B and C, and the strategy also is likely
to impact the treatment of cancer, which follows the same process of immune
cell exhaustion to allow for the growth and spread of tumors.
Tired
and worn out
When
first confronted by an acute viral infection, the immune system’s
T cells are full of pep and vigor, proliferating rapidly, secreting cytokines,
killing infected cells, and decreasing the viral load. Even after the
pathogen is eliminated, a group of these cells remain as highly functional
memory cells, ready to mobilize quickly should the conquered virus reappear.
The same is true in a chronic viral infection,
with T cells starting out strong. However, as the virus holds on, the
cells start to flag. Eventually, they become too exhausted—“exhausted”
serving as the scientific as well as descriptive term—to function
well. Without effective T cells, the immune system is unable to eliminate
the pathogen.
Until the study by Ahmed and his team, no
one understood why the immune cells should become exhausted in one type
of battle and not in another. The researchers tracked down the essential
difference between “good,” or highly functional T cells, and
“bad,” or exhausted ones. Using a mouse virus that has both
acute and chronic strains, they performed a genome-wide analysis of the
genes expressed by exhausted T cells overcome by the challenge of the
chronic strain. They compared those with genes expressed by functional
memory T cells. The exhausted T cells expressed high levels of an inhibitory
receptor. The functional memory T cells had no detectable level of this
receptor.
No wonder the T cells are exhausted in chronic
infections, says Ahmed. It is as if a driver kept pressing down on the
accelerator of a car, not realizing the emergency brake was on.
Although scientists in Japan first discovered
the presence of the inhibitory receptor, Ahmed’s group was the first
to show its role in T cell exhaustion. More important, they also demonstrated
how the braking effect of the inhibitory receptor signals could be blocked
with antibodies. The team used mice that were infected with the chronic
strain of the virus and genetically engineered to be immunosuppressed.
Despite the mice’s crippled immune systems, when they were given
antibodies that blocked the expression of the inhibitory receptors, their
T cells’ ability to function against the infection was significantly
restored. Whereas the virus curbed the body’s natural immune defenses,
the blockade treatment revved it up again.
Applications
in the developing world
Ahmed’s
group now will apply the same immunologic strategy to nonhuman primates,
focusing on hepatitis C. Hepatitis C is the most common blood-borne viral
disease in the United States, affecting more than 2.5 million Americans
and a staggering 170 million people worldwide. Without effective treatment,
many of those infected develop cirrhosis or liver cancer. The best treatment
regimens now available are effective in only half the cases, and they
are so difficult, expensive, and laden with serious side effects as to
essentially preclude their use in the developing world.
The health and economic impact of the hepatitis
C challenge and the promise of this new immunologic blockade strategy
recently won Ahmed’s research team a $12.5 million grant from the
Grand Challenges in Global Health Initiative. Funded by the Bill &
Melinda Gates Foundation, the initiative seeks to achieve scientific breakthroughs
against diseases that kill millions of people each year in the world’s
poorest countries. Headed by Ahmed, the research project includes collaborators
at Harvard, Columbus Children’s Research Institute, Rockefeller
University, and the NIH. If all goes well, Ahmed expects clinical trials
of a blockade-type vaccine to begin within the next five to 10 years for
those with hepatitis C and other chronic infections and potentially for
patients with certain forms of deadly cancer.
Ahmed hypothesizes that the blockade vaccine
could enhance the effect of other vaccines given therapeutically. “The
combination of the two could be highly synergistic in both chronic disease
and cancer,” he says.
Closing
a hole in the nation's containment strategies
Whereas
Ahmed’s research seeks to amplify the body’s natural immunity,
his long-time collaborator, Christian Larsen, is working at the other
end of the spectrum. Larsen, the Carlos and Marguerite Mason Professor
of Surgery and director of the Emory Transplant Center, seeks to selectively
tamp the immune response to allow continued tolerance of a transplanted
organ while maintaining ability to fight infection. He is asking a different
set of questions about immune memory. Does a transplant recipient’s
immune system “remember” earlier vaccinations, for example,
against tetanus, measles, or smallpox? Do suppressed immune systems respond
to new vaccinations differently from immune systems that are intact?
