Method Blocks Growth of Adhesions After Surgery

Inflammation-induced postsurgical adhesions cost the United States more than $1 billion annually, and there are very few treatment options. Inflammatory diseases, including irritable and inflammatory bowel syndromes, asthma, and allergies, also exact a huge toll. But now Begonia Ruiz-Perez, HMS instructor in medicine at Brigham and Women’s Hospital; Arthur Tzianabos, formerly an HMS associate professor of medicine (microbiology and molecular genetics) at BWH who recently joined Shire Pharmaceuticals; and their collaborators describe research that could lead to a new way of suppressing these inflammatory responses. The study appears in the Nov. 15 Proceedings of the National Academy of Sciences.

Image courtesy of Arthur Tzianabos

Dangerous developments. Panel A shows an animal treated with saline after surgery and panel B, with the zwitterionic polysaccharide CP1. The first reveals adhesions connecting the abdominal wall with the cecum; one of the fibrotic growths is being grasped by the instrument. The animals treated with CP1 exhibited fewer and less severe adhesions. The graphs show adhesion scores of animals treated with saline, CP1, and the nonzwitterionic polysaccharide PG.

The researchers showed in vivo that zwitterionic polysaccharides (ZPSs), which coat the gut bacterium Bacteroides fragilis, induced T cells to make interleukin-10 (IL-10), whose powerful immunosuppressive activity has been well characterized. IL-10, in turn, prevented postsurgical fibrosis, or adhesions, from developing in one set of experimental animals and prevented abscess formation in another. These fibrotic host responses are common complications of abdominal and pelvic surgery.

The investigators purified zwitterionic polysaccharides (which have both positive and negative charges) from B. fragilis and then injected them subcutaneously into mice. The sugars induced a subset of CD4+ cells to make IL-10, and these cells were able to transfer protection against fibrosis into untreated animals. “These studies clearly demonstrate that the mechanism of protection induced by ZPS treatment depends on IL-10 production from CD4+CD45RB^lo T cells,” the researchers report.

Investigators have previously attempted to harness IL-10’s anti-inflammatory power by removing certain T cells from a patient, somehow “tricking them” in vitro into making IL-10, and then transferring them back into the patient, said Tzianabos. However, the strategy is too labor intensive to be practical, he said. The researchers’ methodology is potentially a far more practical way of harnessing the ability of IL-10 to treat inflammatory diseases.

In earlier work, Tzianabos and co-author Dennis Kasper, the William Ellery Channing professor of medicine at HMS and Brigham and Women’s Hospital and an HMS professor of microbiology and molecular genetics, showed that zwitterionic polysaccharides are capable of activating T cells and that this activation was involved in stimulating production of IL-10 (see Focus, June 4, 2004) . Most polysaccharides activate only B cells and induce antibody protection.

More recent studies published in Cell by Sarkis Mazmanian, Tzianabos, and Kasper showed that zwitterionic polysaccharides made by B. fragilis play a key role in shaping the immune system (see Focus, July 15, 2005). At birth, immunity is skewed toward th2 responses, which drive production of cytokines involved in asthma and allergy. The B. fragilis zwitterionic polysaccharides were shown to shift the immune system toward a more balanced mix of th2 and th1 immunity. The th1 system attacks intracellular bacterial pathogens and is responsible for protective immune responses.

Currently, the researchers are negotiating to license the zwitterionic polysaccharide–treatment technology to a biotechnology company.

—David Holzman

Model Devised—and Validated—for Virulent Childhood Cancer

Using an analytical technique for validating animal models of human cancers, HMS researchers have started to map the mechanics of usually fatal rhabdoid tumors, which strike during childhood. Their report appears in the Dec. 6 Proceedings of the National Academy of Sciences.

These tumors involve a mutation in a potent tumor-suppressor gene, Snf5. “We became interested in the Snf5 gene because it is associated with an aggressive pediatric cancer that we’re terrible at curing,” said principal investigator Charles W.M. Roberts, HMS associate professor of pediatrics at the Dana–Farber Cancer Institute. Snf5 is part of the SWI/SNF chromatin remodeling complex, which contributes to packing DNA for storage and unpacking it for transcription. Improper packing can lead to abnormal gene regulation.

