Red alert: Body kills ‘spontaneous’ blood cancers on a daily basis

Immune cells undergo ‘spontaneous’ changes on a daily basis that could lead to cancers if not for the diligent surveillance of our immune system, Melbourne scientists have found.The research team from the Walter and Eliza Hall Institute found that the immune system was responsible for eliminating potentially cancerous immune B cells in their early stages, before they developed into B-cell lymphomas (also known as non-Hodgkin’s lymphomas). The results of the study were published in the journal Nature Medicine.This immune surveillance accounts for what researchers at the institute call the ‘surprising rarity’ of B-cell lymphomas in the population, given how often these spontaneous changes occur. The discovery could lead to the development of an early-warning test that identifies patients at high risk of developing B-cell lymphomas, enabling proactive treatment to prevent tumours from growing.Dr Axel Kallies, Associate Professor David Tarlinton, Dr Stephen Nutt and colleagues made the discovery while investigating the development of B-cell lymphomas.Dr Kallies said the discovery provided an answer to why B-cell lymphomas occur in the population less frequently than expected. “Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B cell lymphoma is not more common in the population.”Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle, and proves that immune surveillance is essential to preventing the development of this blood cancer.”B-cell lymphoma is the most common blood cancer in Australia, with approximately 2800 people diagnosed each year and patients with a weakened immune system are at a higher risk of developing the disease.The research team made the discovery while investigating how B cells change when lymphoma develops. “As part of the research, we ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said. “It seems that our immune system is better equipped than we imagined to identify and eliminate cancerous B cells, a process that is driven by the immune T cells in our body.”Associate Professor Tarlinton said the research would enable scientists to identify pre-cancerous cells in the initial stages of their development, enabling early intervention for patients at risk of developing B-cell lymphoma.”In the majority of patients, the first sign that something is wrong is finding an established tumour, which in many cases is difficult to treat” Associate Professor Tarlinton said. “Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumours develop and they progress to cancer. There are already therapies that could remove these ‘aberrant’ B cells in at-risk patients, so once a test is developed it can be rapidly moved towards clinical use.”Story Source:The above story is based on materials provided by Walter and Eliza Hall Institute. Note: Materials may be edited for content and length.

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Being alive with mesothelioma and celebrating the birth of a new grandchild!

My daughter Jo gave birth today to a beautiful and healthy little boy! I am going to visit tomorrow and have my first cuddle – so looking forward to doing so.Also today I have turned the corner after 2 weeks since my last 2 lots of chemo my side effects have eased apart from shallow/tight breathing and slight bile/metallic taste so my immune system is now getting strength again and ready to have chemo next Tuesday (gemzar) and Weds overnight in hospital for the cisplatin.10 years ago when I actually started having palliative treatment for mesothelioma I so wanted to be here to see my little grandchildren being born … I am now up to the count of 5! Now my wish is to see every one of them …

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Mesothelioma Prognosis – Why Do Some Patients Survive Longer?

There have been some few patients who have survived far beyond the usual one year prognosis for most mesothelioma victims and a handful that have even been cured, with no trace of the aggressive cancer several years after treatment (though recurrence is always possible).Many medical experts are baffled by this observation and for most of the time they are yet to find a real scientific basis to explain why some mesothelioma patients survive and others do not.There seems to be one common factor amongst those that have survived the disease for longer times – the immune system. Studies of those who have either survived or been cured of the disease reveal that most of these patients participated in some sort of therapy that enhanced their immune …

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Autoimmune disease strategy emerges from immune cell discovery

Sep. 9, 2013 — Scientists from UC San Francisco have identified a new way to manipulate the immune system that may keep it from attacking the body’s own molecules in autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis.The researchers, led by immunologist Mark Anderson, MD, PhD, a professor with the UCSF Diabetes Center, have discovered a distinctive type of immune cell called an eTAC, which puts a damper on immune responses.Anderson’s research team found that eTACs reside in lymph nodes and spleen in both humans and mice, and determined that they could be manipulated to stop the destruction of the pancreas in a mouse model of diabetes. The study appears in the September issue of the journal Immunity.Using green fluorescent protein (GFP) to highlight a key regulatory protein called AIRE, Anderson’s research team tracked down the rare eTACs and their role in a phenomenon known as peripheral tolerance, which helps prevent autoimmune disease throughout the body.The newly described immune cells are of a type known as dendritic cells, which make up less than 3 percent of the cells in the immune system. ETAC cells account for a small fraction of all dendritic cells, Anderson said.Dendritic cells already have been the focus of new cell therapies to treat cancer. These therapies, which include treatments evaluated in clinical trials at UCSF, have been used to prod dendritic cells to rev up a complementary class of immune cells, called T cells. Treatment causes the T cells to target cancer cells, which, despite being abnormal, would not otherwise be subjected to vigorous attack in the same way as foreign microbial invaders.However, eTAC cells have the opposite effect. Instead of priming T cells to do battle, eTACs counteract the overactive immune response in autoimmune diseases. Anderson’s team took advantage of this property to demonstrate that eTACs could prevent autoimmune diabetes in mice.By displaying “self” molecules to T cells that target them, and turning off these T cells for good, eTACs help the immune system tolerate the molecules naturally present within us, Anderson said.”The mouse model we are working with involves using T cells that normally attack the islet cells of the pancreas, specifically by recognizing a molecule called chromagranin A that is present on islet cells,” Anderson said. “But if the eTACs can get to the T cells first and display chromagranin A, they can prevent T cells from attacking the islets.”Anderson aims to exploit eTACs therapeutically by finding out how to grow them in large numbers outside the body. “We need to figure out how to grow a lot of these cells, to load them up with whatever molecule it is that we want to induce tolerance to, and then to load them back into a patient,” he said. …

