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

November 4, 2013 by Elizabeth Cooney, Harvard Medical School
Immune turbocharger
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. Credit: von Andrian Lab

(Medical Xpress)—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.

"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 ," 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 . 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 . 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 and enhancing their expansion and .

'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 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.

Explore further: Antibodies are not required for immunity against some viruses

More information: www.cell.com/cell-reports/abst … -1247%2813%2900512-3

Related Stories

Antibodies are not required for immunity against some viruses

March 1, 2012
A new study turns the well established theory that antibodies are required for antiviral immunity upside down and reveals that an unexpected partnership between the specific and non-specific divisions of the immune system ...

Adjuvanted vaccine boosts flu protection for elderly

October 16, 2013
A recent study has strengthened the current knowledge of the increased effectiveness of adjuvanted flu vaccines in the elderly—a population highly affected by seasonal influenza.

Patient, heal thyself: Solution to personalised treatment for chronic infections could lie in patient's own blood

September 20, 2013
A recent discovery by scientists at A*STAR's Singapore Institute for Clinical Sciences (SICS), in close collaboration with researchers at the Singapore Immunology Network (SIgN), provides hope for a new personalised treatment ...

Anti-CD47 antibody may offer new route to successful cancer vaccination

May 21, 2013
(Medical Xpress)—Scientists at the School of Medicine have shown that their previously identified therapeutic approach to fight cancer via immune cells called macrophages also prompts the disease-fighting killer T cells ...

Vaccine adjuvant uses host DNA to boost pathogen recognition

April 5, 2013
Aluminum salts, or alum, have been injected into billions of people as an adjuvant to make vaccines more effective. No one knows, however, how they boost the immune response. In the March 19, 2013, issue of the Proceedings ...

New modular vaccine design combines best of existing vaccine technologies

July 29, 2013
A new method of vaccine design, called the Multiple Antigen Presentation System (MAPS), may result in vaccines that bring together the benefits of whole-cell and acellular or defined subunit vaccination. The method, pioneered ...

Recommended for you

Novel genomic tools provide new insight into human immune system

January 19, 2018
When the body is under attack from pathogens, the immune system marshals a diverse collection of immune cells to work together in a tightly orchestrated process and defend the host against the intruders. For many decades, ...

Genomics reveals key macrophages' involvement in systemic sclerosis

January 18, 2018
A new international study has made an important discovery about the key role of macrophages, a type of immune cell, in systemic sclerosis (SSc), a chronic autoimmune disease which currently has no cure.

First vaccine developed against grass pollen allergy

January 18, 2018
Around 400 million people worldwide suffer in some form or other from a grass pollen allergy (rhinitis), with the usual symptoms of runny nose, cough and severe breathing problems. In collaboration with the Viennese firm ...

Researchers discover key driver of atopic dermatitis

January 17, 2018
Severe eczema, also known as atopic dermatitis, is a chronic inflammatory skin condition that is driven by an allergic reaction. In their latest study, researchers at La Jolla Institute reveal an important player that promotes ...

Who might benefit from immunotherapy? New study suggests possible marker

January 16, 2018
While immunotherapy has made a big impact on cancer treatment, the fact remains that only about a quarter of patients respond to these treatments.

Researchers identify new way to unmask melanoma cells to the immune system

January 16, 2018
system, which enables these deadly skin cancers to grow and spread.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.