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(Anatomy) Immune System: New Tool for an Old Disease

 
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PostPosted: Thu Jan 05, 2006 11:30 am    Post subject: (Anatomy) Immune System: New Tool for an Old Disease Reply with quote






A new tool for an old disease
STAR SCIENCE By Luz P. Acosta, Dr PH
The Philippine STAR 01/05/2006

We may be blessed with beautiful tropical islands and a whole year round of warm weather. Unfortunately, however, the tropical islands of the Philippines are also haven for many deadly tropical infectious diseases afflicting many of our fellow Filipinos. We have malaria, still the number one killer parasite that threatens the lives of young children in practically all provinces where there are mountain streams and malaria mosquitoes. And schistosomiasis, a blood fluke infection, ranks second to malaria in terms of public health importance. Most of us who are from the city have probably never heard of schistosomiasis, which is still affecting thousands in the remote rice-farming villages of Sorsogon, Leyte, Samar, Bohol and Mindanao. Like malaria, schistosomiasis has probably been afflicting man since ancient times. There is archeological evidence of the disease from schistosome eggs found inside mummies of ancient Egypt.

It is now almost 100 years since the first case of schistosomiasis was accidentally discovered in the Philippines in 1906 among "Waray" (originating from Samar) inmates of the Bilibid prison in Manila. After a routine course of intestinal parasite screening, eggs were found in stools, later to be identified as Schistosoma japonicum eggs. Popularly called "snail fever" among the local folk in Leyte, the disease is caused by flukes that infect man and other mammals, including dogs and carabaos, feed on their blood and reside as adult worms in the blood vessels of the liver and intestines.

The disease creeps in very slowly. Early symptoms such as paleness and malnutrition may be mistaken for ordinary symptoms of roundworm or hookworm infections common among kids in the rural and urban areas alike. One female worm can lay thousands of eggs, majority lodged in tissues causing inflammation of the liver and intestines, disrupting intestinal blood flow, later to manifest as the "big protruding belly" syndrome in severe intestinal schistosomiasis.

The parasite initially develops into different forms inside the Oncomelania quadrasi snail. These are minute snails, smaller than a grain of rice, found thriving in swampy rice-farming ecosystems of endemic municipalities. The parasite’s infective form can penetrate the bare skin of its targets, thus farmers and their families who are in frequent contact with water and rice paddies where the snails are found are the ones who are ready prey for these blood-feeding parasites.

Vicious as they may seem, schistosome worms are no match to the drug Praziquantel (Biltricide). Discovered by Bayer to treat animal parasites in 1975, Praziquantel was shown to be very effective in killing all types of human schistosome worms in one single dose. While large-scale community-based treatment made a major impact in decreasing infection and disease worldwide, sad to say, it is clear that the control of schistosomiasis was never an easy task. Schistosomiasis remains a public health nuisance in many endemic villages in the country where the snails still abound. In fact, a new endemic focus was recently discovered north of Luzon in Cagayan Valley. Even if treated regularly, due to extensive occupational exposure and the presence of infected animals continuously contaminating the environment with eggs, many continue to get re-infected, thus requiring repeated treatments (yearly treatment), which is often very expensive for many resource-poor endemic communities.

The detection of infection relies on finding eggs in stools of infected patients. This technique, however, is not 100-percent accurate in detecting all infections. A trained microscopist will not find eggs in as many as 35 percent of cases after examining duplicate slides (stool smears) from a single collection of stool sample. Far better techniques (e.g., DNA tests or the use of antibody targeting specific antigens) are available than simply demonstrating the presence of eggs from a very small amount of fecal material. For schistosomiasis, a sensitive test that is simple and affordable, one that can be used in the field for community-based control programs, is a better alternative diagnostic tool.

In our effort to contribute to and uphold sustainable development in our country, the Research Institute for Tropical Medicine (RITM), in Alabang, Muntinlupa, currently headed by Dr. Remigio M. Olveda, continues to enhance tools in biotechnology to upgrade its research and development program. Mandated as the research arm of the Department of Health, the RITM focuses on carrying out high-quality, multi-disciplinary research activities to contribute to the fight against tropical and infectious diseases.

