Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
NIH scientists identify paradoxical response to HIV medication in five individuals
Antiretroviral therapy (ART) is usually very effective at suppressing HIV in the body, allowing a person’s immune system to recover by preventing the virus from destroying CD4+ T cells. Scientists have now identified a rare, paradoxical response to ART known as extreme immune decline, or EXID. Five individuals evaluated at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, experienced a significant decline in CD4+ T cell levels despite suppression of HIV below detectable levels for more than three years, according to a report published online today in JCI Insight. The research team was led by Irini Sereti, M.D., chief of the HIV Pathogenesis Section in NIAID’s Laboratory of Immunoregulation, and Andrea Lisco, M.D., Ph.D.
The NIAID researchers found that the immune systems of people with EXID fared even worse than those of another subset of individuals defined as immunological-non-responders, or INRs, who respond inadequately to ART. INR participants consistently taking ART for four years had CD4+ T cell counts that increased on average by 193 cells per microliter (µL) of blood. Participants who responded normally to ART increased their CD4+ T cell count by more than twice that amount. In contrast, the five participants with EXID experienced an average decline of 157 CD4+ T cells/µL while consistently maintaining viral suppression on ART.
Colorized scanning electron micrograph of a T lymphocyte.
NIH scientists and funding contributed to development of experimental treatment
A small clinical trial has shown that gene therapy can safely correct the immune systems of infants newly diagnosed with a rare, life-threatening inherited disorder in which infection-fighting immune cells do not develop or function normally. Eight infants with the disorder, called X-linked severe combined immunodeficiency (X-SCID), received an experimental gene therapy co-developed by National Institutes of Health scientists. They experienced substantial improvements in immune system function and were growing normally up to two years after treatment. The new approach appears safer and more effective than previously tested gene-therapy strategies for X-SCID.
These interim results from the clinical trial, supported in part by NIH, were published today in The New England Journal of Medicine.
Infants with X-SCID, caused by mutations in the IL2RG gene, are highly susceptible to severe infections. If untreated, the disease is fatal, usually within the first year or two of life. Infants with X-SCID typically are treated with transplants of blood-forming stem cells, ideally from a genetically matched sibling. However, less than 20% of infants with the disease have such a donor. Those without a matched sibling typically receive transplants from a parent or other donor, which are lifesaving, but often only partially restore immunity. These patients require lifelong treatment and may continue to experience complex medical problems, including chronic infections.
NIH research could be a step toward a treatment to prevent heart attacks
Two proteins that bind to stress hormones work together to maintain a healthy heart in mice, according to scientists at the National Institutes of Health and their collaborators. These proteins, stress hormone receptors known as the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), act in concert to help support heart health. When the signaling between the two receptors is out of balance, the mice have heart disease.
The work, published April 16 in Science Signaling, may lead to the development of therapeutic compounds that help people with an increased risk of a heart attack.
Stress increases risk of dying from heart failure by inducing adrenal glands to make a hormone called cortisol. Cortisol is involved in the fight-or-flight response and binds to GRs and MRs in different tissues of the body to reduce inflammation, among other functions. If the level of cortisol remains too high over a long period of time, common risk factors for heart disease may arise, such as increased cholesterol and glucose in the blood and high blood pressure.
Lead author Robert Oakley, Ph.D., first identified a malfunctioning GR in the 1990s when he was a graduate student working with John Cidlowski, Ph.D., at the University of North Carolina at Chapel Hill. Soon after the discovery, other scientists determined that people with above average amounts of this altered GR had greater risk of heart disease. Based on this finding, Oakley and Cidlowski tested a mouse strain without heart GR in their lab at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. These animals spontaneously developed enlarged hearts leading to heart failure and death. When the team produced a mouse strain missing cardiac MR, the animals’ hearts functioned normally.
NIH study suggests our brains may use short rest periods to strengthen memories
In a study of healthy volunteers, National Institutes of Health researchers found that our brains may solidify the memories of new skills we just practiced a few seconds earlier by taking a short rest. The results highlight the critically important role rest may play in learning.