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Turning to parasites as potential disease fighters

Sep. 9, 2013 — There is a new weapon in the fight against autoimmune diseases such as Type 1 diabetes, rheumatoid arthritis, Crohn’s disease and lupus, the common trait of which is an immune system that attacks its own organs and tissues.William Gause, an immunologist at Rutgers New Jersey Medical School, is among those leading the charge against these diseases by studying how the human body reacts to worms. The worms Gause studies, or helminths as biologists call them, are small parasites that live in human intestines, especially in the developing world.According to an article in Nature Reviews Immunology by Gause and colleagues from the National Institutes of Health and the University of Edinburgh, the worms’ presence through millennia of human evolution likely has led to an immune response called type 2 immunity. This includes immune regulatory pathways that help control the inflammation that can contribute to autoimmune diseases.The immune reaction, the researchers say, appears to have developed as a way to rapidly repair wounds caused by these invaders as they move through the body. In fact, components of the type 2 immune response may someday be used to enhance the wound healing process. Additionally, this response triggers regulatory networks that block harmful immune responses, or inflammation, that otherwise would exacerbate the tissue injury.”What we would like to do now is harness components of the type 2 immune response to target the control of harmful inflammation that can lead to autoimmune diseases like diabetes and inflammatory bowel disease,” Gause says. He adds that inflammatory responses also have been linked to other diseases, including cardiovascular disease and metabolic disorders, and even to allergic reactions and fibrosis that may result when titanium shavings that flake away from artificial joints settle in the body. “Finding new ways to stimulate these regulatory components of the type 2 immune response may provide us with a new set of tools to target the control of harmful inflammatory responses now associated with this wide array of different diseases.”For now, live helminths or helminth byproducts may be introduced into the body on a short-term basis to train compromised immune systems. A 2012 study by a Gause-led team found that the introduction of helminths for two weeks caused the immune systems of mice to produce cytokines, or signaling molecules, which gave them lasting protection against Type 1 diabetes.That finding mirrors human experience in the developing world where helminth infection is endemic, but the incidence of autoimmune diseases such as Type 1 diabetes is extremely low.”There is a growing body of evidence to support the hygiene hypothesis, which suggests that decreased exposure to microbes and helminths in industrialized countries may impair the development of immune regulatory networks that would otherwise control harmful inflammatory responses,” Gause says.The end result of that process, according to Gause, is increased incidence of a variety of diseases linked to harmful inflammation. “If we find a controlled way to apply the benefit that helminths appear to provide to the workings of the immune system, it is conceivable that we as a society would no longer need to endure the apparent tradeoff between clean living conditions and inflammatory diseases.”

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Novel therapeutic cancer vaccine goes to human clinical trials

Sep. 6, 2013 — A cross-disciplinary team of scientists, engineers, and clinicians announced today that they have begun a Phase I clinical trial of an implantable vaccine to treat melanoma, the most lethal form of skin cancer.The effort is the fruit of a new model of translational research being pursued at the Wyss Institute for Biologically Inspired Engineering at Harvard University that integrates the latest cancer research with bioinspired technology development. It was led by Wyss Core Faculty member David J. Mooney, Ph.D., who is also the Robert P. Pinkas Family Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences (SEAS), and Wyss Institute Associate Faculty member Glenn Dranoff, M.D., who is co-leader of Dana-Farber Cancer Institute’s Cancer Vaccine Center.Most therapeutic cancer vaccines available today require doctors to first remove the patient’s immune cells from the body, then reprogram them and reintroduce them back into the body. The new approach, which was first reported to eliminate tumors in mice in Science Translational Medicine in 2009, the year the Wyss Institute was launched, instead uses a small disk-like sponge about the size of a fingernail that is made from FDA-approved polymers. The sponge is implanted under the skin, and is designed to recruit and reprogram a patient’s own immune cells “on site,” instructing them to travel through the body, home in on cancer cells, then kill them.The technology was initially designed to target cancerous melanoma in skin, but might have application to other cancers. In the preclinical study reported in Science Translational Medicine, 50 percent of mice treated with two doses of the vaccine — mice that would have otherwise died from melanoma within about 25 days — showed complete tumor regression.”Our vaccine was made possible by combining a wide range of biomedical expertise that thrives in Boston and Cambridge,” said Mooney, who specializes in the design of biomaterials for tissue engineering and drug delivery. “It reflects the bioinspired engineering savvy and technology development focus of engineers and scientists at the Wyss Institute and Harvard SEAS, as well as the immunological and clinical expertise of the researchers and clinicians at Dana-Farber and Harvard Medical School.””This is expected to be the first of many new innovative therapies made possible by the Wyss Institute’s collaborative model of translational research that will enter human clinical trials,” said Wyss Founding Director Don Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and a Professor of Bioengineering at Harvard SEAS. “It validates our approach, which strives to move technologies into the clinical space much faster than would be possible in a traditional academic environment. …

