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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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