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February 03

Study Shows Molecule Can Infiltrate Immune Cells to Treat Rheumatoid Arthritis

'Ghostly' Drug May Help Fight RA

Study Shows Molecule Can Infiltrate Immune Cells to Treat Rheumatoid Arthritis

By Daniel J. DeNoon
WebMD Health News

Reviewed by Louise Chang, MD

Jan. 28, 2010 - A ghostly "suicide" drug wafts into immune cells in joints, making the cells self-destruct and reducing rheumatoid arthritis in mice.

The drug, technically a BH3 mimetic dubbed TAT-BH3, is a man-made molecule. One part of the molecule lets it drift through cell walls. The other part mimics a chemical signal missing in the macrophage immune cells that build up inside joints afflicted by rheumatoid arthritis (RA).

Because they are missing this signal, macrophages in RA joints don't die off as they are supposed to do. They live on, destroying bone and inflaming the joint, says Harris Perlman, PhD, associate professor of medicine at Chicago's Northwestern University Feinberg School of Medicine.

"In RA, there is this persistent inflammation that never shuts down. Part of the reason is these macrophages are missing a protein they need to die off," Perlman tells WebMD. "So this drug says OK, let's replace this protein. Let's bring back the death pathway."

Perhaps because normal cells aren't clinging to life like the zombie macrophages involved in RA, the drug doesn't kill normal macrophages. The drug was not toxic to mice.

But in mice with RA, injections of TAT-BH3 cut bone erosion by as much as 39% and thinned the too-thick lining of the joint by up to 34%.

Perlman says that by hitting it's Bim-protein target, TAT-BH3 has therapeutic effects that go beyond just killing macrophages.
"This drug does far more than cause cell death," he says. "We think this Bim protein has multiple functions and may be a great target for disease."

Perlman's team and others are making their molecule more appropriate for human treatment. One approach they are trying is to use tiny nanoparticles to speed the BH3 mimetic through cell walls. Much work remains before their drug prototype is ready for human studies.

Other BH3 mimetics, with targets different from the so-called Bim protein that is the focus of the Perlman study, are being developed as cancer treatments. Some already are showing promising results in clinical trials.

The Perlman study appears in the February issue of Arthritis & Rheumatism.

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The Lancet Journal Retracts Controversial Autism Paper

Retraction of 1998 Wakefield Study May Not Sway Those Who Fear Vaccine-Autism Link
Source ABC News

It was the scientific paper that served as a central pillar for the idea that vaccination could increase children’s risk of developing autism.

Now, with a formal retraction from the Lancet, the medical journal which in 1998 published this piece of research by Dr. Andrew Wakefield, most researchers will view the study as if it had never been published in the first place.

In a statement explaining its retraction of Wakefield’s paper, the Lancet said: “Following the judgment of the U.K. General Medical Council’s Fitness to Practice Panel on Jan. 28, 2010, it has become clear that several elements of the 1998 paper by Wakefield et al are incorrect … in particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false. Therefore we fully retract this paper from the published record.”

“The Lancet is an enormously prestigious journal with worldwide circulation, so its action of repudiation is very important,” said Dr. William Schaffner, chair of the Vanderbilt University School of Medicine’s Department of Preventive Medicine in Nashville, Tenn. “The retraction puts another nail in the coffin of this awful, painfully erroneous study.”

But the retraction is unlikely to close the Pandora’s Box that the Wakefield study opened, other vaccination experts said.

“Unfortunately, the idea that vaccines cause autism is already out there and the damage has already been done,” said Robert Field, professor of Health Management and Policy at the Drexel University School of Public Health in Philadelphia. “Years of research have clearly disproven a vaccine-autism link, yet many people continue to believe in it. If all of that research hasn’t changed their minds, the Lancet’s retraction is not likely to make much difference.”

Dr. Gregory Poland, editor-in-chief of the journal VACCINE and director of the Mayo Vaccine Research Group in Rochester, Minn., called the Lancet’s action merely “procedural.”

“What is more important is that an investigator, on the basis of false pretenses, published a paper and propelled a controversial hypothesis forward that led to decisions among individuals and groups to reject vaccination, with resultant outbreaks of these diseases,” he said. “The results are highly significant: millions spent needlessly, hundreds of thousands — maybe even millions — unimmunized, and a fog of suspicion cast upon vaccines.”