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Body’s ‘safety procedure’ could explain autoimmune disease

Sep. 5, 2013 — Monash University researchers have found an important safety mechanism in the immune system that may malfunction in people with autoimmune diseases, such as Multiple Sclerosis, potentially paving the way for innovative treatments.Published today in Immunity, the research, led by Head of the Monash Department of Immunology Professor Fabienne Mackay, described for the first time how the body manages marginal zone (MZ) B cells, which form a general first line of attack against germs, but are potentially harmful.MZ B cells are integral to our defenses as they rapidly produce polyreactive antibodies that are capable of destroying a variety of pathogens. This first response gives the body time to put in place an immune reaction specific to the invading microbe.However, MZ B cells have the potential to turn against the body. Some are capable of producing antibodies which attack healthy, rather than foreign, cells — known as an autoimmune response. Bacteria trigger MZ B cells irrespective of whether these cells are dangerous or benign, effectively placing anyone with a bacterial infection at risk of developing an autoimmune disease.Professor Mackay’s team has discovered the mechanism that regulates this response, ensuring that that the majority of infections do not result in the body attacking its own tissue.”We found that while MZ B cells are rapidly activated, they have a very short life span. In fact, the very machinery which triggers a response leads to MZ B cells dying within 24 hours,” Professor Mackay said.”This means that in a healthy person, the potentially harmful immune cells are not active for long enough to cause in tissue damage. We now need to look at whether a malfunction in this safety feature is leading to some autoimmune diseases.”When MZ B cells are activated by bacteria, they express greater amounts of a protein known as TACI. When TACI binds to another protein as part of the immune response, this triggers the activation of the ‘death machinery’ inside MZ B cells. The detection of a pathogen sets of a chain reaction that both activates and then destroys MZ B cells.Professor Mackay said this was an entirely new way of looking at the immune system.”The research suggests that through evolution the immune system has not solely been vulnerable to infections but has learned to take advantage of pathogens to develop its own internal safety processes,” Professor Mackay said.”This says something important about our environment — pathogens are not always the enemy. They can also work hand in hand with our immune system to protect us against some immune diseases.”

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Some immune cells appear to aid cancer cell growth

Sep. 5, 2013 — The immune system is normally known for protecting the body from illness. But a subset of immune cells appear to be doing more harm than good.A new study from researchers at the University of Michigan Comprehensive Cancer Center found that these cells, called myeloid derived suppressor cells, provide a niche where the cancer stem cells survive.Cancer stem cells are thought to be resistant to current chemotherapy and radiation treatments, and researchers believe that killing the cancer stem cells is crucial for eliminating cancer.At the same time that these immune cells help the cancer, they also are suppressing the immune system.”This cell and its mechanisms are not good for your body and it helps the cancer by allowing the stem cells to thrive. If we can identify a therapy that targets this, we take away the immune suppression and the support for cancer stem cells. Essentially, we kill two birds with one stone,” says senior study author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of surgery, immunology and biology at the University of Michigan Medical School.The researchers believe the immune cells give the cancer cells their “stemness” — those properties that allow the cells to be so lethal — and that without this immune cell, the cancer stem cells may not efficiently progress.The study, which was led by Tracy X. Cui, Ph.D., and Ilona Kryczek, Ph.D., looked at cells from the most common and lethal type of ovarian cancer, a disease in which patients often become resistant to chemotherapy, causing the cancer to return.Targeting the immune system for cancer treatment, called immunotherapy, has been well-received with many potential therapeutics currently being tested in clinical trials for a variety of cancer types. The U-M team is a worldwide leader in the field of tumor immunology.Additional authors: Other contributors are Lili Zhao, Ende Zhao, Rork Kuick, Michael H. Roh, Linda Vatan, Wojciech Szeliga, Yujun Mao, Dafydd G. Thomas, Max S. …

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Mutations in a gene that impacts immune function increase susceptibility to prostate cancer