With research funds provided by the Department of Science and Technology through the Philippine Center for Health Research and Development (PCHRD), the RITM developed an immunodiagnostic "dipstick" kit, called the SJ-URIDIP, for diagnosis of Schistosoma japonicum infection. The technique makes use of a locally produced monoclonal antibody to specifically bind or target the S. japonicum circulating cathodic antigen (CCA). CCA is a highly glycosylated proteoglycan molecule largely secreted by cells lining the intestines of adult worms. It is just one of the many antigenic molecules secreted by the parasite which are released in the blood. The good thing is, CCA is also found in the urine and therefore, the use of urine instead of blood or stool for diagnosis makes the collection of samples easier for community-based screening in schistosomiasis.

Antibodies are not only for the immune system. These molecules are now widely used in developing diagnostic kits for various infectious and systemic diseases. Many of these techniques rely on the strong binding affinity of antibodies to its specific antigen, addressing problems of sensitivity and specificity in many detection systems. Monoclonal antibodies are produced by fusing antibody secreting B cells of mice with mutant myeloma cells to allow the continuous propagation of these cells in cell cultures. There is no need for growing them inside the body. From a single cell, these are propagated and grown in large amount, secreting one type of antibody, and therefore the use of the term "monoclonal" antibody.

The SJ-URIDIP kit was tested in the field and gave promising results. Urine samples collected from several endemic barangays in Samar and Leyte were tested for the presence of CCA in urine and compared with the results of multiple stool examinations for the presence of eggs in stools. We demonstrated that the URIDIP test is very sensitive in detecting moderate and heavy infections. However, it is not much better than a stool examination in detecting very light infections, but still it is better than the results of examining a single stool sample. We also collected urine from infected individuals after they received Praziquantel treatment. The test results showed that one month after treatment, almost all CCA-positive individuals became negative in the urine. Since other parasitic infections are very common in these populations, and were not killed with Praziquantel treatment, this shows us that the URIDIP test specifically targets the schistosome antigen and not the other parasites. The ease of collecting a urine specimen for the test instead of stool or blood would result in high compliance for screening and treatment in many endemic communities nationwide.

Clearly, we now have in our hands a new tool for an old disease. But getting this where it is needed is another challenge to hurdle. The Philippines is now lagging far behind its neighbors in Asia in the field of biotechnology. It is high time that we promote biotechnology and contribute to the nation’s sustainable development. As for RITM’s concerns, we still have other diseases to target – malaria, TB, rabies, dengue and many other deadly infections. Developmental research may be a long and painful path, but it is worth pursuing and it can result in significant benefits to our countrymen. * * *
Luz P. Acosta, DrPH, is the head of the Department of Immunology of the Research Institute for Tropical Medicine, Department of Health, Alabang, Muntinlupa City. E-mail her at lacosta@ritm.gov.ph.

*************************************************************

Questions to explore further this topic:

What is the immune system?

http://kidshealth.org/parent/g.....mmune.html
http://www.thebody.com/nih/immune_system.html
http://www-micro.msb.le.ac.uk/MBChB/2b.html
http://biology.clc.uc.edu/cour.....immune.htm
http://www.cancerhelp.org.uk/h.....p?page=118
http://www.thebody.com/step/immune.html
http://uhaweb.hartford.edu/BUGL/immune.htm#intro
http://www.antigenics.com/dise.....hatis.html
http://uuhsc.utah.edu/healthin.....immune.htm
http://www.ohsuhealth.com/htaz.....system.cfm
http://en.wikipedia.org/wiki/Immune_system

What are the parts of the immune system?

http://nobelprize.org/medicine.....etail.html

What is bone marrow?

http://www.betterhealth.vic.go.....enDocument
http://www.wisegeek.com/what-is-bone-marrow.htm?

What is the lymphatic system?

http://www.cancerhelp.org.uk/h.....p?page=117

What are lymphocytes?

http://www.immunecentral.com/i.....m/iss6.cfm

What is the thymus?

http://en.wikipedia.org/wiki/Thymus

What is the spleen?

http://www.betterhealth.vic.go.....enDocument

How does the immune system work?

http://www.immunecentral.com/i.....m/iss5.cfm
http://www.immunecentral.com/i...../iss12.cfm

How does vaccination work?

http://kidshealth.org/teen/sch.....tions.html

What are the cells of the immune system?