In earlier work, these researchers had demonstrated the importance of Snf5’s tumor-suppressing activity. “It turns out if you turn Snf5 off in a conditional mouse model, 100 percent get cancer, and the time to onset is only 11 weeks,” said Roberts, referring to a mouse model in which an engineered “switch” regulates a gene of interest so investigators can leave it on or turn it off. “That’s remarkably rapid for turning off a single normal gene.” By comparison, turning off either of two other tumor suppressors in these mice, p53 or p16, leads to cancer in 20 or 60 weeks, respectively.

Having confirmed Snf5’s tumor-suppressing activity, Roberts and colleagues turned it off in primary mouse cells taken from these conditional mice, which were otherwise completely normal. Expression of the tumor suppressor p16 immediately plummeted, and that of E2F targets—genes associated with cell proliferation—skyrocketed. One might reasonably suppose that these occurrences could lead to rapid proliferation; however, abnormal activation of E2F by itself induces cell cycle arrest. The cell “realizes that the strong stimulation of cell cycle progression and growth is a mistake and triggers p53-mediated cell death,” said Roberts.

“p53 is almost like the police,” Roberts explained. “If somebody pulls a gun, and the police can arrest him, no violence will occur. It’s when the police aren’t there and somebody pulls a gun that can be a real problem.”

And, in fact, in Snf5-negative mice, “when we also turn off p53, the mice now get cancer in only three weeks,” said Roberts. In this case, the mice get the same cancers as mice that are merely Snf5-negative, and the lack of p53 just accelerates the process.

Also notable in this work, Roberts and colleagues used a novel algorithm, which Roberts helped develop, to evaluate how well the mouse actually models the human cancer. It is a microarray for examining gene expression, containing 22,650 different probes. The researchers compared expression in the mouse model tumor to that of human rhabdoid tumors, as well as other pediatric cancers that arise in the same location. “Ours turned out to be a very good model,” he said. So the research stands a good chance of illuminating oncogenesis in human rhabdoid tumors.

—David Holzman

Off-label Use Of Antipsychotic Drugs Risky to Elderly Dementia Patients

Older antipsychotic drugs may be just as dangerous for elderly people with dementia as newer medications, reports a study in the Dec. 1 New England Journal of Medicine.

Despite not being approved for these uses, antipsychotic drugs have been popular in the last decade to tame aggression, delusions, and other behavioral problems for people with dementia.

In April, the U.S. Food and Drug Administration warned that the second generation of antipsychotic drugs, also called atypical, nearly doubled the risk of death of elderly people with dementia compared to placebos. The FDA provided no data.

The first generation of antipsychotic medications may be just as risky, report Brigham and Women’s Hospital researchers. Their retrospective cohort study included nearly 23,000 people age 65 or older who were prescribed an antipsychotic drug for the first time between 1994 and 2003.

To place the risk of conventional antipsychotic drugs in context, only cancer, congestive heart failure, and HIV infection conveyed a greater short-term risk of death, wrote first author Philip Wang, HMS assistant professor of health care policy at BWH, and his colleagues.

“If confirmed, our results suggest that conventional antipsychotic medications may not be safer than atypical agents and should not simply replace atypical drugs that are stopped in response to recent FDA warnings, as may be happening,” they conclude.

So far, evidence does not justify a warning label on the older drugs, said Crystal Rice, an FDA spokesperson, in an e-mail.

“So what should a clinician do when caring for a patient with dementia who develops psychotic symptoms or aggression?” queried an editorial in the Oct. 19 Journal of the American Medical Association that accompanied a meta-analysis that found a higher risk of death among people with dementia taking the new drugs. “Antipsychotic drugs should not be used when nondrug treatments are available and the risk of harm or significant distress is low. Fortunately a range of alternative therapies, including behavioral interventions and antidepressant drugs, can be effective.”

—Carol Cruzan Morton

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