Aug. 29, 2013 — A team of researchers led by Janet Stanford, Ph.D., of Fred Hutchinson Cancer Research Center has discovered that mutations in the gene BTNL2, which encodes a protein involved in regulating T-cell proliferation and cytokine production — both of which impact immune function — increase the risk of developing prostate cancer.The findings, by Stanford and colleagues from the University of Washington Genome Sciences Department and the National Human Genome Research Institute, are online ahead of the print issue of Cancer Epidemiology, Biomarkers & Prevention.A complex disease with a strong genetic componentProstate cancer is a complex disease and its causes include a strong genetic component. It is estimated that about 42 percent of prostate cancer cases are due to heredity, or genetic variations present at birth. Five to 10 percent of those prostate cancer cases are thought to result from rare inherited mutations.The researchers studied multiple prostate cancer patients from families with a pattern of hereditary prostate cancer, or HPC. Germline DNA provided by patients with more aggressive or early onset disease was sequenced in an attempt to identify rare genetic mutations that predispose to prostate cancer. All the participants were men of European ancestry.Several genes with candidate mutations were highlighted, but two coding variants in the butyrophilin-like 2, or BTNL2, gene were most strongly related to the development of prostate cancer. These missense mutations that change the genetic code were subsequently confirmed to be clearly associated with prostate cancer in an independent set of HPC families and in a case-control study population.The team found that the two BTNL2 mutations associated with elevated prostate cancer risk are rare. In the 270 HPC families used for confirmation, about 1.5 percent of affected men carried one of the mutations but unaffected men carried none. In the population-based case-control study, 2 percent of prostate cancer cases and less than 1 percent of men without prostate cancer carried one of the variants.Mutations increased risk of both hereditary and sporadic prostate cancerIn the case-control study, men who carried one of these variants had a significant 2.5- to 2.7-fold higher risk for developing prostate cancer compared to men who did not carry either mutation.”This research demonstrates for the first time that rare mutations in the BTNL2 gene enhance susceptibility to both hereditary and sporadic prostate cancer,” said Stanford, co-director of the Program in Prostate Cancer Research a member of the Public Health Sciences Division at Fred Hutch. Common variants in this gene have been previously linked to several autoimmune and inflammatory diseases such as sarcoidosis and ulcerative colitis.The researchers used a next-generation sequencing technology called whole-exome sequencing, which consists of sequencing all the coding regions, called exons, across the genome. …

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Dialing back Treg cell function boosts cancer-fighting immune activity

Aug. 18, 2013 — By carefully adjusting the function of crucial immune cells, scientists may have developed a completely new type of cancer immunotherapy — harnessing the body’s immune system to attack tumors. To accomplish this, they had to thread a needle in immune function, shrinking tumors without triggering unwanted autoimmune responses.The new research, performed in animals, is not ready for clinical use in humans. However, the approach, making use of a key protein to control immune function, lends itself to further study using candidate drugs that employ the same mechanisms.”This preclinical study demonstrates proof of principle that using a drug to regulate the function of a special, immunosuppressive subset of so-called T-regulatory (Treg) cells safely controls tumor growth,” said study leader Wayne W. Hancock, M.D., Ph.D., of the Division of Transplant Immunology at The Children’s Hospital of Philadelphia (CHOP). “It really moves the field along towards a potentially major, new cancer immunotherapy.”Hancock and colleagues published the study today in Nature Medicine.”There’s a basic paradox in immunology: why doesn’t the immune system prevent cancer in the first place?” said Hancock. The answer is complicated, he adds, but much of it involves a delicate balancing act among elements of the immune system: while immunity protects us against disease, an overly aggressive immune response may trigger dangerous, even life-threatening, autoimmune reactions in which the body attacks itself.In the current study, Hancock focused on a subtype of immune cells called Foxp3+ Tregs, for short. Tregs were already known to limit autoimmunity, but often at the cost of curtailing immune responses against tumors. “We needed to find a way to reduce Treg function in a way that permits antitumor activity without allowing autoimmune reactions,” he said.Hancock’s group showed that inhibiting the enzyme p300 can affect the functions of another protein, Foxp3, which plays a key role in controlling the biology of Tregs. By deleting the gene that expresses p300, the researchers safely reduced Treg function and limited tumor growth in mice. …

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Researchers report a critical role for the complement system in early macular degeneration

