Transition to exhaustion: clues for cancer immunotherapy

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results were published Tuesday, Dec. 3 in Immunity. Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins Read more

Radiologists wrestle with robots - ethically

Emory bioethicist John Banja says: don’t believe the hype about AI replacing Read more

Opioids: crunching the Tweets

The aim is to be able to spot patterns of overdoses faster than prescription drug monitoring Read more

immunology

Two heavy hitters in this week’s Nature

Two feature articles in Nature this week on work by Emory scientists.

One is from Virginia Hughes (Phenomena/SFARI/MATTER), delving into Kerry Ressler’s and Brian Dias’ surprising discovery in mice that sensitivity to a smell can be inherited, apparently epigenetically. Coincidentally, Ressler will be giving next week’s Dean’s Distinguished Faculty lecture (March 12, 5:30 pm at the School of Medicine).

Another is from Seattle global health writer Tom Paulson, on immunologist Bali Pulendran and using systems biology to unlock new insights into vaccine design.

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

Dissecting a pediatric autoimmune disease

When a child is just learning to play sports, swim or even simply get dressed on her own, it can be heartbreaking to see that she is already being affected by symptoms of arthritis: swelling, limping, and/or restricted range of motion.

At the recent research retreat held by the Emory–Children’s Pediatric Research Center, rheumatologist Sampath Prahalad described his efforts to define the genetics and contributing factors for juvenile idiopathic arthritis (JIA).

Sampath Prahalad, MD

A challenge in this area is determining what makes juvenile idiopathic arthritis both different from other autoimmune diseases such as lupus or type I diabetes and what makes the disease appear early in life, decades before adult-onset rheumatoid arthritis usually appears.

Determining genetic and other risk factors for the disease can help increase understanding of the mechanisms of disease, leading to better treatments, and knowing how the cheap oakley disease develops can improve diagnosis. On this second point, we asked Prahalad two questions about his work:

What proportion of patients come to you because there is a suspected genetic connection?

Most come because of symptoms of rheumatic disease. I would estimate about 20 percent of our referrals come because of a mild symptom or abnormal lab test plus a family cheap oakley sunglasses history of autoimmunity, which prompts the PCP to seek a rheumatology evaluation. Less than 2 percent come purely for a family history of autoimmunity where they are concerned the child also has it.

Under what circumstances would a doctor seek to determine a genetic risk score for a child?

We know that twins, siblings and children of individuals with an autoimmune disease have a higher risk of the condition. So a genetic risk score could help identify those at risk for closer follow up or further evaluation. Conceivably in a child with symptoms suspicious for an autoimmune disease but not definitive, a genetic risk score could help increase the probability of being able to diagnose a specific condition.

Prahalad and colleagues published a paper in the June issue of Arthritis & Rheumatism investigating the applicability of a genetic risk score for JIA involving variations in four genes. In their study looking at 155 children with JIA and 684 controls, individuals with a risk score in the top fifth have odds of childhood-onset disease 12 times of those in the bottom fifth.

A key passage from the discussion of the Arthritis & Rheumatism paper indicates that genetic factors specific for childhood onset remain to be found.

Studying children has the advantage of focusing more on the influence of genetic factors compared to the influence of environmental factors, such as smoking. Notably, the magnitude and direction of the association between childhood-onset RA [rheumatoid arthritis] and TNFAIP3, STAT4, and PTPN22 variants were similar to those observed in RA. The observation that the selected variants did not have an elevated OR in childhood-onset RA as compared to RA suggests that there are other variants still to be investigated that may influence the risk of childhood-onset RA.

Prahalad says he wants to find out whether genetic http://www.gooakley.com/ factors contributing to childhood onset are simply cumulatively more intense, and thus drive the appearance of the disease earlier, or whether they are active in a childhood-specific context.

Notably, many of the genetic risk factors identified so far are shared with other autoimmune diseases. A recent Nature Genetics paper, which Prahalad contributed to, used a customized “Immunochip” to find several new risk factors for JIA.

Non-genetic risk factors: At the retreat, Mina Rohani Pichavant, a researcher working with Prahalad, had a poster discussing her preliminary data on the types of microorganisms found in the intestines of JIA patients. Previous studies in adults with rheumatoid arthritis have shown a link between intestinal bugs and disease risk, but this area of research is new for JIA. There are also connections between gum disease and JIA.