http://www-micro.msb.le.ac.uk/MBChB/2a.html

B cells and antibodies
http://www.immunecentral.com/i.....m/iss7.cfm

T cells and lymphokines
http://www.immunecentral.com/i.....m/iss8.cfm

Natural Killer Cells
http://www.immunecentral.com/i.....m/iss9.cfm

Phagocytes, Granulocytes, and Their Relatives
http://www.immunecentral.com/i...../iss10.cfm

What are antibodies?

http://www.immunecentral.com/i...../iss13.cfm
http://www.accessexcellence.or.....odies.html

How are antibodies produced?

http://www.cellsalive.com/antibody.htm

What are monoclonal antibodies?

http://users.rcn.com/jkimball......onals.html
http://users.path.ox.ac.uk/~sc.....mabth.html

Disorders of the Immune System:

Allergy
http://www.immunecentral.com/i...../iss18.cfm

Autoimmune diseases
http://www.immunecentral.com/i...../iss19.cfm

Immunodeficiency Diseases
http://www.immunecentral.com/i...../iss21.cfm

What are HIV and AIDS?

http://hivinsite.ucsf.edu/hiv?page=basics-00-01

How do you get and avoid getting HIV?

http://hivinsite.ucsf.edu/hiv?page=basics-00-05
http://hivinsite.ucsf.edu/hiv?page=basics-00-07

What is Leukemia?

http://www.leukemia-lymphoma.o.....em_id=7026

What is Lymphoma?

http://www.leukemia-lymphoma.o.....em_id=7030

What is Myeloma?

http://www.leukemia-lymphoma.o.....em_id=7032

-------------------------------------------------------------------------------------

What is schistosomiasis?

http://www.pitt.edu/~super1/le...../index.htm
http://www.cdc.gov/ncidod/dpd/.....miasis.htm
http://www.schisto.org/Schistosomiasis/
http://www.tulane.edu/~dmsande.....histo.html
http://healthlink.mcw.edu/article/935097450.html

GAMES

http://biology.about.com/libra.....ysquiz.htm
http://www.healingkids.net/Pages/games.html
http://www.nutritionexploratio.....nster2.asp


Last edited by adedios on Sat Jan 27, 2007 4:37 pm; edited 2 times in total
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PostPosted: Wed Feb 01, 2006 6:15 am    Post subject: Source Of Crucial Immune Cell In The Skin Discovered Reply with quote

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Posted: January 31, 2006

Source Of Crucial Immune Cell In The Skin Discovered

Mount Sinai School of Medicine researchers have identified the precursors of cells in the skin that are part of the first line of defense against invading pathogens. The study will appear on Nature Immunology's website this week and will be published in a future issue.

A tight network of cells covering the entire body is formed in the skin by a group of cells known as Langerhans cells. These cells ingest antigens present in the skin and transport them to lymph nodes, activating the immune system to protect the body against pathogens.

"Langerhans cells are particularly important to the development of tumor immunotherapy," said Miriam Merad, MD, PhD, Assistant Professor of Gene and Cell Medicine at Mount Sinai and lead author of the study. "Most vaccines being developed for tumors are injected into the skin and rely on these cells to transport the antigen to the lymph nodes to trigger an immune response against the tumor."

Once Langerhans cells transport an antigen, they need to be replaced to maintain the tight network in the skin. Dr. Merad and colleagues at Mount Sinai School of Medicine recently discovered that when skin is inflamed Langerhans cells are replaced by circulating precursor cells. They have now identified what this precursor cell is and identified a protein that is essential to the transformation of these precursor cells into Langerhans cells.

The researchers put fluorescent beads in mice in a group of immune cells known as monocytes. They then followed the cells to observe their fate. They found that a specific type of monocyte know as Gr-1 homes to inflamed skin, proliferates, and then differentiates to form Langerhans cells. They also found that a protein, called colony stimulating factor receptor (Csf-1) is necessary for the transformation of Gr-1 cells into Langerhans cells.

The researchers state that discovery of how Langerhans cells are replaced "should contribute to ongoing efforts to engineer immune responses in vaccine design and tumor immunotherapy and to a better understanding of the immune response against skin pathogens."

"Now that we know which cells are the precursors to Langerhans cells and the importance of Csf-1, we may be able to enhance tumor vaccines by increasing the recruitment of Langerhans cell precursors to the skin," said Dr. Merad.