Aug. 15, 2013 — In a study published on line this week in the journal Human Molecular Genetics, Drs. Donita Garland, Rosario Fernandez-Godino, and Eric Pierce of the Ocular Genomics Institute at the Massachusetts Eye and Ear, Harvard Medical School along with their colleagues, reported the unexpected finding that in mice genetically engineered to have an inherited form of macular degeneration, turning off the animals’ complement system, a part of the immune system, prevented the disease.Macular degenerations, which occur in several forms, are important causes of vision loss. Juvenile or early-onset macular degeneration includes several inherited disorders that can affect children and young adults. In contrast, age-related macular degeneration (AMD) affects older individuals; it is the leading cause of blindness for individuals over 65 years of age in developed countries, and its prevalence is increasing worldwide. Both inherited macular degeneration and AMD lead to the loss of central vision. While therapies exist for some forms of late AMD, and nutritional supplements can slow the progression of early AMD for some patients, improved therapies to prevent vision loss from these disorders are needed.This is the first report to demonstrate a role for the complement system in an inherited macular degeneration. Previous genetic studies have shown that variants in the genes that encode several complement system components are important risk factors for AMD. Based on this, drugs that inhibit specific complement system activities are being tested clinically as treatments for AMD. However, it is not entirely clear how alterations in complement system components lead to AMD.The new results reported suggest that complement activation by abnormalities in the extracellular matrix or the scaffold secreted by retinal cells plays an important role in the formation of basal deposits, one of the earliest stages of macular degeneration. …

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Potent mechanism helps viruses shut down body’s defense system against infection

Aug. 14, 2013 — Researchers at the Salk Institute for Biological Studies have discovered a powerful mechanism by which viruses such as influenza, West Nile and Dengue evade the body’s immune response and infect humans with these potentially deadly diseases. The findings may provide scientists with an attractive target for novel antiviral therapies.Published in the August issue of the journal Cell Host and Microbe, the findings describe a novel mechanism that this group of so-called “enveloped viruses” uses to disarm the host’s innate immune response. The mechanism the scientists uncovered is based on these viruses activating a class of molecules, known as TAM receptors, which are located on the outside of certain immune cells.In the immune system, TAM receptors are used by cells, such as macrophages and dendritic cells, to clean up dead cells, and they are also central inhibitors of the body’s innate immune response to bacteria, viruses and other pathogens.The Salk scientists found that a substance called phosphatidylserine (PtdSer), which is found on the surface of enveloped viruses (viruses with an outer wrapping of a lipid membrane), binds to extracellular proteins and activates TAM receptors on immune cells. In dendritic cells, a type of immune cell that interacts with T and B cells to initiate the adaptive immune response, TAM receptor activation turns off a set of genes called interferons that play a key role in antiviral defense.”Our findings suggest a unique way in which TAM receptors contribute to the establishment of viral infection by disabling the interferon response,” says co-lead study author John A.T. Young, a professor in Salk’s Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis. “As a consequence, the interferon-stimulated defense genes are not turned on, rendering the target cell more permissive for virus infection.”This is a previously unknown mechanism for enveloped viruses, which are very common, to inhibit the body’s normal antiviral response. Since PtdSer exposure seems to be a general feature of enveloped viruses, the researchers say many different viruses may use the mechanism to counteract the cellular antiviral response in cells with TAM receptors.Understanding this mechanism allows researchers to work on developing broad-spectrum antiviral drugs that prevent viruses from shutting down the interferon response in cells by blocking TAM receptor activation. In their study, the Salk scientists tested a small-molecule drug called BMS-777607, initially developed for anti-cancer therapy, that does just that.”With this small molecule, viruses can’t activate TAM receptors, so they can’t shut down the interferon response,” says co-lead author Greg Lemke, a professor in Salk’s Molecular Neurobiology Laboratory and the Françoise Gilot-Salk Chair, in whose laboratory TAM receptors were discovered.With other scientists around the country, the Salk researchers are testing a variety of small molecule drugs in series of different viruses, including West Nile, Dengue, influenza, Ebola, Marburg, and hepatitis B. These drugs work, in large part, by blocking the virus’ ability to activate TAM receptors, thereby leaving the interferon-mediated antiviral response intact.”This is a completely novel approach,” says Young, who holds the Nomis Foundation Chair at Salk. …

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Researchers use nanoparticles to fight cancer

Aug. 14, 2013 — Researchers at the University of Georgia are developing a new treatment technique that uses nanoparticles to reprogram immune cells so they are able to recognize and attack cancer.The findings were published recently in the early online edition of ACS Nano.The human body operates under a constant state of martial law. Chief among the enforcers charged with maintaining order is the immune system, a complex network that seeks out and destroys the hordes of invading bacteria and viruses that threaten the organic society as it goes about its work.The immune system is good at its job, but it’s not perfect. Most cancerous cells, for example, are able to avoid detection by the immune system because they so closely resemble normal cells, leaving the cancerous cells free to multiply and grow into life-threatening tumors while the body’s only protectors remain unaware.Shanta Dhar and her colleagues are giving the immune system a boost through their research.”What we are working on is specifically geared toward breast cancer,” said Dhar, the study’s co-author and an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences. “Our paper reports for the first time that we can stimulate the immune system against breast cancer cells using mitochondria-targeted nanoparticles and light using a novel pathway.”In their experiments, Dhar and her colleagues exposed cancer cells in a petri dish to specially designed nanoparticles 1,000 times finer than the width of a human hair. The nanoparticles invade the cell and penetrate the mitochondria — the organelles responsible for producing the energy a cell needs to grow and replicate.They then activated the nanoparticles inside the cancer cells by exposing them to a tissue-penetrating long wavelength laser light. Once activated, the nanoparticles disrupt the cancer cell’s normal processes, eventually leading to its death.The dead cancer cells were collected and exposed to dendritic cells, one of the core components of the human immune system. What the researchers saw was remarkable.”We are able to potentially overcome some of the traditional drawbacks to today’s dendritic cell immunotherapy,” said Sean Marrache, a graduate student in Dhar’s lab. “By targeting nanoparticles to the mitochondria of cancer cells and exposing dendritic cells to these activated cancer cells, we found that the dendritic cells produced a high concentration of chemical signals that they normally don’t produce, and these signals have traditionally been integral to producing effective immune stimulation.”Dhar added that the “dendritic cells recognized the cancer as something foreign and began to produce high levels of interferon-gamma, which alerts the rest of the immune system to a foreign presence and signals it to attack. We basically used the cancer against itself.”She cautions that the results are preliminary, and the approach works only with certain forms of breast cancer. …

