Team Finds Drug Lessens Body's Massive and Often Deadly Immune Response to Flu Virus

By Anna Sobkowski

A team led by scientists from The Scripps Research Institute has shown that a drug that acts on a specific aspect of the immune system – rather than by killing the virus itself – may mitigate the virulence of influenza infection. The drug impacts the cytokine response, the body's signature immune reaction to influenza infection that can itself be lethal.

The study, led by Scripps Research Professors Michael Oldstone and Hugh Rosen was published January 21 in the Early Edition of the Proceedings of the National Academy of Sciences.

When the influenza virus invades, it causes injury in two ways – by killing lung cells outright and by triggering an immunopathologic response that begins when T cells and dendritic cells respond to the pathogen by causing the excessive release of cytokines. Cytokines are small proteins or biological factors with specific effects on cell-cell interaction, communication, and behavior of other cells. These cytokines, in turn, attract damaging amounts of the immune T cells, polymorphonuclear leukocytes and macrophages to the infected site.

A cytokine reaction can be severe enough to cause a "cytokine storm," a condition in which the alveoli of the lungs become so flooded and clogged with infection fighting cells that they can no longer properly absorb oxygen. The ability to elicit cytokine storms is what, in large part, makes certain epidemic strains of flu, such as bird flu, so deadly. Permanent lung damage often results from a severe cytokine reaction, even if the individual survives.   

In this study, Oldstone, Rosen, and colleagues showed that administering a compound known as sphingosine analog AAL-R directly into the lungs of mice diminished the release of cytokines. Significantly, this effect was achieved while maintaining the humoral immune response – the aspect of immunity in which differentiated B cells (plasma cells) make anti-viral antibodies. In addition, even though the level of influenza virus-specific T cells was lowered, it was still sufficient to control the viral load. This is the first time scientists have been able to tamp down one aspect of the immune response while keeping another intact.

"With this work we showed that by reducing the numbers of T cells and cytokines in the lungs, we can reduce the numbers of infiltrating polymorphonuclear leukocytes and macrophages, which are most destructive to the lung," Oldstone says. "Even though this compound does not kill the virus itself, the immunopathologic response was significantly impaired."  

Broader Applications

In a paper published last year in the journal Molecular Pharmacology (74:896-903, 2008), Rosen, Oldstone, and colleagues described the technique that could be used in mice to administer sphingosine analog AAL-R into the lung by injection. (In humans the drug would be administered via a nasal spray.) Such local administration of the drug significantly slowed lymphocyte trafficking into the lung and expansion of virus-specific T lymphocytes by lung dendritic cells.

In the short term, the researchers plan to study the basic mechanism for sphingosine analog AAL-R receptors in order to lay the foundation for designing the best possible drug. They also plan to look at the effects of combination therapy – adding Tamiflu to the drug treatment – as a way to both kill the virus and block the immunopathologic response.

Of immediate concern is the H5N1 virus, more commonly known as bird flu, which resurfaced in Asia in 2003. Since then it has killed millions of birds worldwide and more than 60 percent of the nearly 400 people infected, according to World Health Organization estimates. So far, bird flu has been contained by health authorities by killing infected flocks, but the fear is that if the virus is one day able to jump from birds to humans, and spread human to human, a worldwide epidemic could result.

"We know that many of those who died in the 1918 influenza pandemic were young people, those with the strongest immune systems whose bodies mounted the strongest immunopathologic responses," Oldstone says.  "Our hope is that our current research will yield answers about how to treat this kind of immune response not only in influenza, but also in other viral diseases such as hantavirus and SARS in which pulmonary infiltration is severe."

First authors of the study, "A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection," were David Marsolais of Scripps Research, Bumsuk Hahm of Scripps Research and the University of Missouri, and Kevin Walsh of Scripps Research. In addition to Oldstone and Rosen, additional authors were Kurt H. Edelmann and Dorian McGavern of Scripps Research, Yasuko Hatta of the University of Wisconsin-Madison, and Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, Japan.  For more information, see http://www.pnas.org/content/early/2009/01/21/0812689106.abstract.

This work was supported by the U.S. Public Health Service and the National Institutes of Health, as well as grants and fellowships from the Ministries of Education, Culture, Sports, Science and Technology and of Health, Labor, and Welfare of Japan, the Kyorin Pharmaceutical Company, and Le Fonds de la Recherche en Sante du Quebec.

Send comments to: mikaono[at]scripps.edu

"Even though this compound does not kill the virus itself, the immunopathologic response was significantly impaired," says Professor Michael Oldstone.

Professor Hugh Rosen was another leader of the study.