Posted on by Quinn Eastman in Immunology Leave a comment

Emory scientists co-signers of H5N1 flu letter

Emory influenza researchers Richard Compans, Anice Lowen and John Steel are co-signers of a statement announcing the end of a self-imposed moratorium on H5N1 avian flu research.

Last year, an international group of researchers called for the moratorium after public concern over studies of H5N1 transmissibility in ferrets, a model for spread of infection between humans. The group of researchers has now recommended ending the moratorium, citing safeguards and safety review procedures put in place by the National Institutes of Health and authorities in other countries. From the letter published today in Science and Nature:

In January 2012, influenza virus researchers from around the world announced a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. We declared a pause to this important research to provide time to explain the public-health benefits cheap oakley of this work, to describe the measures in place to minimize possible risks, and to enable organizations and governments around the world to review their policies (for example on biosafety, biosecurity, oversight, and communication) regarding these experiments.

…Thus, acknowledging that the aims of the voluntary moratorium have been met in some countries and are close to being met in others, we declare an end to the voluntary moratorium on avian flu transmission studies.

Dan Vergano has a more extensive story in USA Today.

Compans is professor of microbiology and immunology at Emory University School of Medicine and scientific director of Emory’s Influenza Pathogenesis and Immunology Research Center. Lowen and Steel are assistant professors of microbiology and immunology at Emory and IPIRC investigators.

Posted on by Quinn Eastman in Immunology Leave a comment

Present at the creation: immunology from chickens to lampreys

You can get far in biology by asking: “Which came first, the chicken or the egg?” Max Cooper discovered the basis of modern immunology by asking basic questions.

Cooper was selected for the 2012 Dean’s Distinguished Faculty Lecture and Award, and on Thursday evening dazzled an Emory University School of Medicine audience with a tour of his scientific career. He joined the Emory faculty in 2008 as a Georgia Research Alliance Eminent Scholar.

Max Cooper, MD

Cooper’s research on the development of the immune system, much of it undertaken before the era of cloned genes, formed the underpinnings of medical advances ranging from bone marrow transplants to monoclonal antibodies. More recently, his research on lampreys’ divergent immune systems has broadened our picture of how adaptive immunity evolved.

Cooper grew up in Mississippi and was originally trained as a pediatrician, and became interested in inherited disorders that disabled the immune system, leaving children vulnerable to infection. He joined Robert Good’s laboratory at the University of Minnesota, where he began research on immune system development in chickens.

In the early 1960s, Cooper explained, scientists thought that all immune cells developed in one place: the thymus. Working with Good, he showed that there are two lineages of immune cells in chickens: some that develop in the thymus (T cells) and other cells responsible for antibody production, which develop in the bursa of Fabricius (B cells). [On Thursday, he evoked chuckles by noting that a critical discovery that drove his work was published in the journal Poultry Science after being rejected by Science.]

Cooper moved on to the University of Alabama, Birmingham, and there made several discoveries related to how B cells develop. A collaboration with scientists at University College, London led to the identification of the places where B cells develop in mammals: fetal liver and adult bone marrow.

Cooper’s research on lampreys began in Alabama and has continued after he came to Emory in 2008. Primitive lampreys are thought to be an early offshoot on the evolutionary tree, before sharks, the first place where an immune system resembling those of mammals and birds is seen. Lampreys’ immune cells produce “variable lymphocyte receptors” that act like our antibodies, but the molecules look very different in structure. These molecules were eventually crystallized and their structure probed, in collaboration with Ian Wilson in San Diego.

Lampreys have variable lymphocyte receptors, which resemble our antibodies in function but not in structure

Cooper said he set out to figure out “which came first, T cells or B cells?” but ended up discovering something even more profound. He found that lampreys also have two separate types of immune cells, and the finding suggests that the two-arm nature of the immune system may have preceded the appearance of the particular features that mark those cells in evolution.

 

 

 

Posted on by Quinn Eastman in Immunology 1 Comment

One reason why SIV-infected sooty mangabeys can avoid AIDS

Sooty mangabeys are a variety of Old World monkey that can be infected by HIV’s cousin SIV, but do not get AIDS. Emory immunologist and Georgia Research Alliance Eminent Scholar Guido Silvestri, MD, has been a strong advocate for examining non-human primates such as the sooty mangabey, which manage to handle SIV infection without crippling their immune systems. Silvestri is division chief of microbiology and immunology at Yerkes National Primate Research Center.