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Who benefits from vitamin D?

Aug. 13, 2013 — Studying the expression of genes that are dependent on vitamin D makes it possible to identify individuals who will benefit from vitamin D supplementation, shows a University of Eastern Finland study published recently in PLoS One.Share This:Population-based studies have shown that vitamin D deficiency may increase the risk for chronic diseases and weaken the body’s immune system. In the present study carried out at the University of Eastern Finland, Kuopio, the study participants were given a daily dose of either 40 or 80 micrograms of vitamin D, or a placebo, over a course of 5 months during Finnish winter.. The results showed that the expression of vitamin D dependent genes in adipose tissue and monocytes, i.e. white blood cells, correlated only in half of the study participants with their vitamin D concentrations in the blood.The researchers concluded that persons whose expression of the CD14 and thrombomodulin genes was not altered as a result of vitamin D supplementation already had a sufficiently high serum vitamin D concentration or their utilization of vitamin D was disturbed, which calls for further study. The researchers believe that studying the expression of vitamin D dependent genes in tissues is a novel way to identify individuals who might benefit from long-term vitamin D supplementation. This observation is further supported by the fact that studying alterations in the expression of genes also made it possible to identify persons whose levels of interleukin 6, an inflammation marker, were reduced as their serum vitamin D levels increased.Share this story on Facebook, Twitter, and Google:Other social bookmarking and sharing tools:|Story Source: The above story is based on materials provided by University of Eastern Finland. Note: Materials may be edited for content and length. For further information, please contact the source cited above. Journal Reference:Carsten Carlberg, Sabine Seuter, Vanessa D. …

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New strategy to disarm the dengue virus brings new hope for a universal dengue vaccine

Aug. 13, 2013 — A new strategy that cripples the ability of the dengue virus to escape the host immune system has been discovered by A*STAR’s Singapore Immunology Network (SIgN). This breakthrough strategy opens a door of hope to what may become the world’s first universal dengue vaccine candidate that can give full protection from all four serotypes of the dreadful virus.This research done in collaboration with Singapore’s Novartis Institute of Tropical Diseases (NITD) and Beijing Institute of Microbiology and Epidemiology is published in the Plos Pathogens journal, and is also supported by Singapore STOP Dengue Translational and Clinical Research (TCR) Programme grant.Early studies have shown that a sufficiently weakened virus that is still strong enough to generate protective immune response offers the best hope for an effective vaccine. However, over the years of vaccine development, scientists have learnt that the path to finding a virus of appropriate strength is fraught with challenges. This hurdle is compounded by the complexity of the dengue virus. Even though there are only four different serotypes, the fairly high rates of mutation means the virus evolve constantly, and this contributes to the great diversity of the dengue viruses circulating globally. Furthermore, in some cases, the immune response developed following infection by one of the four dengue viruses appears to increase the risk of severe dengue when the same individual is infected with any of the remaining three viruses. With nearly half the world’s population at risk of dengue infection and an estimated 400 million people getting infected each year[2], the need for a safe and long-lasting vaccine has never been greater.The new strategy uncovered in this study overcomes the prevailing challenges of vaccine development by tackling the virus’ ability to ‘hide’ from the host immune system. Dengue virus requires the enzyme called MTase (also known as 2′-O-methyltransferase) to chemically modify its genetic material to escape detection. In this study, the researchers discovered that by introducing a genetic mutation to deactivate the MTase enzyme of the virus, initial cells infected by the weakened MTase mutant virus is immediately recognised as foreign. …

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Nanodrug targeting breast cancer cells from the inside adds weapon: Immune system attack

