Update on SIV remission studies

Recently presented insights on how an antibody used to treat intestinal diseases can suppress Read more

Granulins treasure not trash - potential FTD treatment strategy

Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously Read more

Blood vessels and cardiac muscle cells off the shelf

How to steer induced pluripotent stem cells into becoming endothelial cells, which line blood Read more

Rafi Ahmed

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

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Revived T cells still need fuel

Cancer immunotherapy drugs blocking the PD-1 pathway – known as checkpoint inhibitors – are now FDA-approved for melanoma, lung cancer and several other types of cancer. These drugs are often described as “releasing the brakes” on dysfunctional T cells.

A new study from Emory Vaccine Center and Winship Cancer Institute researchers shows that even if the PD-1-imposed brakes are released, the tumor-specific T cells still need “fuel” to expand in numbers and restore effective immune responses. That fuel comes from co-stimulation through a molecule called CD28.

The results were published Thursday by the journal Science.

Despite the success of PD-1-targeting drugs, many patients’ tumors do not respond to them. The study’s findings indicate that CD28’s presence on T cells could be a clinical biomarker capable of predicting whether drugs targeting PD-1 will be effective. In addition, the requirement for CD28 suggests that co-stimulation may be missing for some patients, which could guide the design of combination therapies.

For the rest of our press release and quotes from authors Rafi Ahmed, Alice Kamphorst and Suresh Ramalingam, please go here. For some additional links and thoughts on PD-1 and CD28, read on:

Read more

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

Dengue infection makes exhausted T cells?

An ongoing collaboration between the Emory Vaccine Center and the ICGEB (International Centre for Genetic Engineering and Biotechnology) in New Delh, investigating immune responses to dengue virus, is getting some attention.

A Journal of Virology paper published by the collaboration was highlighted by Nature Asia. In that paper, the researchers show that in dengue infection, the group of antiviral immune cells known as CD8+ T cells undergoes a massive expansion. That could be dangerous if all of the CD8 T cells were making inflammatory cytokines, but they do not. Only a small fraction are making cytokines.

The authors point out that this phenomenon is “somewhat reminiscent of T-cell exhaustion seen under the conditions of prolonged antigenic stimulus in chronic viral infections [which has been studied in detail by Rafi Ahmed and colleagues] or closely resembles the ‘stunned’ phenotype reported in febrile phase of other acute infections such as HIV and viral hepatitis… The IFN-γ unresponsiveness acquired during the massive antigen-driven clonal expansion is likely to ensure that these cells do not cause excessive inflammation at the time that their numbers are high during the febrile phase of dengue disease.” Read more

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How antiviral antibodies become part of immune memory

Weapons production first, research later. During wartime, governments follow these priorities, and so does the immune system.

When fighting a bacterial or viral infection, an otherwise healthy person will make lots of antibodies, blood-borne proteins that grab onto the invaders. The immune system also channels some of its resources into research: storing some antibody-making cells as insurance for a future encounter, and tinkering with the antibodies to improve them.

In humans, scientists know a lot about the cells involved in immediate antibody production, called plasmablasts, but less about the separate group of cells responsible for the “storage/research for the future” functions, called memory B cells. Understanding how to elicit memory B cells, along with plasmablasts, is critical for designing effective vaccines.

EbolaBcells

Activated B cells (blue) and plasmablasts (red) in patients hospitalized for Ebola virus infection, with a healthy donor for comparison. From Ellebedy et al Nature Immunology (2016).

Researchers at Emory Vaccine Center and Stanford’s Department of Pathology have been examining the precursors of memory B cells, called activated B cells, after influenza vaccination and infection and during Ebola virus infection. The Ebola-infected patients were the four who were treated at Emory University Hospital’s Serious Communicable Disease Unit in 2014.

The findings were published Monday, August 15 in Nature Immunology.

“Ebola virus infection represents a situation when the patients’ bodies were encountering something they’ve never seen before,” says lead author Ali Ellebedy, PhD, senior research scientist at Emory Vaccine Center. “In contrast, during both influenza vaccination and infection, the immune system generally is relying on recall.”

Unlike plasmablasts, activated B cells do not secrete antibodies spontaneously, but can do so if stimulated. Each B cell carries different rearrangements in its DNA, corresponding to the specificity and type of antibody it produces. The rearrangements allowed Ellebedy and his colleagues to track the activated B cells, like DNA bar codes, as an immune response progresses. Read more

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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

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Immune ‘traffic jam’ from viral infection

Several drugs now used to treat cancer and autoimmune diseases are actually repurposed tools derived from the immune system. One of the ways these “therapeutic antibodies” work is to grab onto malignant or inflammatory cells and escort them to their doom.