Research shows sooty mangabeys have T cells that can do the same job as those targeted by SIV, even if they don't have the same molecules on their surfaces

A recent paper in the Journal of Clinical Investigation reveals that sooty mangabeys have T cells that perform the same functions as those targeted by SIV and HIV, but have different clothing.

Silvestri and James Else, the animal resources division chief at Yerkes, are co-authors on the paper, while Donald Sodora at Seattle Biomedical Research Institute is senior author.

One main target for SIV and HIV is the group of T cells with the molecule CD4 on their surfaces. These are the “helper” T cells that keep the immune system humming. Doctors treating people with HIV infections tend to keep an eye on their CD4 T cell counts.

In the paper, the scientists show that sooty mangabeys infected with SIV lose their CD4 T cells, without losing the ability to regulate their immune systems. What’s remarkable here is that sooty mangabeys appear to have “double negative” or DN T cells that can perform the same functions as those lost to SIV infection, even though they don’t have CD4.

CD4 isn’t just decoration for T cells. It’s a part of how they recognize bits of host or pathogen protein in the context of MHC class II (the molecule that “presents” the bits on the outside of target cells). Somehow, the T cells in sooty mangabeys have a way to get around this requirement and still regulate the immune system competently. How they do this is the topic of ongoing research.

The authors write:

It will be important to assess DN T cells in HIV-infected patients, particularly to determine whether these cells are preserved and functional in long-term nonprogressors. These efforts may lead to future immune therapies or vaccine modalities designed to modulate DN T cell function. Indeed, the main lesson we have learned to date from this cohort of SIV-infected CD4-low mangabeys may be that managing immune activation and bolstering the function of nontarget T cells through better vaccines and therapeutics has the potential to contribute to preserved immune function and a nonprogressive outcome in HIV infection even when CD4+ T cell levels become low.

Posted on by Quinn Eastman in Immunology Leave a comment

Another avenue of HIV trickery reveals opportunity

Emory and University of Rochester researchers have discovered an extra way by which HIV adapts to survive in a hiding spot in the human immune system. The results are published in the Journal of Biological Chemistry.

A team led by Baek Kim from the University of Rochester and Raymond Schinazi from Emory found that when HIV faces a shortage of the building blocks it usually uses to replicate, the virus adapts by using different building blocks. The discovery may offer scientists a new way to try to stop the virus.

One of HIV’s favorite hiding spots is an immune cell called a macrophage, whose job is to chew up and destroy foreign invaders and cellular debris. One can think of macrophages as worker bees: they don’t reproduce because they’re focused on getting stuff done.

Raymond Schinazi, PhD, DSc, is director of the Laboratory of Biochemical Pharmacology at Emory's Center for AIDS Research

Normally, HIV uses “dNTPs” (building blocks of DNA), but dNTPs are found at very low levels in macrophages because they’ve stopped dividing and making new DNA. Current drugs generally target dNTPs, and aim at the infection in a different type of cells: T cells.

Macrophages do have high levels of RNA building blocks (“rNTPs”). The team found that HIV uses primarily rNTPs instead of dNTPs to replicate inside macrophages. When the team blocked the ability of the virus to interact with rNTPs, its ability to replicate in macrophages was cut by more than 90 percent.

“The first cells that HIV infects in the genital tract are non-dividing target cell types such as macrophages,” Kim says. “Current drugs were developed to be effective only when the infection has already moved beyond these cells. Perhaps we can use this information to help create a microbicide to stop the virus or limit its activity much earlier.”

Compounds that interfere with the use of rNTPs already exist and have been tested as anti-cancer drugs.

“We are now developing new anti-HIV drugs jointly based on this novel approach that are essentially non-toxic and can be used to treat and prevent HIV infections,” Schinazi says.

Baek Kim, PhD

The first authors of the paper are graduate students Edward Kennedy from Rochester and Christina Gavegnano from Emory. Other authors include graduate students Laura Nguyen, Rebecca Slate and Amanda Lucas from Rochester, and postdoc Emilie Fromentin from Emory.

The research was funded by the National Institute of Allergy and Infectious Disease and the Department of Veterans Affairs.