Additionally, the researchers point out that the new findings hold promise for potential therapeutic for patients with a Langerhans histocytosis, a rare disease effecting approximately 200,000 children annually. In children with this disorder, large numbers of Langerhans cells infiltrate organs and tissues throughout the body. So, targeting the pathway by which these cells are formed could lead to new therapies to help children who now face the possibility of lifelong complications.

"It is known that Csf-1 levels are elevated in patients with Langerhans histocytosis," said Dr. Merad. "Our findings indicated that finding ways to lower Csf-1 levels may produce new therapeutics for these patients."
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PostPosted: Wed May 24, 2006 7:48 am    Post subject: U of M researchers find immune-activating cells in intestine Reply with quote

23 May 2006
University of Minnesota

U of M researchers find immune-activating cells in intestines

Discovery may suggest future treatments for intestinal disorders
University of Minnesota researchers have found a group of cells in the intestinal system of mice that are proven to turn on T-cells, cells that help fight infection.
The research will be published in the May 2006 issue of the journal Immunity, released today.

"This connection between the group of cells and immune response will help in studying and developing treatments for diseases that affect the gastrointestinal system," said Stephen McSorley, Ph.D., professor of medicine and primary investigator on the project.

Researchers at the University developed a tracking system that allowed them to identify when T-cells are activated in response to a salmonella infection. T-cells are one type of white blood cell involved in the body's immune system that helps fight infection.

The researchers found a tiny population of cells in the intestine that signal the T- cells to fight infections. "Without these cells, the T-cells are blind, and the body's immune response in the intestinal system would not engage to fight the infection," McSorley said.

While the researchers used a mouse model to find this cell group, McSorley said in the future they will examine human tissue samples to try to identify a similar group in people.

He added this population of cells may be important in many responses in the gastrointestinal system, which may be helpful in studying diseases and conditions such as ulcerative colitis, and Crohn's disease.

The research was done in collaboration with scientists at Harvard University.
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PostPosted: Mon Jun 05, 2006 2:10 pm    Post subject: Natural born killers Reply with quote

Salk Institute
5 June 2006

Natural born killers

La Jolla, CA - A collaboration between scientists at the Salk Institute for Biological Studies and the Pasteur Institute in Paris has uncovered the molecular signals that trigger maturation of natural killer cells, an important group of immune system cells, into fully armed killing machines. Their findings will be published in a forthcoming issue of Nature Immunology.
Born to kill, natural killer cells are constantly on the prowl for potentially dangerous invaders, ready to unleash their deadly arsenal at a moment's notice. Prior to the study, scientists were familiar with the diverse repertoire of surface molecules that helps natural killer cells distinguish friend from foe, but how they acquired their reconnaissance tool kit had remained unclear.

"We suspected that an environmental signal triggered the differentiation of immature natural killer cells into cells that could recognize and kill invading pathogens," says one of the senior authors, Greg Lemke, Ph.D., a professor in the Salk's Molecular Neurobiology Laboratory, "but we didn't know what it was."

When co-senior author Claude Roth, Ph.D., an immunologist at the Institut Pasteur, discovered that low levels of a protein called Axl, which belongs to a class of molecules collectively known as receptor tyrosine kinases, correlated with diminished killer activity in natural killer cells, he turned to Lemke.

Lemke's lab had studied the effects of deleting or "knocking out" the Axl gene and its two cousins Mer and Tyro3, sometimes referred to as the Tyro3 family, for over a decade. Although the Salk scientists had been initially interested in how a missing Tyro3 protein impacted brain development, they found that mice lacking all three Tyro3 genes developed autoimmune diseases closely resembling the perplexing symptoms observed in human autoimmunity.

According to Lemke, they couldn't help noticing that the Tyro3 "knock-out" animals were very sick and prone to infections, which – now that we know that their natural killers were compromised – makes perfect sense. As part of the innate arm of the immune system, natural killer cells are the body's immediate line of defense, keeping invaders in check until T and B cells of the immune system, which take a few days to mobilize, kick into full gear.

Natural killer cells are armed with enzyme-filled sacs that spill their deadly contents when infected or cancerous cells cross the killer's path. In addition, they secrete cytokines, chemical messengers that jumpstart the T and B cell response.

What the Salk and Pasteur teams discovered is that when all three Tyro3 proteins are missing, natural killer cells are still armed with their arsenal of enzymes and cytokines, but they can't dip into their weapons cache because they lack the full spectrum of surface molecules that gives them the "license to kill".

