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The tracers enabled the scientists to observe specific immune cells as they sprang into action in response to the cancer. “This lets us see not only how but where” the body is responding to disease, Witte explains. Eventually, he believes, such PET scans could allow clinicians to observe the ebb and flow of the immune system over the course of a disease, such as cancer or an autoimmune disorder, and to evaluate the effectiveness of treatment.
Meanwhile, HHMI investigator Philippa Marrack, a onetime doubter of the benefits of video recordings of the immune system in action, has been converted. Her team at the National Jewish Medical and Research Center in Denver will soon begin recording T cells to probe a phenomenon they discovered. They found that T cells compete with each other for antigens on a type of antigen-presenting cell called a dendritic cell. Dendritic cells gather antigens in tissue and then carry them into lymph nodes where they activate the T-cell response.
Now her laboratory is going to use multiphoton microscopy to find out if the T cells' competition leads the “winning” T cell to deny other T cells access to the antigen. This may prove important to the design of multivalent vaccines, which are composed of two or more antigens to stimulate a broader response to infection or a response to more than one type of disease. By recording the immune response in action when two antigens are present, she hopes to determine whether T-cell competition is undermining the immune response to multiple antigens. If so, perhaps this competition needs to be taken into account when designing certain types of multivalent vaccines, particularly complex DNA vaccines such as those being developed against HIV.
According to Davis, “You always have more questions to ask than the current state of the technology is capable of answering.” But he believes the broadening array of video imaging studies will eventually lay out the molecular choreography of the immune system. Knowing just which steps and missteps occur in that biochemical dance may be key in improving health for all—from developing new vaccines to helping the body rid itself of cancer cells.
Watching how the immune system responds throughout the body to a localized threat has provided new insights into autoimmune disorders, asthma, and allergies. Richard M. Locksley, an HHMI investigator at the University of California, San Francisco, has engineered a mouse with fluorescent probes in its immune-signaling system that light up when mucosal barriers, such as the intestinal lining or lung, come under attack.
He introduced hookworms into the mouse's gut and then sliced and analyzed tissue from the entire mouse to find where the immune cells that signal such an attack, called effector cells, glowed. “This allowed us to find where every effector cell in the body ended up,” Locksley says.
As expected, certain known types of effector cells lit up in the intestinal lining where the hookworms bit. He was surprised, however, to find effector cells widely distributed, even in areas such as the lungs where the worms had not been. Watching these cells appear in such large numbers in the lungs in response to intestinal worms led Locksley to believe he had identified a response that overlaps with the lung's response to airborne irritants in asthma and other allergic disorders.
He has made the mouse model freely available to the scientific community, encouraging others to use it to test new therapies for hookworms or other parasites, and to monitor effector cell activation and movement into unexpected places, such as the lungs and skin. “It's early days,” he says, “but I'm convinced we're on the right track to show how these cells might contribute to chronic diseases like asthma. Eventually, manipulating the distribution and survival of these potent effector cells may provide new pathways for treating these diseases.”