University of Rochester press release

Posted on by Quinn Eastman in Immunology 1 Comment

Adjuvants: once immunologists’ “dirty little secret”

Two presentations on Emory research at last week’s AIDS Vaccine 2010 conference concerned adjuvants. These are substances that act as amplifiers, stimulating the immune system while keeping its focus on the specific components of a vaccine.

Charlie Janeway (1943-2003)

Immunologist Charlie Janeway once described adjuvants as immunology’s “dirty little secret,” because for a long time scientists did not know how they worked. Some adjuvants can sound irritating and nasty, such as alum and oil emulsion. Alum is the only vaccine adjuvant now licensed for human clinical use in the US. Over the last few years, scientists have learned that adjuvants rev up what is now known as the “innate immune system,” so that the body knows that the vaccine is something foreign and dangerous.

Rama Rao Amara, a vaccine researcher at Emory Vaccine Center and Yerkes National Primate Research Center, and Harriet Robinson, former head of microbiology and immunology at Yerkes and now chief scientific officer at the firm GeoVax, both described extra ingredients for the DNA/MVA vaccine that Robinson designed while at Yerkes in collaboration with NIH researchers.

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Respiratory infection may lead to weaker immunological memory

How you vaccinate helps determine how you protect. This idea lies behind many researchers’ interest in mucosal vaccines. How a vaccine is administered (orally/nasally vs intramuscular, for example) could make a difference later, when the immune system faces the bad guys the vaccine is supposed to strengthen defenses against.

How does the route of immunization affect the quality of immunity later on? For example, is a nasal spray best when trying to prevent respiratory infections?

A recent paper from Emory Vaccine Center director Rafi Ahmed’s laboratory challenges this idea. The paper was published in the Journal of Immunology. Scott Mueller, now an Australian Research Council research fellow at the University of Melbourne, is first author.

Memory T cells are a key part of a response to a vaccine, because they stick around after an infection, enabling the immune system to fight an invading virus more quickly and strongly the second time around. In the paper, the Emory team compared memory T cells that form in mice after they are infected in the respiratory system by a flu virus or throughout their bodies by a virus that causes meningitis (lymphocytic choriomeningitis virus or LCMV).

The authors engineered a flu virus to carry a tiny bit of LCMV (an epitope, in immunological terms) so that they could compare apples to apples by measuring the same kind of T cells. They found that memory T cells generated after a flu infection are weaker, in that they proliferate and stimulate other immune cells less, than after a LCMV infection. This goes against the idea that after a respiratory infection, the immune system will be better able to face a challenge in the respiratory system.

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When your immune system calls the shots

Bali Pulendran, PhD

A tiny invader, perhaps a virus or a microbe, enters the body, and our ancient immune system responds. But how does it know what kind of invader has landed? And once it knows, how does it decide what kind of immune response it should launch?

In humans, the immune system consists of two parallel systems working with one another to fend off invaders. One is the innate immune system, the other the adaptive immune system.

Immunologist Bali Pulendran studies how those two systems work together to identify and respond to all kinds of intruders including pathogens, viruses and microbes.

It’s the innate immune system’s job to recognize the first signs of infection—that is, the moment a pathogen enters the body. “In a sense they act as smoke detectors if you will,” says Pulendran. “Little alarms.”

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Posted on by Robin Tricoles in Immunology Leave a comment

Moving flu vaccine research forward

The scientists in the lab of Richard Compans, PhD, professor of microbiology and immunology at Emory, are hard at work, imagining the unimaginable: A time when patients can self-administer flu vaccines. A time when vaccination does not require exposure to inactive viruses. A time when a universal vaccine could protect from all varieties of influenza: swine, avian, seasonal and strains still emerging.

Richard Compans, PhD (right), with colleague Mark Prausnitz, PhD, from Georgia Tech

But it’s not just hope that motivates them as they work. Emory’s scientists are fighting the clock against another possible future: a time of pandemic and uncontrollable virus mutation. The recent emergence of H1N1 and H5N1, known colloquially as swine flu and avian flu, have added an even greater sense of urgency to their task.

“The H5N1—the virus derived from avian species—has a 60 percent mortality,” says Emory microbiologist Sang-Moo Kang, PhD. Yet that strain of influenza hasn’t resulted in many human deaths, because, so far, avian flu spreads only to humans who are in contact with infected birds.

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Posted on by Jennifer Johnson in Immunology Leave a comment