"From these data it was clear that Tyro3 receptor kinases transmit the environmental signals, which we knew are crucial for the maturation of precursor cells," says Lemke. Receptor tyrosine kinases normally receive signals from a cell's environment and, upon activation, add a phosphate group to intracellular proteins, initiating a new repertoire of cellular behaviors.

For natural killer cells those signals - two well-established ligands of Tyro3 proteins called Gas6 and protein S - are secreted by bone marrow stromal cells, which form the local support network for natural killer cell precursors constantly generated in the bone marrow. As the immature natural killer cells get ready to move out of the bone marrow, stromal cells give them the go ahead to acquire the full spectrum of surface receptors, allowing them to attack with discrimination rather than raw determination.


###
In addition to Drs. Roth and Lemke, researchers contributing to this study include co-first author Anouk Caraux, Ph.D., and James P. Di Santo, Ph.D., both at the Institut Pasteur, Salk staff scientist and co-first author Qingxian Lu, Ph.D., Nadine Fernandez, Ph.D., formerly a postdoctoral researcher at the University of California at Berkeley and now at Laboratoire Français du Fractionnement et des Biotechnologies (LFB) in France, and David H. Raulet, Ph.D., a professor at the University of California at Berkeley.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
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PostPosted: Thu Aug 03, 2006 10:35 am    Post subject: Immune system police learn early and sometimes badly Reply with quote

Immune system police learn early and sometimes badly
Toni Baker
Aug. 3, 2006

Regulatory T cells, which function like immune system police, learn early in life what to protect, and that may include viruses, bacteria and tumors, researchers have shown.

Using genetically manipulated mice and technology that enables a snapshot of the repertoire of antigen receptors that determine what cells recognize, Medical College of Georgia researchers followed T cells as they spent time in the thymus then moved to the body.

They found regulatory T cells learn what to protect while in the thymus and that everything the cells learn may not be good, according to research in the August issue of Immunity.

It is widely believed that regulatory T cells only recognize endogenous body tissue so they can stop T cells that are predisposed to attacking it, says Dr. Leszek Ignatowicz, MCG immunologist and the study’s corresponding author.

By examining receptors on all types of T cells before and after they leave the thymus, researchers found regulatory T cells are very diverse and able to recognize endogenous tissue and invaders, Dr. Ignatowicz says.

Unfortunately, the cells also may not learn to recognize all endogenous tissue which, along with environmental and other factors, can lead to autoimmune disease.

T cell schooling in the thymus peaks in the first six weeks of life in the mouse, which roughly translates to the first 15 years of human life. Those early lessons seem to last a lifetime and the few regulatory cells that develop later will be like the early cells, says Dr. Rafal Pacholczyk, MCG immunologist and lead author.

The findings mean, essentially from the beginning, some people may have regulatory T cells less skilled at keeping the immune system from attacking their bodies and/or too skilled at protecting invaders.

It also means one day physicians might steer early education of regulatory T cells in the thymus as a way to vaccinate children against diseases such as lupus, arthritis and type 1diabetes. Or, they might add regulatory T cells to improve the mix in people who already have some bad police.

“We need some of the regulatory cells more than others,” says Dr. Ignatowicz. “We probably need more of the ones that recognize autoantigens on the pancreas and we need the ones that recognize tumors to be less frequent.”

The fact that most regulatory T cells in the body come directly from the thymus, not from other circulating T cells, also was previously unknown, Dr. Pacholczyk says. “Where they come from is the main question we wanted to answer,” says Dr. Ignatowicz.

It has been thought that some T cells circulating in the body might make the transformation, possibly because of what they are exposed to in the body. In fact T cells most aggressive at attacking endogenous tissue likely would be among those converting to protective regulatory cells, Dr. Ignatowicz says. “We did not find that does not happen, but it’s not the major mechanism for generating regulatory cells in the body,” Dr. Pacholczyk says.

All T cells are made in the bone marrow then move to the thymus as progenitor cells where they differentiate, upregulating surface receptors, which are molecules that detect different antigens. It’s a brutal process – 95 percent of the cells die in the thymus primarily because they recognize body tissue – that winds down after puberty.

