Before the cardiologist goes nuclear w/ stress #AHA17

Measuring troponin in CAD patients before embarking on stress testing may provide Read more

Virus hunting season open

Previously unknown viruses, identified by Winship + UCSF scientists, come from a patient with a melanoma that had metastasized to the Read more

#AHA17 highlight: cardiac pacemaker cells

Highlighting new research on engineering induced pacemaker cells from Hee Cheol Cho's Read more

bone marrow

Cell therapy clinical trial in stroke

Emory neurosurgeon Robert Gross was recently quoted in a Tennessee newspaper article about a clinical trial of cell therapy for stroke. He used cautionary language to set expectations.

“We’re still in the very early exploratory phases of this type of work,” Gross told the Chattanooga Times Free Press. “In these cases, a significant area of the brain has been damaged, and simply putting a deposit of undifferentiated cells into the brain and magically thinking they will rewire the brain as good as new is naive. None of us think that.”

A more preliminary study (just 18 patients) using the same approach at Stanford and University of Pittsburgh was published this summer in Stroke, which says it was the “first reported intracerebral stem cell transplant study for stroke in North America.” The San Diego Union Tribune made an effort to be balanced in how the results were described:

Stroke patients who received genetically modified stem cells significantly recovered their mobility… Outcomes varied, but more than a third experienced significant benefit.

The newspaper articles made us curious about what these cells actually are. They’re mesenchymal stromal cells, engineered with an extra modified Notch gene. That extra gene drives them to make more supportive factors for neurons, but it doesn’t turn them into neurons. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

ACC 2016: Stem cell study sees improved heart failure outcomes

Patients with heart failure who received an experimental stem cell therapy experienced a reduced rate of death, hospitalization and unplanned clinic visits over the next year compared to a placebo group, according to results presented Monday at the American College of Cardiology meeting in Chicago.

The results of the ixCELL-DCM study were published online Monday by The Lancet. It was reportedly the largest cell therapy study done in patients with heart failure so far (58 treated vs 51 placebo).

Emory University School of Medicine investigators led by Arshed Quyyumi, MD, and their patients participated in the study, and Emory was one of the largest enrolling sites. Lead authors were Timothy Henry, MD of Cedars-Sinai Heart Institute in Los Angeles and Amit Patel, MD of the University of Utah.

“For the first time, a clinical trial has shown that administration of a cellular therapeutic results in an improvement in cardiac outcomes based on a prespecified analysis,” an editorial accompanying the paper in The Lancet says.

This study, which was sponsored by Vericel Corporation, was phase II, meaning that a larger phase III study will be needed before FDA approval. Read more

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‘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

CV cell therapy: bridge between nurse and building block

In the field of cell therapy for cardiovascular diseases, researchers see two main ways that the cells can provide benefits:

*As building blocks – actually replacing dead cells in damaged tissues

*As nurses — supplying growth factors and other supportive signals, but not becoming part of damaged tissues

Tension between these two roles arises partly from the source of the cells.

Many clinical trials have used bone marrow-derived cells, and the benefits here appear to come mostly from the “paracrine” nurse function. A more ambitious approach is to use progenitor-type cells, which may have to come from iPS cells or cardiac stem cells isolated via biopsy-like procedures. These cells may have a better chance of actually becoming part of the damaged tissue’s muscles or blood vessels, but they are more difficult to obtain and engineer.

A related concern: available evidence suggests introduced cells – no matter if they are primarily serving as nurses or building blocks — don’t survive or even stay in their target tissue for long.

Transplanted cells were labeled with a red dye, while a perfused green dye shows the extent of functional blood vessels. Blue is DAPI, staining nuclear DNA. Yellow arrows indicate where red cells appear to contribute to blood vessels.

Transplanted cells were labeled with a red dye, while a perfused green dye shows the extent of functional blood vessels. Blue is DAPI, staining nuclear DNA. Yellow arrows indicate where red cells appear to contribute to green blood vessels. Courtesy of Sangho Lee.