Aug. 10, 2013 — A unique nanoscale drug that can carry a variety of weapons and sneak into cancer cells to break them down from the inside has a new component: a protein that stimulates the immune system to attack HER2-positive breast cancer cells.The research team developing the drug — led by scientists at the Nanomedicine Research Center, part of the Maxine Dunitz Neurosurgical Institute in the Department of Neurosurgery at Cedars-Sinai Medical Center — conducted the study in laboratory mice with implanted human breast cancer cells. Mice receiving the drug lived significantly longer than untreated counterparts and those receiving only certain components of the drug, according to a recent article in the Journal of Controlled Release.Researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, the Division of Surgical Oncology at UCLA, and the Molecular Biology Institute at UCLA also participated in the study.Unlike other drugs that target cancer cells from the outside, often injuring normal cells as a side effect, this therapy consists of multiple drugs chemically bonded to a “nanoplatform” that functions as a transport vehicle.HER2-positive cancers — making up 25 to 30 percent of breast and ovarian cancers — tend to be more aggressive and less responsive to treatment than others because the overactive HER2 gene makes excessive amounts of a protein that promotes cancer growth. One commonly used drug, Herceptin (trastuzumab), often is effective for a while, but many tumors become resistant within the first year of treatment and the drug can injure normal organs it contacts.But Herceptin is an antibody to the HER2 gene — it naturally seeks out this protein — so the research team used key parts of Herceptin to guide the nanodrug into HER2-positive cancer cells.”We genetically prepared a new ‘fusion gene’ that consists of an immune-stimulating protein, interleukin-2, and a gene of Herceptin,” said Julia Y. Ljubimova, MD, PhD, professor of neurosurgery and biomedical sciences and director of the Nanomedicine Research Center. “IL-2 activates a variety of immune cells but is not stable in blood plasma and does not home specifically to tumor cells. By attaching the new fusion antibody to the nanoplatform, we were able to deliver Herceptin directly to HER2-positive cancer cells, at the same time transporting IL-2 to the tumor site to stimulate the immune system. Attaching IL-2 to the platform helped stabilize the protein and allowed us to double the dosage that could be delivered to the tumor.”Ljubimova led the study with Manuel Penichet, MD, PhD, associate professor of surgery, microbiology, immunology and molecular genetics at the University of California, Los Angeles, David Geffen School of Medicine. Ljubimova said the UCLA collaborators developed the fusion gene, and Cedars-Sinai chemists Eggehard Holler, PhD, professor in the Department of Neurosurgery, and Hui Ding, PhD, assistant professor, performed the technically difficult task of attaching it to the nanoplatform. Ding is the journal article’s first author.The researchers also attached other components, such as molecules to block a protein (laminin-411) that cancer cells need to make new blood vessels for growth.The nanodrug, Polycefin, is in an emerging class called nanobiopolymeric conjugates, nanoconjugates or nanobioconjugates. …

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Narrower range of helpful bacteria in guts of C-section infants

Aug. 7, 2013 — Decreased gut microbiota diversity delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by Caesarean section.The range of helpful bacteria in the guts of infants delivered by caesarean section, during their first two years of life, is narrower than that of infants delivered vaginally, indicates a small study published online in the journal Gut.This has implications for the development of the immune system, say the researchers, particularly as the C-section infants had lower levels of the major group of gut bacteria associated with good gut health, Bacteroidetes phylum, as well as chemicals that help curb allergic responses.The researchers assessed the patterns of bacterial colonisation of the guts of 24 infants, nine of whom had been born by caesarean section one week, and then again at one, three, six, 12 and 24 months after birth.They also took blood samples at six, 12 and 24 months to test for levels of immune system chemicals known as Th1 and 2 associated chemokines. Excess Th2 chemokines have been implicated in the development of allergies, which Th1 responses can counteract, say the authors.The results showed that babies delivered by caesarean section, and who therefore did not pass down the mother’s birth canal, either lacked or acquired late one of the major groups of gut bacteria, the Bacteroidetes, compared with the babies born vaginally.In some C-section infants acquisition of Bacteroidetes did not occur until a year after birth. The total range of bacteria among those born by C-section was also lower than that of their vaginally delivered peers.The differences in bacterial colonisation between the two groups of infants were not down to their mums having been given antibiotics during C-section or after the procedure to prevent infection: the levels and range of bacteria sampled from both sets of mums were similar, the analysis showed.Bacteria are important for priming the immune system to respond appropriately to triggers, and not overreact as is the case in allergies, diabetes, and inflammatory bowel disease, say the authors.This includes the development of immune system T cells and the correct balance between their chemical messengers, Th1 and Th2.The C-section infants had lower circulating levels of Th1 chemical messengers in their blood, indicating an imbalance between Th1 and Th2. “Failure of Th2 silencing during maturation of the immune system may underlie development of Th2-mediated allergic disease,” write the authors.They point out that previous research has indicated that Bacteroides fragilis, one of the many Bacteroidetes, strongly influences the immune system, which ultimately enhances T cell activity and the Th1-Th2 balance.”Thus, the lower abundance of Bacteroides among the C-section infants may be a contributing factor to the observed differences in the Th1-associated chemokines,” they write.