Ahmed and Larsen have been collaborating
on protective immunity for almost a decade now, a partnership so productive
that the NIH has repeatedly called for relationship advice to pass on
to other, less amicably functioning research teams. This past year, as
part of a federal biodefense effort, the NIH asked for a different kind
of advice. Because transplant patients are severely immunosuppressed,
NIH leaders figured that what Larsen and Ahmed are learning about immune
memory in this population will apply many times over to those with immune
systems partially suppressed by chronic viral or autoimmune diseases or
by chemotherapy. The NIH wants to know how to protect these rapidly expanding
groups of patients from the triple threats of bioterrorism, emerging infectious
diseases, and the ever-present possibility of a new influenza pandemic.
That leads to another question: how to protect
the whole population from new risks that result from a continually expanding
number of people with compromised immune systems in its midst. Immunosuppressed
people represent a sizeable hole in any national and global containment
strategies against bioterrorism or threats from emerging infectious disease,
says Larsen. First, they are unable to take some live attenuated vaccines—smallpox,
for example—and when given vaccinations against other diseases,
such as flu, they may be less likely to develop clinically significant
levels of protective antibodies. Second, they may even intensify the spread
of infectious disease, as the 2003 SARS outbreak demonstrated. The patient
known as the “Toronto super-spreader,” whose extraordinarily
high levels of the SARS virus caused infection among health care workers
despite all precautions, was a lung transplant recipient.
Larsen and Ahmed want to change this double
whammy. As part of a $10 million grant from NIH, they are mapping the
intricate twists and turns of how immunosuppression changes the response
to vaccinations against influenza and smallpox. They also want to determine
whether using new immunosuppressive drugs can improve that response.
Kidney transplant patients—the largest
transplant population—have been quick to volunteer for the study
measuring immune response following a standard flu shot. (As part of the
control group, Larsen pulls up his own sleeve for blood tests on a regular
basis.) Transplant patients know that even if they’ve been vaccinated,
they get sicker and are more likely to die of flu. Having the flu also
raises the risk of organ rejection.
Thanks to the availability of new tools
developed by Ahmed and others, researchers have what they need to describe
the magnitude, character, and molecular signature of the full spectrum
of immune responses following vaccination against flu: the antibodies
that neutralize invading viruses; flu-specific T cells that screen infected
cells in the body and destroy them before they can replicate; and memory
T cells that remain vigilant for any appearance of the virus seen in the
vaccine.
The current study will determine if altering
the drug regimen inducing immunosuppression can strengthen transplant
recipients’ response to the flu vaccine (good) without strengthening
recognition and response to the transplanted kidney (very bad). Currently,
scientists do not know what effect different immunosuppressive drugs have
on immunologic memory, although animal studies have suggested that some
drugs cause more memory decay than others.
The team is making similar comparisons of
immune response to a new form of smallpox vaccine in rhesus macaques,
some immunologically healthy, others taking one of the immunosuppressant
drugs given to humans after transplant. When smallpox was last active,
mortality among the general population infected with the highly contagious
virus was approximately 30%. The general assumption among scientists and
clinicians is that, should smallpox reappear today, mortality among infected
immunosuppressed patients would approach 100%.
Currently, available smallpox vaccines use
live vaccinia virus. This vaccine works well, effectively establishing
a pool of virus-specific memory T cells that slowly decline over several
decades and B cell populations that remain stable even longer. But that’s
the scenario only in people with reasonably functioning immune systems.
Some people who were later found to have defects in T cell immunity have
had life-threatening complications to this vaccine. Such findings mean
that smallpox vaccination is contraindicated for immunosuppressed patients,
at least with the current vaccine.
However, a different vaccine, known as modified
vaccinia Ankara strain (MVA), has been created by passing the live vaccinia
virus through 500 generations of chick embryos, during which time the
virus mutates and loses its capacity to replicate effectively in human
cells. Larsen and others now are studying the immune response to the MVA
vaccine in immunosuppressed monkeys at Yerkes Primate Research Center,
research that may well be applicable to human patients. Does the new vaccine
protect against smallpox infection in these monkeys? Is it safe, or does
it trigger organ rejection? Do monkeys taking one of the new immunosuppressant
drugs have a better immune response?
Mapping,
then tailoring the immune response
The
questions raised in these studies go straight to the heart of how the
immune system works in health and when challenged by chronic infectious
diseases or immune suppression. The devil is in the details, of course,
but once researchers complete the precise roadmap of immune response over
time, the way to change those details to create a desired immune response
will be clearer. Whether they are restoring memory to T cells long tired
of fighting hepatitis C or teaching the immune system to selectively “forget”
about a transplanted organ, Ahmed and Larsen each hope to help the other
find the keys to perfect immune balance.
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