Stem cell biologist Young-sup Yoon and colleagues recently published a paper in Biomaterials in which the authors use chitosan, a gel-like carbohydrate material obtained by processing crustacean shells, to aid in cell retention and survival. Ravi Bellamkonda’s lab at Georgia Tech contributed to the paper.

More refinement of these approaches are necessary before clinical use,  but it illustrates how engineered mixtures of progenitor cells and supportive materials are becoming increasingly sophisticated and complicated.

The chitosan gel resembles the alginate material used to encapsulate cells by the Taylor lab. Yoon’s team was testing efficacy in a hindlimb ischemia model, in which a mouse’s leg is deprived of blood. This situation is analogous to peripheral artery disease, and the readout of success is the ability of experimental treatments to regrow capillaries in the damaged leg.

The current paper builds a bridge between the nurse and building block approaches, because the researchers mix two complementary types of cells: an angiogenic one derived from bone marrow cells that expands existing blood vessels, and a vasculogenic one derived from embryonic stem cells that drives formation of new blood vessels. Note: embryonic stem cells were of mouse origin, not human. Read more

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Decoding lupus using DNA clues

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

A team of Emory scientists has been investigating some fundamental questions about lupus: where do the cells that produce the self-reactive antibodies come from? Are they all the same?

In the accompanying video, Kelli Williams, who helps study the disease and has lupus herself, describes what a flare feels like. In addition, Emory researchers Iñaki Sanz, MD and Chris Tipton, PhD explain their findings, which were published this summer in Nature Immunology.

Judging by the number and breadth of abstracts on lupus at the Department of Medicine Research Day (where Tipton won 1st place for basic science poster), more intriguing findings are in the pipeline. Goofy Star Wars metaphors and more explanations of the science here.

Posted on by Quinn Eastman in Immunology Leave a comment

Low doses of imatinib can stimulate innate immunity

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.

The results were published this week in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

“We think that low doses of imatinib are mimicking ‘emergency hematopoiesis,’ a normal early response to infection,” says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.

Imatinib, is an example of a “targeted therapy” against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.

Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens – both bacteria and viruses – exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, including tuberculosis bacteria and Ebola virus. Read more

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

Stress of public speaking mobilizes progenitor cells from bone marrow

The stress of public speaking is enough to drive damage-repairing progenitor cells out of the bone marrow into the blood, a study of patients with heart disease has found.

Public speaking raises the blood pressure -- it also drives progenitor cells out of the bone marrow

Public speaking raises the blood pressure — it also drives progenitor cells out of the bone marrow

Endothelial progenitor cells (EPCs) are found in the bone marrow, and thought to repair damaged blood vessels once mobilized into the blood by injury or stress. Previous research has shown that strenuous exercise can lead to a dramatic increase in blood EPC levels, but the effects of psychological stress on EPCs had not been examined before.

This report emerges Magliette Calcio A Poco Prezzo from a large NHLBI-funded study of mental stress ischemia previously described in Emory Public Health magazine.

The new findings were presented Saturday, March 9 at the American College of Cardiology conference in San Francisco. The presenter was cardiovascular research fellow Ronnie Ramadan, MD. Senior authors are Arshed Quyyumi, MD, professor of medicine and director of the Emory Cardiovascular Research Institute, and Viola Vaccarino, MD, PhD, professor and chair of the Department of Epidemiology, Rollins School of Public Health.

In some patients with coronary artery disease, mental stress may precipitate ischemia– a deficiency in blood flow to the heart – a risk factor for adverse events and death independent of other cardiovascular risk factors such as smoking, cholesterol and diabetes.

Read more

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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

Emory transplant roundup

A recent Associated Press story highlighted clinical trials aimed at helping kidney transplant recipients give up their anti-rejection drugs:

The experimental approach: Transplant the seeds of a new immune system along with a new kidney. It’s the 21st-century version of a bone marrow transplant, and possible for now only if the transplanted kidney comes from a living donor.