All T cells wear their receptors for life, like signature hats. “We decided to compare receptors on the regulatory cells in the periphery with those in the thymus,” says Dr. Pacholczyk. By analyzing receptors on individual cells, they were able to follow the cells after they left the thymus and see if they changed.

Another key question was how regulatory T cells, which make up about 5 percent of the total T cell population, can control millions of roaming T cells. They found it was a simple matter of numbers: by wearing many hats, or antigen receptors, regulatory T cells can keep their eyes on a lot of different non-regulatory cells.

“The next question we will ask, which is a hot topic right now, is what antigens trigger receptors on regulatory T cells?” says Dr. Pacholczyk. “What do they recognize? We know now they are coming from the thymus but how they are being generated is still a question. We want to look into the nature of antigens those receptors recognize which will allow us to predict more how they are being developed in the thymus.”

Other study authors include Dr. Hanna Ignatowicz, geneticist, and Dr. Piotr Kraj, immunologist.

The research was funded by the National Institutes of Health and the Roche Foundation.
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PostPosted: Wed Sep 20, 2006 11:00 pm    Post subject: Antibody vs antibody Reply with quote

Antibody vs antibody
STAR SCIENCE By Eduardo A. Padlan, Ph.D.
The Philippine STAR 09/21/2006

Antibodies protect us from parasites, germs, toxins, and other foreign substances (antigens) that may enter our body. Binding of antibodies to an antigen causes the neutralization of the substance, its immobilization and increased susceptibility to elimination by natural processes, or death in the case of an invading cell. Antibodies can be produced against virtually any foreign substance – actually, against any accessible part of the antigen – and biotechnology allows us to produce virtually unlimited amounts of any antibody whose properties we desire. Not surprisingly, antibodies have found many uses in medicine and industry.

Yet, despite the many benefits we derive from antibodies, and despite our body’s stringent screening to prevent its occurrence, some wayward antibodies do sometimes get produced – and they do harm. For example, some of us produce antibodies to our own molecules – an autoimmune disorder – and we could die from it. A case in point is systemic lupus erythematosus in which the patient has antibodies that bind DNA, or other nuclear components, resulting in immune complexes (antibody:antigen complexes) that could clog up vital organs. Another apparent malfunction of the immune system is allergy.

The antibody type that is responsible for allergy is IgE. This antibody type seems to be our natural response to parasitic infestation. But even in the absence of parasites, we produce IgE – and we suffer from allergies. In fact, the incidence of allergy is increasing worldwide, possibly from increased pollution and exposure to unnatural food additives and other substances.

Mast cells (granulated cells in connective tissue associated with all blood vessels) and basophils (in the blood) have high-affinity receptors for IgE on their surfaces. Most of the IgE that we produce are soon bound to mast cells and basophils. There they wait for allergens (antigens that trigger an allergic response). When an allergen that the IgE recognizes comes along and the IgE binds to it (and is crosslinked), the mast cell (or basophil) "degranulates" and releases histamine and other vasoactive compounds (molecules that act on blood vessel permeability). The result is the sneezing, coughing, watery eyes, runny nose, and other symptoms that we usually associate with allergy. Worse, local edema could occur that may cause our throats to close or even worse, a systemic reaction could result in a sudden drop in blood pressure (anaphylactic shock) that could mean death.

We take anti-histamines or steroids to relieve our allergies, and some of us even carry along ready-to-administer epinephrine in case of severe allergic reactions. Some of us have food allergies and we wisely avoid those foods. Many of us know what we are allergic to, although we do not know why.

Could we develop a universal treatment for allergies? Better yet, could we develop a vaccine against allergy?

Since we can generate antibodies against almost anything, can’t we use antibodies to fight allergies? In fact, we can. There is now in the market, sold under the trade name Xolair, an antibody treatment for allergies. (Before I proceed, I must first assure you that I have no business interest in Xolair nor any connection with the companies that make it.) Xolair is an anti-IgE, an antibody against IgE. It is a "humanized" mouse antibody directed against human IgE. How does it work?

Xolair binds to soluble IgE and prevents it from binding to the high-affinity receptor on mast cells and basophils. Obviously, Xolair binds to that part of IgE that binds to the receptor, or at least near enough to it to prevent the binding. Xolair does not bind to IgE that is already bound to the receptor. (If it did, there will be mass degranulation of mast cells and basophils and shock will likely occur. The researcher who developed Xolair admitted killing hundreds of mice before finding an anti-IgE that worked.) But IgE, like all antibodies, has two-fold symmetry, so that it has a receptor-binding site on one side and another binding site on the other side. So, even if the IgE is already bound to the receptor, there is the other binding site that should still be available for binding by Xolair? But Xolair does not bind to IgE that is already bound. Why not?

