Fragile X: preclinical portfolio for PI3k drug strategy

An alternative drug strategy for fragile X is gathering strength. Lots of data on behavior and biochemistry from mouse Read more

Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. This is one way to get rid of a particular Read more

The blue spot: where seeds of destruction begin

Learn more about the locus coeruleus, a "canary in the coal Read more

Immunology

Starvation signals control intestinal inflammation in mice

Intestinal inflammation in mice can be dampened by giving them a diet restricted in amino acids, the building blocks of proteins, researchers have found. The results were published online by Nature on Wednesday, March 16.

The findings highlight an ancient connection between nutrient availability and control of inflammation. They also suggest that a low protein diet — or drugs that mimic its effects on immune cells — could be tools for the treatment of inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis.

The research team, led by Emory Vaccine Center immunologist Bali Pulendran, discovered that mice lacking the amino acid sensor GCN2 are more sensitive to the chemical irritant DSS (dextran sodium sulfate), often used to model colitis in animals. This line of research grew out of the discovery by Pulendran and colleagues that GCN2 is pivotal for induction of immunity to the yellow fever vaccine.

“It is well known that the immune system can detect and respond to pathogens, but these results highlight its capacity to sense and adapt to environmental changes, such as nutritional starvation, which cause cellular stress,” he says.

Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Mulligan WABE interview on Ebola vaccine research

A recent WABE “Closer Look” interview with Mark Mulligan, executive director of the Emory Vaccine Center’s Hope Clinic, covers a lot of ground. It starts off with a segment — also aired on Marketplace — from reporter Michell Eloy, who visited the Hope Clinic’s lab. We hear a machine processing blood samples from a study testing an experimental Ebola vaccine and a roundup of Ebola vaccine developments.

We also hear from Carl Davis, postdoc in Rafi Ahmed’s lab, who is part of the DARPA-funded team research project studying the utility of antibodies from Ebola survivors. [Other recent news on this topic from The Scientist.]

Then, reporters Rose Scott and Jim Burress discuss several different Ebola vaccines with Mulligan. One is based on chimpanzee adenovirus, was tested at the Hope Clinic and elsewhere in the USA and the UK, and then in Liberia. While this vaccine was safe and it appears to stimulate the immune system appropriately, the outbreak fizzled out (a good thing!) before it was possible to tell if the vaccine protected people from Ebola infection. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Wound-healing intestinal bacteria: like shrubs after a forest fire

In injured mouse intestines, specific types of bacteria step forward to promote healing, Emory scientists have found. One oxygen-shy type of bacteria that grows in the wound-healing environment, Akkermansia muciniphila, has already attracted attention for its relative scarcity in both animal and human obesity.

NMicro

An intestinal wound brings bacteria (red) into contact with epithelial cells (green). The bacteria can provide signals that promote healing, if they are the right kind.

The findings emphasize how the intestinal microbiome changes locally in response to injury and even helps repair breaches. The researchers suggest that some of these microbes could be exploited as treatments for conditions such as inflammatory bowel disease.

The results were published on January 27 in Nature Microbiology. Researchers took samples of DNA from the colon tissue of mice after they underwent colon biopsies. They used DNA sequencing to determine what types of bacteria were present.

“This is a situation resembling recovery after a forest fire,” says Andrew Neish, MD, professor of pathology and laboratory medicine at Emory University School of Medicine. “Once the trees are gone, there is an orderly succession of grasses and shrubs, before the reconstitution of the mature forest. Similarly, in the damaged gut, we see that certain kinds of bacteria bloom, contribute to wound healing, and then later dissipate as the wound repairs.” Read more

Posted on by Quinn Eastman in Immunology, Uncategorized Leave a comment

Improving long-term outcomes after kidney transplant

Twenty years of research and you start to improve outcomes for transplant patients.

The Nature paper from Chris Larsen and Tom Pearson on “costimulation blockers” and their ability to head off graft rejection in rodents first appeared in 1996.

Almost 20 years later, a seven-year study of kidney transplant recipients has shown that the drug belatacept, a costimulation blocker based on Larsen and Pearson’s research, has a better record of patient and organ survival than a calcineurin inhibitor, previously the standard of care.

Kidney transplant recipients need to take drugs to prevent their immune systems from rejecting their new organs, but the drugs themselves can cause problems. Long-term use of calcineurin inhibitors, such as tacrolimus, can damage the transplanted kidneys and lead to cardiovascular disease and diabetes.

In the accompanying video, Larsen - now dean of Emory University School of Medicine – and Pearson - executive director of Emory Transplant Center – explain.

Belatacept was approved by the FDA in 2011 and is produced by Bristol Myers Squibb. Results from the BENEFIT study of belatacept, led by Larsen and UCSF transplant specialist Flavio Vincenti, were published in the Jan. 28 issue of the New England Journal of Medicine.

To go with the paper, NEJM has an editorial with some revealing statistics (more than 14,000 of the 101,000 patients listed for kidney transplantation are waiting for a repeat transplant) and a explanatory video. MedPage Today has an interview with Larsen, and HealthDay has a nice discussion of the issues surrounding post-transplant drugs. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Galectins defend against bacterial wolves in sheeps’ clothing

To prevent auto-immune attack, our bodies avoid making antibodies against molecules found on our own cells. That leaves gaps in our immune defenses bacteria could exploit. Some of those gaps are filled by galectins, a family of proteins whose anti-bacterial properties were identified by Emory scientists.

In the accompanying video, Sean Stowell, MD, PhD and colleagues explain how galectins can be compared to sheep dogs, which are vigilant in protecting our cells (sheep) against bacteria that may try to disguise themselves (wolves).