How does it work? Doctors cull immune system-producing stem cells and other immunity cells from the donor’s bloodstream. They blast transplant patients with radiation and medications to wipe out part of their own bone marrow, far more grueling than a regular kidney transplant. That makes room for the donated cells to squeeze in and take root, creating a sort of hybrid immunity that scientists call chimerism, borrowing a page from mythology.

Emory Transplant Center scientific director Allan Kirk is leading a study that takes a similar approach, involving a depletion of the recipient’s immune cells and an infusion of bone marrow, which introduces new immune cells from the donor.

Allan Kirk, MD, PhD

Nature Medicine also has a good explanation of this area of research. Kirk is quoted in this recent story:

“The impetus to take the risk and pull people off immunosuppressants completely is lower now,” says Kirk… “It’s all about risk-benefit ratios and about making smart decisions with the tools we have—and we have a lot more tools now.”

Why go through so much trouble to avoid anti-rejection drugs? The most common drugs taken by transplant recipients, called calcineurin inhibitors, can reduce an individual’s ability to fight infections, lead to high blood pressure and high blood sugar and, ironically, tend to damage the kidney over time. Emory scientists played a major role in developing an alternative, belatacept, which was approved last year by the FDA.

Emory transplant surgeon Ken Newell was also mentioned in the AP story for his study of rare individuals who were able to go “cold turkey” and avoid having their immune systems reject their donated kidneys. One of these individuals, Lisa Robinson, had an interesting story to tell about how came to that point:

Three years after her kidney transplant, she found it hard to tolerate the side effects of the immunosuppressive drugs, which included swelling, weight gain and depression. On top of that, her creatinine levels were rising, indicating that her donated kidney was losing function. Without explicit approval from her doctor, she decided to taper off her drugs, first cyclosporine and then steroids.

“This turned out to be the right choice for me, but I’m not suggesting that others do what I did,” she says. “Everyone has to figure out what works for them. My main motivation was that I didn’t want to go through another kidney transplant.”

Based on data from Robinson and other people who had similar experiences, Newell has been able to identify a pattern of genes turned on in their immune cells that may predict whether someone could be able to become “tolerant.” Much of transplant biology focuses on one type of immune cell (T cells), but Newell found that the cells that may make the biggest difference for long-term tolerance are different, B cells. This makes sense because of B cells’ role in chronic rejection, Emory’s Stuart Knechtle has written.

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A path to treatment of lymphedema

Lymphedema, or swelling because of the impaired flow of lymph fluid, can occur as a consequence of cancer or cancer treatment. Chemotherapy can damage lymph ducts, and often surgeons remove lymph nodes that may be affected by cancer metastasis. Lymphedema can result in painful swelling, impaired mobility and changes in appearance.

Young-sup Yoon, MD, PhD

Emory scientists, led by cardiologist and stem cell biologist Young-sup Yoon, have shown that they can isolate progenitor cells for the lining of lymph ducts. This finding could lead to doctors being able to regenerate and repair lymph ducts using a patient’s own cells. The results are described in a paper published recently in the journal Circulation.

The authors used the cell surface marker podoplanin as a handle for isolating the progenitor cells from bone marrow. Previous research has demonstrated that podoplanin is essential for the development of the lymphatic system.
In the paper, the authors use several animal models to show that the progenitor cells could contribute to the formation of new lymph ducts, both by becoming part of the lymph ducts and by stimulating the growth of nearby cells.

“This lymphatic vessel–forming capability can be used for the treatment of lymphedema or chronic unhealed wounds,” Yoon says.

Isolated lymphatic endothelial cells (red) incorporate into lymph ducts (green) in a model of wound healing in mice.

The authors also show that mice with tumors show an increase in the number of this type of circulating progenitor cells. This suggests that tumors send out signals that encourage lymph duct growth – a parallel to the well-known ability of tumors to drive growth of blood vessels nearby. Yoon says the presence of these cells could be a marker for tumor growth and metastasis. Because tumors often metastasize along lymph ducts and into lymph nodes, studying this type of cells could lead to new targets for blocking tumor metastasis.

A recent review in the journal Genes & Development summarizes additional functions of the lymphatic system in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension.

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