The answer comes from the work of the husband-and-wife team of David Holowka and Barbara Baird at Cornell. David and Barbara showed several years ago that IgE, when bound to cells, is actually bent. Now, it is easily shown by modeling that bending the IgE will cause the second binding site to be occluded and inaccessible. That then is the reason Xolair can no longer bind to IgE that is already bound to cells. That’s why Xolair can be used to treat allergy (without killing the patient).

Now, can we develop a vaccine against allergy? We actually tried several years ago – with some success. Birgit Helm and her group in Sheffield, England had determined the location of the binding site on IgE for the high-affinity receptor. At that time, I had built a model of IgE and Birgit asked me to look for a stretch of polypeptide in the receptor binding site that might be useful as a vaccine. I subsequently proposed a segment, engineered to be a cyclized peptide, and we had it synthesized and injected into a rabbit. It worked! Serum from the immunized rabbit was found to prevent the degranulation of sensitized basophils. It was clear that the rabbit had actually produced antibodies that presumably bound to the receptor binding site of the IgE. So, we have developed a vaccine to protect rabbits against human allergies. Big deal! What we need is an allergy vaccine for humans! No, we haven’t developed one yet.
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PostPosted: Wed Sep 27, 2006 10:01 pm    Post subject: Solved: The Mystery of Flesh-Eating Bacteria's Relentless At Reply with quote

September 27, 2006
Howard Hughes Medical Institute

Solved: The Mystery of Flesh-Eating Bacteria's Relentless Attack

A Howard Hughes Medical Institute (HHMI) international research scholar in Israel has discovered one reason why so-called “flesh-eating” bacteria are so hard to stop.

Emanuel Hanski, a microbiologist at Hebrew University in Jerusalem, and colleagues have found that the success of group A Streptococcus is due in part to a protein that blocks the immune system's distress calls. The findings, published in the October 4, 2006, issue of the EMBO Journal, could lead to new strategies for treating necrotizing fasciitis and halting its rapid destruction of tissue. The paper was published in advance online.


“There are different avenues you could explore for treatment, all based on reducing the amount of ScpC the bacteria produces.”
Emanuel Hanski

The bacterium, group A Streptococcus, wreaks destruction on muscle and skin tissue in the form of necrotizing fasciitis, which kills roughly 30 percent of its victims and leaves the rest disfigured. Antibiotics and surgical interventions, the known treatments, often fail. Necrotizing fasciitis is a serious but rare infection of the skin and the tissues beneath it.

The work began two years ago, when Hanski developed a mouse model for necrotizing fasciitis. After injecting the mice with a virulent strain of Streptococcus of a type known as M14, isolated from a necrotizing fasciitis patient, the team noticed that unlike most strep infections, in which white blood cells swarm invading bacteria to clear them from the body, few white blood cells appeared at the M14 infection site. A similar phenomenon had been observed in patients with necrotizing fasciitis but did not receive sufficient attention at the time.

“We knew that the pathology of the disease in people was typified by various degrees of a lack of white blood cells," said Hanski. After publishing their findings in the British medical journal The Lancet in 2004, the team began to search for the factor that blocked the recruitment of white blood cells during M14 infection.

They focused on the gene for a Streptococcus peptide called SilCR, after finding that the gene product was turned off in the M14 strain. “This gene is supposed to produce a peptide that acts as a signaling molecule that the Streptococcus bacteria use to communicate with each other,” said Hanski. “Since the bacteria were not producing the peptide, we decided to synthesize it ourselves and give it to mice infected with M14.”

The mice receiving this peptide survived at a much higher rate than mice that did not receive it. The team also observed many white blood cells at the infection site in mice receiving the peptide.

Next, the team turned its attention to an important human immune system signaling molecule, interleukin-8. In healthy people, an infection triggers the production of interleukin-8(IL-Cool, which acts as a distress call. “When the body senses an infection, it creates interleukin-8 to recruit white blood cells to the infection,” said Hanski.