“Everyone thinks you need to ‘practice, practice, practice’ when learning something new. Instead, we found that resting, early and often, may be just as critical to learning as practice,” said Leonardo G. Cohen, M.D., Ph.D., senior investigator at NIH’s National Institute of Neurological Disorders and Stroke and a senior author of the paper published in the journal Current Biology. “Our ultimate hope is that the results of our experiments will help patients recover from the paralyzing effects caused by strokes and other neurological injuries by informing the strategies they use to ‘relearn’ lost skills.”
The study was led by Marlene Bönstrup, M.D., a postdoctoral fellow in Dr. Cohen’s lab. Like many scientists, she held the general belief that our brains needed long periods of rest, such as a good night’s sleep, to strengthen the memories formed while practicing a newly learned skill. But after looking at brain waves recorded from healthy volunteers in learning and memory experiments at the NIH Clinical Center, she started to question the idea.
In a study of healthy volunteers, NIH researchers found that taking short breaks, early and often, may help our brains learn new skills.
Small-scale, NIH-led clinical study offers early hope for developing a treatment
The anti-cancer drug pembrolizumab has shown promise in slowing or stopping the progression of progressive multifocal leukoencephalopathy (PML), a typically fatal infection of the brain caused by the JC virus (JCV). This finding comes from a small-scale study by scientists at National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. The study appears in the New England Journal of Medicine.
Pembrolizumab blocks the interaction between two proteins, PD-1 and PD-L1. Normally, these proteins work by putting the brakes on the immune system to limit excessive inflammation. However, some tumors that have PD-L1 on their surface can exploit this “off switch,” limiting the immune system’s ability to attack the cancer. Recent studies of PML patients have suggested that this mechanism may also be involved in JCV brain infections.
“We found both PD-1 and PD-L1 proteins in the infected parts of brains of patients with PML,” said Irene Cortese, M.D., director of the NINDS Neuroimmunology Clinic and first author of the paper. “This led us to ask whether pembrolizumab could be a potential treatment for PML.”
MRI of a PML patient showing significant lesions in the brain (white signal).
A research team led by scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) has determined how several antibodies induced by Epstein-Barr virus (EBV), a herpesvirus that causes infectious mononucleosis and is associated with certain cancers, block infection of cells grown in the laboratory. They then used this information to develop novel vaccine candidates that, in animals, elicited potent anti-EBV antibody responses that blocked infection of cell types involved in EBV-associated cancers.
Currently, there is no licensed vaccine for EBV. The virus is associated with certain cancers (nasopharyngeal and gastric) of epithelial cells, which form the lining of the body’s surfaces, as well as Burkitt and Hodgkin lymphomas, which are cancers of the immune system’s B cells. Worldwide, about 200,000 cases of EBV-associated cancers occur annually, resulting in 140,000 deaths.
Jeffrey I. Cohen, M.D., and Wei Bu, Ph.D., both of NIAID, led the investigation. Prior efforts to develop an EBV vaccine focused on a viral surface protein, gp350, that the virus uses to enter B cells. However, EBV infects not only B cells, but also epithelial cells that line the mouth and upper throat. These cells are usually infected after contact with saliva from an EBV-infected individual. The new research helps define the contributions of virus-neutralizing antibodies other than those directed at gp350 on B cells. Among other findings, the team determined that antibodies to viral proteins called the gH/gL complex play a major role in inhibiting EBV fusion with epithelial cells.
A cryo-EM image of the gH/gL/gp45 candidate vaccine construct.
Young children who live close to a major roadway are twice as likely to score lower on tests of communications skills, compared to those who live farther away from a major roadway, according to an analysis by researchers at the National Institutes of Health and the University of California, Merced. Moreover, children born to women exposed during pregnancy to higher-than-normal levels of traffic-related pollutants — ultra-fine airborne particles and ozone — had a small but significantly higher likelihood of developmental delays during infancy and early childhood. The study appears in Environmental Research.