Emory researchers have found that in a mouse model of chronic viral infection, a kind of traffic pileup inside the body limits how effective therapeutic antibodies can be.

The results, published this week in Immunity, have implications for biotechnology researchers who continue to refine antibodies for therapeutic purposes, as well as bolster our understanding of how chronic viral infections impair the immune system.

Researchers led by Rafi Ahmed, PhD, director of the Emory Vaccine Center, were studying mice infected by LCMV (lymphocytic choriomeningitis virus). They injected several antibodies with the goal of removing various types of immune cells from the mice.  One end of the antibody molecule is supposed to bind the target cell, while another acts as a flag for other cells to get rid of the target cell.

However, during a chronic LCMV infection, the mouse’s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from having the effect the scientists wanted, which was to deplete their target cells.

Excessive amounts of immune complexes appear to be “clogging” the Fc gamma receptors that immune cells would use to grab the antibodies bound to the target cell, says postdoctoral fellow Andreas Wieland, PhD, first author of the Immunity paper. That these immune complexes form was not news; but how much they interfere with other antibodies was, Wieland says. Fc gamma receptors were already known to be important for antibodies to be effective against influenza and HIV. Read more

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General-heavy army disastrous in immune battle

Immunologists have identified two big groups of T cells: “helper” CD4+ cells and “killer” CD8+ cells.* The helper cells can produce immune regulatory molecules and promote antibody responses, while the killer cells recognize and destroy virally-infected cells.

A vaccine against a virus that stimulates only helper CD4+ cells leads to uncontrolled lethal inflammation in mice once the animals are challenged with the virus, a recent paper in Science shows. Emory Vaccine Center director Rafi Ahmed is a co-author.

Senior author Dan Barouch, from Harvard/Beth Israel Deaconess Medical Center, tells The Scientist that CD4+ cells are like generals directing the battle of the immune system and “if you just have strategic generals and no soldiers, it turns out to be worse than having no army at all.” Rebalancing the system with antiviral CD8+ T cells or antibodies helps limit the problems.

The findings mesh with work by Yerkes investigators [Guido Silvestri and colleagues] suggesting that HIV vaccines that boost CD4+ cells in gateway mucosal tissues lead to higher rates of infection. In both cases, the lesson is: having more helper CD4+ T cells around actually does not help. Read more

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Connections between starvation and immunological memory

Researchers at Emory have been revealing several connections between cells’ responses to starvation and immunological memory. The latest example of this is a paper in Nature Immunology from Rafi Ahmed’s lab, showing that the cellular process of autophagy (literally: self-consumption) is essential for forming and maintaining memory T cells.

This finding has some practical implications for vaccination and could point the way to additives that could boost vaccine effectiveness in elderly humans. Researchers at Oxford have demonstrated that autophagy is diminished in T cells from aged mice, and T cell responses could be boosted in older mice using the autophagy-inducing compound spermidine. Read more

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Key to universal flu vaccine: embrace the unfamiliar

Vaccine researchers have developed a strategy aimed at generating broadly cross-reactive antibodies against the influenza virus: embrace the unfamiliar.

In recent years, researchers interested in a “universal flu vaccine” identified a region of the viral hemagglutinin protein called the stem or stalk, which doesn’t mutate and change as much as other regions and could be the basis for a vaccine that is protective against a variety of flu strains.

In an Emory Vaccine Center study, human volunteers immunized against the avian flu virus H5N1 readily developed antibodies against the stem region of the viral hemagglutinin protein. In contrast, those immunized with standard seasonal trivalent vaccines did not, instead developing most of their antibodies against the more variable head region. H5N1, regarded as a potential pandemic strain, is not currently circulating in the United States and the volunteers had not been exposed to it before.

The results were published Monday, August 25 in PNAS.

The key to having volunteers’ bodies produce antibodies against the stem region seemed to be their immune systems’ unfamiliarity with the H5N1 type of virus, says lead author Ali Ellebedy, PhD, postdoctoral fellow in the laboratory of Rafi Ahmed, PhD, director of Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

Note: for a counterpoint, check out this 2013 Science Translational Medicine paper on how vaccination that induces anti-stem antibodies contributes to enhanced respiratory disease in pigs.

Read more

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