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Immune Turbocharger

Article / Review by on November 1, 2013 – 10:06 pmNo Comments

Immune Turbocharger
In mice, bone-loss drugs boosted the power of vaccines

Could a drug commonly prescribed to prevent bone loss boost the power of vaccines?

New research from Harvard Medical School shows that adding compounds known as bisphosphonates to both commercial and experimental vaccines enhances their effectiveness in mice, raising hopes they could help people mount a more robust immune response.

A micrograph section through a lymph node shows different cell types involved in immune response: The green cells in the periphery are macrophages, B cells are blue; dendritic cells are yellow/orange, and the small red cells reflect a subset of memory T cells. Image: von Andrian LabA micrograph section through a lymph node shows different cell types involved in immune response: The green cells in the periphery are macrophages, B cells are blue; dendritic cells are yellow/orange, and the small red cells reflect a subset of memory T cells. Image: von Andrian Lab

“Here you have this group of drugs that are approved for millions of people, mostly menopausal women but also others, where there is an extensive database of safety data and a lot of clinical experience. And they have this previously unrecognized enhancing effect on immune responses,” said Ulrich von Andrian, HMS Edward Mallinckrodt Jr. Professor of Immunopathology.

“Perhaps down the line it would be possible to use bisphosphonates in combination with existing vaccines, at least in specific groups of patients who are at particular risk of acquiring disease or at risk of not responding well to a conventional vaccine,” he said.

These findings are published in Cell Reports.

Traditional vaccines include small amounts, weakened versions or components of a given pathogen to induce creation of antibodies without causing disease. The addition of compounds called adjuvants makes vaccines more effective, but elderly people and others with weakened immune systems still don’t gain as much protection from a vaccine as healthier people do.

“Oftentimes those groups of individuals who are in the greatest need of the protection afforded by vaccines are the ones who don’t respond well,” said von Andrian. “If you could make a more potent vaccine that has a more vigorous adjuvant effect, perhaps more of these patients would actually develop protective immune response that would ultimately be beneficial.”

Clodronate conundrum

Von Andrian’s team established the bisphosphonate-vaccine connection while exploring a well known—but not well understood—phenomenon involving players in the immune system called macrophages. Strategically positioned within lymph nodes, these highly specialized molecules capture viruses ferried from the lymphatic system.

In a paper published in Nature in 2007, von Andrian and his colleagues reported that these macrophages do more than simply consume viruses; they also play a key role in spurring antibody production by presenting viral material—the antigen—to B cells that prepare an antibody in response to the threat. The next time the antigen is encountered, the immune system recognizes it and mounts an enhanced attack.

Secondary to that discovery was a puzzling revelation associated with the experimental use of bisphosphonates, which are widely used in people to slow the bone thinning that can accompany age or disease. One particular form, clodronate, is a handy laboratory tool for interfering with macrophages. Packaged inside lipid vesicles, clodronate is appetizing but fatal to macrophages.

Von Andrian and Matteo Iannacone, a former postdoctoral fellow and senior author of the current paper, faced a conundrum: Although their results showed that lymph node macrophages promote B cell activation, the presence of clodronate and other bone-loss drugs revved up B cell-dependent antibody production even after the macrophages were destroyed.

To understand this, the scientists tested a variety of cells and molecular pathways involved in the intricate immune response. They used advanced microscopy to look at cells interacting with one another, capturing viral infections in real time with fluorescence-based imaging techniques.

One clue came from experiments showing that immune responses were not enhanced when macrophages were eliminated without bisphosphonates. This suggested that bisphosphonates boost vaccines by a novel mechanism that does not depend on macrophage depletion.

Experiments in mice ruled out multiple other immune system cells and key pathways that could conceivably be boosting antibody production. Bisphosphonates stood alone, increasing antibody responses to live and inactive viruses, proteins, helper molecules called haptens and an existing vaccine against hepatitis B. The scientists concluded that they work by directly targeting B cells and enhancing their expansion and antibody production.

‘Overdrive’

“The activity these bisphosphonates had was strikingly similar to what you like to have when you use a vaccine adjuvant,” von Andrian said. “You take an antigen, you add a second compound to it, whereby that second compound is not seen as an antigen but enhances the response to whatever antigen you combine it with. Clinically there are just a handful of compounds approved for that.”

Further cementing the role of bisphosphonates was a boost in the number of antibodies found in blood drawn from 20 patients taking bisphosphonates after cancer had spread to their bones.

“It appears that systemic treatment with bisphosphonate somehow put this entire system in overdrive,” von Andrian said.

In another experiment, the scientists gave mice a low dose of a hepatitis B vaccine along with a bisphosphonate and compared them to mice given the vaccine alone.

“We showed that this commercial vaccine, one that’s given to people every day, when combined with bisphosphonate would actually have a turbocharged effect,” von Andrian said.

The next step would be to find out if these results can be applied to people.

“We wouldn’t do this ourselves but I would be delighted if that was the outcome,” he said. “Of course, humans are not mice, so one needs to do the proper research to see whether it will be useful and how useful it would be, based on the benefit relative to any risk.”

Long-term use of bisphosphonates has been associated with a jaw disease called mandibular necrosis, but von Andrian said he is not aware of any reports of side effects with single doses.

By ELIZABETH COONEY

This work was supported by European Research Council grants 281648 and 250219; National Institutes of Health grants AI40696, AI078897 and AI069259; Italian Association for Cancer Research grant 9965; and a career development award from the Giovanni Armenise-Harvard Foundation.

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About Harvard Medical School (HMS)

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“Since 1872, Harvard Medical School has been the incubator of bold ideas—a place where extraordinary people advance education, science and health care with unrelenting passion.

Whether training tomorrow’s doctors and scientists, decoding the fundamental nature of life, advancing patient care or improving health delivery systems around the world, we are never at rest. Allied with some of the world’s best hospitals, research institutes and a University synonymous with excellence, the School’s mission remains as ambitious as it is honorable: to alleviate human suffering caused by disease.”

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About Harvard School of Public Health (HSPH)

Harvard School of Public Health is dedicated to advancing the public’s health through learning, discovery and communication. More than 400 faculty members are engaged in teaching and training the 1,000-plus student body in a broad spectrum of disciplines crucial to the health and well being of individuals and populations around the world. Programs and projects range from the molecular biology of AIDS vaccines to the epidemiology of cancer; from risk analysis to violence prevention; from maternal and children’s health to quality of care measurement; from health care management to international health and human rights.

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About Harvard University.

Established in 1636, Harvard is the oldest institution of higher education in the United States. The University, which is based in Cambridge and Boston, Massachusetts, has an enrollment of over 20,000 degree candidates, including undergraduate, graduate, and professional students. Harvard has more than 360,000 alumni around the world.

Harvard University is devoted to excellence in teaching, learning, and research, and to developing leaders in many disciplines who make a difference globally. Harvard faculty are engaged with teaching and research to push the boundaries of human knowledge. For students who are excited to investigate the biggest issues of the 21st century, Harvard offers an unparalleled student experience and a generous financial aid program, with over $160 million awarded to more than 60% of our undergraduate students. The University has twelve degree-granting Schools in addition to the Radcliffe Institute for Advanced Study, offering a truly global education.

‘Universities nurture the hopes of the world: in solving challenges that cross borders; in unlocking and harnessing new knowledge; in building cultural and political understanding; and in modeling environments that promote dialogue and debate… The ideal and breadth of liberal education that embraces the humanities and arts as well as the social and natural sciences is at the core of Harvard’s philosophy. ’/ Drew Gilpin Faust

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* The above story is adapted from materials provided by Harvard University

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