Previous studies have linked exposure to common air pollutants in pregnancy to low birthweight, preterm birth and stillbirth. A few studies have found a higher risk of autism and of lower cognitive functioning in children living near freeways, but results of studies about how prenatal and early childhood exposure to air pollution might affect development have been inconsistent.
Small IRP clinical trial conducted in partnership with AstraZeneca
A drug approved to treat a severe form of asthma dramatically improved the health of people with rare chronic immune disorders called hypereosinophilic syndromes (HES) in whom other treatments were ineffective or intolerable. This finding comes from a small clinical trial led by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted through a partnership with the global biopharmaceutical company AstraZeneca. The results were published online today in the New England Journal of Medicine.
“People living with a rare disease often have few, if any, effective treatment options,” said NIAID Director Anthony S. Fauci, M.D. “This promising treatment advance for people with hypereosinophilic syndromes is just one example of how NIH research responds to the unique medical needs of individuals with rare diseases.”
HES is caused by higher-than-normal numbers of white blood cells called eosinophils in the blood, tissues or both. While most people have 0 to 500 eosinophils per microliter (µL) of blood, people with HES typically have more than 1,500 eosinophils/µL. The symptoms of HES vary widely from one patient to the next and can affect the heart, lungs, skin, gastrointestinal tract, central nervous system and other organ systems.
Activated eosinophils in the peripheral blood of a patient with idiopathic hypereosinophilic syndrome.
Investigational vaccine designed to provide broad, durable protection from flu
The first clinical trial of an innovative universal influenza vaccine candidate is examining the vaccine’s safety and tolerability as well as its ability to induce an immune response in healthy volunteers. Scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, developed the experimental vaccine, known as H1ssF_3928.
H1ssF_3928 is designed to teach the body to make protective immune responses against diverse influenza subtypes by focusing the immune system on a portion of the virus that varies relatively little from strain to strain. The vaccine candidate was developed as part of a broader research agenda to create a so-called “universal” influenza vaccine that can provide long-lasting protection for all age groups from multiple influenza subtypes, including those that might cause a pandemic.
“Seasonal influenza is a perpetual public health challenge, and we continually face the possibility of an influenza pandemic resulting from the emergence and spread of novel influenza viruses,” said NIAID Director Anthony S. Fauci, M.D. “This Phase 1 clinical trial is a step forward in our efforts to develop a durable and broadly protective universal influenza vaccine.”
A healthy volunteer receives an experimental universal influenza vaccine known as H1ssF_3928 as part of a Phase 1 clinical trial at the NIH Clinical Center in Bethesda, Maryland. Scientists at NIAID’s Vaccine Research Center (VRC) developed the vaccine.
The drug colchicine, used to treat the arthritic condition gout, could potentially reduce complications accompanying metabolic syndrome, a combination of high blood pressure, high blood sugar and other conditions that increase the risk of heart disease and type 2 diabetes, according to researchers at the National Institutes of Health. Their study appears in Diabetes, Endocrinology, and Metabolism.
Previous studies have indicated that the system-wide inflammation that occurs in obesity plays a role in the development of type 2 diabetes. In the current study, researchers led by Jack A. Yanovski, M.D., Ph.D., of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) randomly assigned 21 study participants to received colchicine twice a day for three months, while 19 participants received a placebo. Colchicine suppresses a multi-protein complex called NLRP3, which triggers the inflammation seen in obesity.
Researchers looked at several measures that reflect how well insulin works in the body to clear sugar from the blood (insulin resistance). There was no difference between the two groups in insulin resistance determined by one measure of insulin use (the frequently sampled, insulin-modified intravenous glucose tolerance test). However, the colchicine group showed improvement on the Homeostatic Model Assessment of Insulin Resistance test, which also estimates how much insulin is needed to keep blood sugar at a normal level while fasting. Those in the colchicine group also scored lower on a blood test of C-reactive protein and other tests that indicate inflammation. The authors concluded that larger studies are needed to determine if colchicine could prevent the development of type 2 diabetes in people with metabolic syndrome.