The video was produced to showcase the breadth of research being conducted within Emory’s Antibiotic Resistance Center. Because of their ability to selectively target some kinds of bacteria, galectins could potentially be used as antibiotics to treat infections without wiping out all the bacteria in the body. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Sidestepping the placebo effect when studying depression

Research on depression must deal with a major obstacle: the placebo effect. This is the observation that patients improve in response to the sugar pills given as controls in clinical studies.

Clinical trial designers can incorporate various clever strategies to minimize the placebo effect, which is actually comprised of several statistical and psychological factors. Investigators can try to enhance, dissect or even “harness” them. [A recent piece in the New York Times from Jo Marchant focuses on the placebo effect in studies of pain relief.]

Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.

Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Miller’s team describes here (less guilt!), but they conclude that there is a “high degree of overlap.”

Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitful investigations of inflammation in the context of major depression. More on that soon.

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Ancient protein flexibility may drive ‘new’ functions

A mechanism by which stress hormones inhibit the immune system, which appeared to be relatively new in evolution, may actually be hundreds of millions of years old.

A protein called the glucocorticoid receptor or GR, which responds to the stress hormone cortisol, can take on two different forms to bind DNA: one for activating gene activity, and one for repressing it. In a paper published Dec. 28 in PNAS, scientists show how evolutionary fine-tuning has obscured the origin of GR’s ability to adopt different shapes.

“What this highlights is how proteins that end up evolving new functions had those capacities, because of their flexibility, at the beginning of their evolutionary history,” says lead author Eric Ortlund, PhD, associate professor of biochemistry at Emory University School of Medicine.

GR is part of a family of steroid receptor proteins that control cells’ responses to hormones such as estrogen, testosterone and aldosterone. Our genomes contain separate genes encoding each one. Scientists think that this family evolved by gene duplication, branch by branch, from a single ancestor present in primitive vertebrates. Read more

Posted on by Quinn Eastman in Heart, Immunology Leave a comment

IgG4-related means mysterious

Emory rheumatologist Arezou Khosroshahi was the lead author on a differential diagnosis case report in New England Journal of Medicine published in October, which describes an example of IgG4-related disease. This autoimmune condition’s name was agreed upon only recently, at an international conference she co-directed in 2011.

This review calls IgG4-related disease an “orphan disease with many faces.” It sounds like each case has the potential to be an episode of House. As Khosroshahi explains:

“Most patients undergo invasive procedures for resection or biopsy of the affected organ to exclude other conditions. Unfortunately, most of those patients get dismissed by the clinicians, given the good news that their disease was not malignancy. Many of them have recurrence of the condition in other organs after a few months or years.”

Arezou Khosroshahi, MD

Rheumatologist Arezou Khosroshahi, MD

In the case report, a woman was admitted to Massachusetts General Hospital, because of shoulder and abdominal pain and an accumulation of fluid around her lungs. Surgeons removed a softball-sized mass from her right lung. The mass did not appear to be cancerous, but instead seemed to be the result of some kind of fibrous inflammation, and the patient was treated with antibiotics. Read more

Posted on by Quinn Eastman in Immunology 3 Comments

Emory labs on LabTV

This summer, video producers from the web site LabTV came to two laboratories at Emory. We are pleased to highlight the first crop of documentary-style videos.

LabTV features hundreds of young researchers from universities and institutes around the United States, who tell the public about themselves and their research. The videos include childhood photos and explanations from the scientists about what they do and what motivates them. Screen Shot 2015-12-18 at 9.14.51 AM

The two Emory labs are: Malu Tansey’s lab in the Department of Physiology, which studies the intersection of neuroscience and immunology, focusing on neurodegenerative disease, and Mike Davis’ lab in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, which is developing regenerative approaches and technologies for heart disease in adults and children. Read more

Posted on by Quinn Eastman in Heart, Immunology, Neuro Leave a comment

‘Mountain of data’ on flu vaccine responses

Bali Pulendran’s lab at Emory Vaccine Center teamed up with UCSD researchers and recently published a huge analysis of immune responses after seasonal flu vaccination (Immunity is making it available free this week, no subscription needed). Hundreds of volunteers at the Vaccine Center’s Hope Clinic took part in this study.

Note — this study looked at antibody responses to flu vaccines, but didn’t assess protection: whether study participants actually became sick with flu or not.

Our write-up is here. Immunity’s preview, from the Karolinska Institute’s Petter Brodin, is here, Cell Press’s press release is here.

Three points we wanted to call attention to:

*Long-lasting antibodies A surprising finding was how the “molecular signatures” that predict the strength of the immune response a few weeks after vaccination did not predict how long anti-flu antibodies stayed around. Instead, a separate set of signatures predicted the durability of antibody levels.

These distinct signatures may be connected with how plasma cells, responsible for antibody production, need to find homes in the bone marrow. That sounds like the process highlighted by Eun-Hyung Lee and colleagues in an Immunity paper published in July. In bone marrow samples from middle-aged volunteers, her team had found antibody-secreting cells that survive from childhood infections.

*Interfering (?) activation of NK cells/monocytes in elderly While the researchers found people older than 65 tended to have weaker antibody responses to vaccination, there were common elements of molecular signatures that predicted strong antibody responses in younger and older volunteers. However, elderly volunteers tended to have stronger signatures from immune cells that are not directly involved in producing antibodies (monocytes and ‘natural killer’ cells), both at baseline and after vaccination.

From the discussion: “This indicates a potential connection between the baseline state of the immune system in the elderly and reduced responsiveness to vaccination.” Additional comments on this from Shane Crotty in Brad Fikes’ article for the Union Tribune.

*The mountain of data from this and similar studies is available for use by other researchers on the web site ImmPort.

Posted on by Quinn Eastman in Immunology Leave a comment