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New modular vaccine design combines best of existing vaccine technologies

July 29, 2013 — A new method of vaccine design, called the Multiple Antigen Presentation System (MAPS), may result in vaccines that bring together the benefits of whole-cell and acellular or defined subunit vaccination. The method, pioneered by researchers at Boston Children’s Hospital, permits rapid construction of new vaccines that activate mulitple arms of the immune system simultaneously against one or more pathogens, generating robust immune protection with a lower risk of adverse effects.As reported by Fan Zhang, PhD, Ying-Jie Lu, PhD, and Richard Malley, MD, from Boston Children’s Division of Infectious Disease, in the Proceedings of the National Academy of Sciences on July 29, the method could speed development of new vaccines for a range of globally serious pathogens, or infectious agents.Broadly speaking, the vaccines available today fall into two categories: whole-cell vaccines, which rely on weakened or killed bacteria or viruses; and acellular or subunit vaccines, which include a limited number of antigens — portions of a pathogen that trigger an immune response. Both approaches have advantages and disadvantages.”Whole-cell vaccines elicit a broad range of immune responses, often just as an infection would, but can cause side effects and are hard to standardize,” said Malley. “Acellular vaccines can provide good early immunity with less risk of side effects, but the immune responses they induce wane with time.”The MAPS method may allow vaccine developers to take a middle ground, where they can link multiple protein and polysaccharide (sugar) antigens from one or more pathogens together in a modular fashion, much as one would connect Lego blocks.The resulting complex — which resembles a scaffold of polysaccharides studded with proteins — can stimulate both antibody and T-cell responses simultaneously much like whole-cell vaccines, resulting in stronger immunity to the source pathogen(s). However, because the composition of a MAPS vaccine is well defined and based on the use of isolated antigens (as one would find with an acellular vaccine) the risk of side effects should be greatly reduced.For instance, mice injected with a MAPS vaccine combining proteins from tuberculosis (TB) and polysaccharides from Streptococcus pneumoniae (pneumococcus) mounted vigorous antibody and T-cell responses against TB, whereas those vaccinated with TB protein antigens alone mounted only an antibody response.Similarly, 90 percent of mice given a MAPS-based vaccine containing multiple pneumococcal polysaccharide and protein antigens were protected from a lethal pneumococcus infection, mounting strong antibody and T-cell responses against the bacteria. By contrast, 30 percent of mice vaccinated with the same antigens in an unbound state survived the same challenge.”The MAPS technology gives you the advantages of: whole-cell vaccines while being much more deliberate about which antigens you include; doing it in a quantitative and precise way; and including a number of antigens so as to try to replicate the effectiveness of whole-cell vaccination,” Malley explained. “The immunogenicity of these constructs is greater than the sum of their parts, somewhat because they are presented to the host as particles.”The system relies on the interactions of two compounds, biotin and rhizavidin, rather than covalent binding as is used in most of the current conjugate vaccines. To build a MAPS vaccine, biotin is bound to the polysaccharide(s) of choice and rhizavidin to the protein(s). The biotin and rhizavidin then bind together through an affinity interaction analogous to Velcro. The construction process is highly efficient, significantly reducing the time and cost of vaccine development and production.While his team’s initial work has focused on bacterial pathogens, Malley believes the technology could impact vaccine development for a broad range of pathogens, in particular those of importance in the developing world. …

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Too much of a good thing? Overactive immune response blocks itself

July 26, 2013 — As part of the innate immune system natural killer cells (NK cells) play an important role in immune responses. For a long time they have been known as the first line of defense in the fight against infectious diseases. Therefore, researchers assumed that the body needs as many active NK cells as possible. However, scientists at the Helmholtz Centre for Infection Research (HZI) have now shown that the principle “the more the better” does not apply to this type of immune cells.”During certain phases of the immune response it seems to be beneficial to have less active natural killer cells,” says Dr Jadwiga Jablonska-Koch, member of the research group “Molecular Immunology” at the HZI and responsible author of a new study published in the European Journal of Immunology. “This is particularly true during the beginning stages of an infection, which is precisely when they were assumed to be most important.”Usually, Listeria monocytogenes infection leads to a deadly sepsis in mice and immune suppressed humans. Interestingly, researchers observed that removal of NK cells during the early stages of Listeria monocytogenes infection improves survival of the mice. These new findings could help to prevent sepsis in the future.Until now it was believed that mice and humans die from listeriosis because their killer cells do not fight the infection effectively enough. However, the new results show the exact opposite. Even though the killer cells produce messenger substances that activate the immune system, the overproduction of the interferon IFN-γ causes problems. The large amounts of IFN-γ block the recruitment of neutrophilic granulocytes.Those so-called scavenger cells are the most common white blood cells and are able to engulf bacteria and destroy them. …

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