This overly severe immune reaction, known as a "cytokinestorm," can lead to death in influenza patients. In a cytokine storm, theimmune system floods the small air sacs of the lungs with fluid andinfection-fighting cells in an attempt to stamp out infection that insteadblocks airways and damages tissues and organs. Ordinarily, the human body triesto fight the damage influenza causes—particularly, destruction of the cellslining the alveoli in the lung—by producing cytokines, small cell-signalingprotein molecules, and gathering a variety of immune cells. However, thoughcytokine production is usually regulated by the body, sometimes it overreactsand a cytokine storm results.
This reaction is believed to have played a significant rolein the 1918-1919 worldwide influenza pandemic—in which 50 million people diedat a low-end guess—and also the more recent outbreaks of swine and bird flu.Recently, however, a Scripps team was able to identify the cells that causethese cytokine storms, detailing the results in a study published in the Sept.16, 2011 issue of Cell.
"In the new research, we show directly for the firsttime that the damaging effects of cytokine storm are distinct from the impactof virus replication and pathological changes in infected cells," Scripps research professor Dr. Hugh Rosen, saidin a press release. Rosen led the study along with Scripps research professorDr. Michael B.A. Oldstone. "The findings provide a new paradigm forunderstanding influenza and could point the way to new therapies."
The Scripps team began their work by setting their sights ona receptor S1P1 for a molecule known as Sphingosine-1-phosphate (S1P), whichhas been a point of interest in Rosen's lab and has a connection to autoimmunedisease. The researchers discovered that by manipulating the S1P1 receptors inthe endothelial cells, which line the interior surface of blood vessels, theycould affect the release of cytokines, a discovery that ran contrary to theprevious assumption that cytokine release was triggered through infected cells.From there, the team investigated whether they could affect the course ofcytokine storm in mice carrying the human pandemic influenza strain H1N1. Theyfound that by utilizing a molecule that bound to the S1P1 receptor, they could"down-regulate" the body's immune reaction to achieve an adequate immuneresponse to battle the virus while simultaneously diminishing or eliminatingthe cytokine storm.
"The ability to separate the different contributions ofcytokine amplification and resident and recruited leukocyte responses using theshort-term administration of a specific receptor agonist was very intriguing,"says Rosen. "Further, our previous work that showed that protection by thismechanism did not potentiate viral replication, and still led to a normaleffector T lymphocyte response, normal, class-switched neutralizing antibodiesand long term memory, encouraged us to think that this may have some utilitydown the line."
Rosen noted in a press release that the S1P1 receptors offera target "not subject to the rapid mutational escape of the virus, andtherefore less subject to resistance," and that now that the origin ofcytokines is known, "it is likely that a single oral dose of a compound can bedeveloped that will provide protection from cytokine storm early in infection."Oldstone added that additional research on the receptor could aid in pinpointingwhich individuals have a susceptibility to the cytokine storms and couldbenefit from a drug targeting that particular process.
"This type of therapy, which is against a host response, isas effective—in fact is more significantly effective than giving the currentantiviral therapies that are on the market," said Oldstone in a video clipabout the study. "And interestingly, by getting both in combination, theantiviral therapy and the therapy against the Sphingosine-1-phosphate-1receptor, at least in animal studies, give the maximum protection that'sobserved."
Several companies already have clinical trials focused onS1P1 modulators underway, including Actelion, Novartis and Receptos, whosecompounds were discovered by the Rosen and Roberts laboratories in the ScrippsMolecular Screening Center, supported by the National Institutes of Health(NIH) Common Fund. Rosen notes that the non-selective S1P receptor agonistGilenya "is approved for the treatment of relapsing remitting multiplesclerosis (RRMS)," adding that additional compounds are in development forRRMS, as well as psoriasis and dermatomyositis.
"Diseases that require lymphocyte recruitment to tissues andare amplified by cytokines are of interest," says Rosen of whether thisdevelopment has any merit as a treatment for other conditions. He adds that itis still a bit early to properly gauge "therapeutic potential or downsides,because clinical data are still sparse for this new mechanism."
The Scripps team's findings were published in the study"Endothelial cells are central orchestrators of cytokine amplification duringinfluenza virus infection." Joint first authors of the paper were ScrippsResearch postdoctoral fellows John Teijaro and Kevin Walsh, and additionalauthors included Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona L.Scott, Esther Martinborough and Robert J. Peach. Grants from the United StatesPublic Health Service and the National Institute of Allergy and InfectiousDiseases, part of the NIH, and the NIH Common Fund supported the study.