The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to Read more

A push for reproducibility in biomedical research

At Emory, several scientists are making greater efforts to push forward to improve scientific research and combat what is being called “the reproducibility crisis.” Guest post from Erica Read more

Exosomes as potential biomarkers of radiation exposure

Exosomes = potential biomarkers of radiation in the Read more

Immunology

Skin disease studies go deep: depression/inflammation insight

The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could clear a path around the placebo effect.

Miller and his colleagues have been looking at the connection between inflammation and depression, whose evolutionary dimensions we have previously explored. They’ve examined the ability of inflammation-inducing treatments for hepatitis C and cancer to trigger symptoms of depression, and have shown that the anti-inflammatory drug infliximab (mainly used for rheumatoid arthritis) can resolve some cases of treatment-resistant depression. [Lots of praise for Miller in this September 2017 Nature Medicine feature.]

A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.

When it comes to approving new antidepressants, the FDA is still probably going to want a frontal assault on depression, despite provisions in the 21st Century Cures Act to broaden the types of admissible evidence.

“These studies emphasize how difficult it is to interpret findings when these drugs are treating more than one problem,” Miller says. “Better to have a simpler study with just depression.”

Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways. Two studies now underway at Emory specifically recruit patients with high levels of the inflammatory marker CRP, which Miller’s previous study showed was helpful in predicting response to infliximab.

The new paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more

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

2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.

2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.

In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.

How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality. Read more

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EHR data superior for studying sepsis

Are there more cases of a given disease because something is causing more, or because doctors have become more aware of that disease? A recent paper in JAMA tackles this question for sepsis, the often deadly response to infection that is the most expensive condition treated in US hospitals.

Researchers from several academic medical centers, including Emory, teamed up to analyze sepsis cases using two methods. The first is based on the ICD (International Classification of Diseases) codes recorded for the patient’s stay in the hospital, which the authors refer to as “claims-based.” The second mines electronic medical record (EHR) data, monitoring the procedures and tests physicians used when treating a patient. The first approach is easier, but might be affected by changing diagnosis and coding practices, while the second is not possible at every hospital.

“This project was undertaken by several large, high quality institutions that have the ability to well characterize their sepsis patients and connect their EHR data,” says Greg Martin, MD, who is a co-author of the JAMA paper along with David Murphy, MD, PhD. The lead author, Chanu Rhee, MD, MPH, is from Brigham and Women’s Hospital, and the entire project was part of a Prevention Epicenter program sponsored by the Centers for Disease Control and Prevention.  Read more

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From stinging to soothing: fire ant venom may lead to skin treatments

Compounds derived from fire ant venom can reduce skin thickening and inflammation in a mouse model of psoriasis, Emory and Case Western scientists have shown.

The results were published on Sept. 11 in Scientific Reports.

Update: When this paper was published, Lab Land received an email providing anecdotal support for effectiveness in humans. “I have suffered with psoriasis all my life and in 2015, I went on an expedition to Central America. I got eaten alive by fire ants, as they managed to get into my socks. My psoriasis however got better for a time, and as somebody who has directly experienced fire ant venom, I strongly believe that there is a correlation between it and psoriasis.”

The findings could lead to new treatments for psoriasis, a common autoimmune skin disease. Topical steroids are now most frequently used for mild to moderate psoriasis, but they have side effects such as skin thinning and easy bruising.

Solenopsins are the main toxic components of fire ant venom. They chemically resemble ceramides, which are lipid-like molecules essential for maintaining for the barrier function of the skin. Ceramides can be found in many skin care products.

Ceramides can act as a double-edged sword, says lead author Jack Arbiser, MD, PhD, professor of dermatology at Emory University School of Medicine. Under certain conditions they can be converted by cells into S1P (sphingosine-1-phosphate), an inflammatory molecule.

Arbiser and his colleagues devised two solenopsin analogs that look like ceramides, but can’t be degraded into S1P. They then tested them in a mouse model of psoriasis, applying the compounds in a one percent skin cream for 28 days. Read more

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Troublemaker cells predict immune rejection after kidney transplant

Emory scientists have identified troublemaker cells—present in some patients before kidney transplantation—that are linked to immune rejection after transplant. Their results could guide transplant specialists in the future by helping to determine which drug regimens would be best for different groups of patients. Eventually, the findings could lead to new treatments that improve short- and long-term outcomes.

Transplant patients used to have no choice but to take non-specific drugs to prevent immune rejection of their new kidneys. While these drugs, called calcineurin inhibitors, are effective at preventing early rejection, they lack specificity for the immune system and ironically can damage the very kidneys they are intended to protect. In addition, their side effects lead to higher rates of high blood pressure, diabetes, and cardiovascular disease, ultimately shortening the life of the transplant recipient. This changed with the advent of costimulation blockers, which avoid these harmful side effects. Emory transplant surgeons Chris Larsen and Tom Pearson, together with Bristol-Myers Squibb, helped develop one of these new drugs called belatacept, which blocks signals through the costimulatory receptor CD28.

In a long-term clinical study of belatacept, kidney transplant patients tended to live longer with better transplant function when taking belatacept compared with calcineurin inhibitors. Despite these desirable outcomes, acute rejection rates were higher in patients treated with belatacept.

Andrew Adams, an Emory transplant surgeon who focuses on costimulation blockade research, notes: “While the acute rejection seen with belatacept is treatable with stronger immunosuppression, there may be long-term effects that linger and impair late outcomes.”

Most transplant centers have not yet adopted this new therapy as their standard of care because of the higher rejection rate as well as other logistical concerns, thus limiting patients’ access to potential health benefits afforded with belatacept treatment.