On Jan. 28, the United Kingdom’s General Medical Council (GMC) found Wakefield guilty of acting unethically during the time he conducted the famous case report of 12 children that questioned if a childhood vaccine caused a new form of autism.

Ethical Questions Dog Controversial Autism Study

Wakefield’s hypothesis was that by combining vaccines for measles, mumps and rubella into a single shot, known as MMR, the vaccine weakened the immune system and damaged the gut. He said that this, in turn, led to the development of autism.

The GMC concluded that Wakefield participated in “dishonesty and misleading conduct” while he conducted the research. Specifically, it found Wakefield responsible for an ethics breach because he wrote that the children involved in the case report were referred to his clinic for stomach problems, when he knew nearly half of the children were actually part of a lawsuit looking into the effects of an MMR vaccine. Some children didn’t have stomach issues at all.

Wakefield also failed to disclose he was paid in conjunction with the lawsuit, or that he had a patent related to a new MMR vaccine in development when he submitted the case report for publication.

Moreover, according to one of the findings against the doctor, Wakefield took blood samples from children at his own child’s birthday party and paid them each five British pounds for their trouble.

Following the GMC’s Jan. 28 ruling, Wakefield declined an interview with ABCNews.com, but issued a statement saying, “The allegations against me and against my colleagues are both unfounded and unjust and I invite anyone to examine the contents of these proceedings and come to their own conclusion.”

The GMC ruling is unlikely to erase the apparently false connection between vaccines and autism from the public mind. Nor will it detract from Wakefield’s positive reputation among some activists groups.

Following the GMC’s decision, the advocacy group the Autism Society issued a statement in which it said it “strongly supports funding research into gastrointestinal pathology, as well as any links between this pathology and the symptoms of autism. … In this field, Dr. Wakefield’s contributions to our families and members are greatly appreciated and there are many who support him in his research efforts.”

Wakefield Study Had Big Impact on Vaccination Rates

Similarly, the parent groups who stood behind Wakefield in rallies and in press statements say his theories have led to anecdotally successful treatment in their children and also doubt that a finding by the GMC will change any minds.

It is on this point that critics of Wakefield’s work agree.

“In some ways I think [the GMC ruling] is irrelevant,” said Dr. Paul Offit, chief of the Section of Infectious Diseases at Children’s Hospital of Philadelphia, who has been twice threatened with lawsuits for critical statements he has made of Wakefield’s work.

According to Offit — and international studies supported by the CDC as well as a 2004 review of large international studies by the Institute of Medicine — high-quality studies could not confirm Wakefield’s hypothesis about vaccines.

Still, when the public got word of Wakefield’s work, worried parents skipped vaccines, and the percentage of children who were not vaccinated in the United States rose from 0.77 percent in 1997 to 2.1 percent in 2000, according to an article by Dr. Michael Smith in the journal Pediatrics. A similar rise in children not being vaccinated occurred in Britain.

Although the U.S. Centers for Disease Control declared the United States cleared of measles in 2000, the lower vaccination rate brought back the disease in a 2008 outbreak. At least 131 cases were reported to the CDC, and 11 percent of the cases were hospitalized. A handful of children in Britain died of the measles around the time of the U.S. outbreak.

Since the publication of the 1998 article, Wakefield has left England and has set up an alternative research and treatment organization called Thoughtful House in Austin, Texas. On April 7, the GMC is scheduled to decide whether his ethical breaches constitute “serious professional misconduct” and if so, how Wakefield will be reprimanded or whether he will lose his license.

Regardless of the outcome, many vaccine efforts hope that this latest chapter in the debate over a connection between vaccines and autism will be the last.

“I think it is vital that the public and more importantly the press move past this issue,” said Dr. Nancy Minshew, professor of psychiatry and neurology and director of the University of Pittsburgh’s Autism Center of Excellence.

“It is time for a new script,” she said. “In a time when scientists have discovered a prevention for ASD in infants and toddlers with the tuberous sclerosis gene, the public and press should be racing to understand how this came about and where the next discovery will come from.”

2:42 PM GMT  |  Read comments(0)