Adams and colleague Mandy Ford have identified certain types of memory T cells, which typically provide long-lasting immunity to infection, as potential mischief-makers in the setting of organ transplants treated with belatacept. Evidence is accumulating that the presence of certain memory T cells can predict the likelihood of “belatacept-resistant” rejection. Two recent papers in American Journal of Transplantation by Ford and Adams support this idea. Read more

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Update on SIV remission studies

Tab Ansari’s research at Emory/Yerkes on how an antibody treatment can push monkeys infected with SIV into remission was published in Science last year. At that time, Ansari told Lab Land about follow-up experiments to probe which immune cells are needed for this effect, which surprised many HIV/AIDS experts.

Ansari’s partner on the project, NIAID director Anthony Fauci, described the follow-up work in July at the International AIDS Society Conference in Paris. We thank Treatment Action Group’s Richard Jefferys for taking notes and posting a summary:

The approach that the researchers took was to deplete different types of immune cells in the animals controlling SIV viral load, then assess whether this led to an increase in viral replication. The experiments compared:

*Antibodies to the CD8 receptor alpha chain, which deplete CD8 T cells, natural killer T cells (NKTs) and natural killer (NK) cells

*Antibodies to the CD8 receptor beta chain, which deplete CD8 T cells

*Antibodies to CD20, which deplete B cells

According to Fauci’s slides, which are available online, there was a transient rebound in viral load with the CD8 alpha antibody and to a small degree with the CD8 beta. This suggests NKTs and NK cells are making a contribution to the observed control of SIV replication, but a role for CD8 T cells cannot be ruled out.

For comparison, a study from Guido Silvestri and colleagues at Yerkes published in 2016 found that treating SIV-infected monkeys with anti-CD8 antibodies, without stopping antiretroviral drugs, resulted in a rebound in virus levels. [They used ultrasensitive assays to detect the rebound.] However, the Yerkes team only used antibodies to the CD8 receptor alpha chain.

Read more

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Opioid abuse medicine can control genetic skin disease

Evidence is emerging that naltrexone, a medicine used to treat opioid and alcohol abuse, can also control a genetic skin disease that causes painful, itchy rashes and blisters.

Two separate brief reports last week in JAMA Dermatology, from Emory and Cleveland Clinic investigators, describe the treatment of six patients with Hailey-Hailey disease.

Dermatologist Ron Feldman, MD, PhD is the senior author on the Emory report, which says:

“Low-dose naltrexone has been widely touted on social media platforms, including multiple YouTube videos, as an anecdotal treatment for patients with HHD, with surprisingly no published evidence until this year.”

Feldman tells Lab Land: “We decided to try it based on the patients; we had no clue about low-dose naltrexone until we met one of the patients with Hailey-Hailey disease, who came in asking for this therapy based on social media.”

At Emory, each of the three patients had tried at least four prior treatments, such as antibiotics and corticosteroids, but all were unsuccessful in controlling the disease. Read more

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Flu meeting at Emory next week

We are looking forward to the “Immunology and Evolution of Influenza” symposium next week (Thursday the 25th and Friday the 26th).

The symposium is taking place in Whitehead Auditorium in the Whitehead Biomedical Research Building. Talks from flu researchers based around the country, followed by a poster session, are on Thursday. From Emory, Jacob Kohlmeier and Rafi Ahmed are speaking Friday morning.

Organizers are asking for registration by Friday the 19th. The symposium is jointly sponsored by the Center for Inference and Dynamics of Infectious Diseases, funded by NIGMS, and the Center for Modeling Immunity to Influenza Infection, funded by NIAID.

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Cancer immunotherapy responses in the clinic: T cell revival as predictor

In lung cancer patients who were taking immunotherapy drugs, testing for revived immune cells in their blood partially predicted whether their tumors would shrink. The results were published online by PNAS on April 26.

This finding comes from a small study of 29 patients, who were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, also known as checkpoint inhibitors.

The study supports a straightforward idea: if tumor-specific CD8 T cells appear to respond to the drug (nivolumab, pembrolizumab or atezolizumab), that’s a good sign. This avenue of investigation may also help researchers figure out why some patients do not benefit from checkpoint inhibitor drugs, and how to combine those drugs with other treatments to increase response rates.

While looking for activated immune cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with the treatment or combine it with something else, says co-senior author Suresh Ramalingam, MD, Winship’s deputy director.

“We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue,” says Rafi Ahmed, PhD, director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. “We believe some of the activated T cells in patients’ blood may be on their way to the tumor.”

The rest of the Emory Vaccine Center/Winship Cancer Institute press release is here. A few additional points: Read more

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

Meningitis bacteria adapt to STI niche — again?

A new paper in PNAS from Emory scientists highlights a neat example of bacterial evolution and adaptation related to sexually transmitted infections. Neisseria meningitidis, a bacterium usually associated with meningitis and sepsis, sometimes appears in the news because of cases on college campuses or other outbreaks.

The N meningitidis bacteria causing a recent cluster of sexually transmitted infections in Columbus, Ohio and other US cities have adapted to the urogenital environment, an analysis of their DNA shows.

Update: May 2016 Clinical Infectious Diseases paper on the same urethritis cluster.

Genetic changes make this clade look more like relatives that are known to cause gonorrhea. Some good news is that these guys are less likely to cause meningitis because they have lost their outer capsule. They have also gained enzymes that help them live in low oxygen.

The DNA analysis helps doctors track the spread of this type of bacteria and anticipate which vaccines might be protective against it. Thankfully, no alarming antibiotic resistance markers are present (yet) and currently available vaccines may be helpful. Full press release here, and information about meningococcal disease from the CDC here.

This looks like a well-worn path in bacterial evolution, since N. gonorrhoeae is thought to have evolved from N. meningitidis and there are recent independent examples of N. meningitidis adapting to the urogenital environment. 

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