In a laboratory culture, the M14 strain of Streptococcus destroyed IL-8. But when the team added the SilCR protein to the growing bacteria, the IL-8 survived.

“The amount of IL-8 that survives is inversely related to how much SilCR there is in the culture,” said Hanski. This may be one reason why some strains are less virulent than others; they might make more SilCR. “It would be interesting to study the amount of SilCR produced by the other strains and to determine their degree of tissue invasiveness.” said Hanski.

The link between SilCR and a healthy immune response still did not explain the underlying mechanism. The team knew that SilCR itself did not degrade IL-8, so they began to search for the missing link in the chain of events. They expected to find an enzyme that degrades IL-8. Drawing on a database of enzymes and using advanced techniques that measure the levels of gene transcription products in a cell, they soon identified the culprit: an enzyme called ScpC.

The team then created a mutant variation of the M14 strain of Streptococcus that could not produce ScpC. As expected, this strain was much less virulent than the original M14. Only three of 28 mice receiving the mutant strain succumbed to infection, a death rate much lower than that of mice who received the original strain. Mice receiving the original bacteria developed lesions that grew until the mice died; while mice receiving the mutant strain developed only small lesions that spontaneously healed.

“The experiments show that SilCR down-regulates the production of ScpC, and ScpC is what destroys the IL-8,” said Hanski. “In our strain, M14, SilCR is missing completely, which explains why it is so virulent.”

He said the work points to more effective strategies for treating Streptococcus infection. “There are different avenues you could explore for treatment, all based on reducing the amount of ScpC the bacteria produces,” Hanski said. “You could look for a specific inhibitor of ScpC, or you could explore the activity of SilCR more fully and try to boost its action.”


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PostPosted: Wed Oct 04, 2006 10:03 am    Post subject: Tiny Tampa Bay fish key to evolution of immune system Reply with quote

University of Florida
3 October 2006

Tiny Tampa Bay fish key to evolution of immune system

GAINESVILLE, Fla. - Armed at first with nothing more than boots, a screen and a bucket, scientists studying a tiny primitive fish that makes up 70 percent of the biomass in Tampa Bay now say they have found the "missing link" marking the point in evolution that led to the development of the modern-day human immune system.

The inch-long spineless fish, called a lancelet, produces a key immune system protein that is similar to but much hardier than the version found in people. The bay waters are a microbial soup teeming with microorganisms, yet the worm-like bottom-feeder is remarkably adept at standing up to the bacterial, viral and chemical threats in its environment. Understanding how it does so could lead to improved biodefense and better immune-boosting drugs to fight cancer and disorders such as rheumatoid arthritis, say scientists at the University of Florida and the University of South Florida, who reported their findings recently in Nature Immunology.

"At a basic level, this sea worm tells us about the evolution of the immune response; specifically, it tells us that primitive organisms have more sophisticated immune systems than we previously thought," said X-ray crystallographer David Ostrov, Ph.D., an assistant professor of pathology, immunology and laboratory medicine at UF's College of Medicine who is affiliated with the UF Shands Cancer Center. "This is the first organism below the level of jawed vertebrates that expresses the type of proteins we use in our own complex adaptive immune system."

The human immune system is constantly at work, on guard to tackle new ills while remembering past offenders. Compared with its predecessors on the evolutionary tree, the lancelet shares genes and proteins remarkably similar to ours that enable it to also skillfully elude attack.

"This influences our therapeutic strategy because we must consider that an organism we are trying to target may have an elaborate defensive system of its own, with features that neutralize what we're trying to do to it," Ostrov said. "For example, if we're trying to create a vaccine against a specific pathogen such as anthrax, smallpox or bird flu, we have to take into account the defensive measures those and other organisms might have."

Organisms such as plants, fungi and primitive animal life are classified as having an innate immune system, which defends against invaders by recognizing predetermined patterns of molecules. About 520 million years ago, a different form of immunity emerged - the adaptive immune system, shared by humans and other organisms with jaws and vertebrae. This type relies on an army of antibodies and other immune system cells to customize its response to an array of pathogens and remember the encounter for future reference.

"We were asking the question why and where did this sharp division occur? What were the most primitive organisms that exhibit the molecules that we use in our adaptive immune systems?" Ostrov said.

"In this study, we have identified the missing link between the innate immune system and the adaptive immune system, and we have found this link just below the level of jawed vertebrates," he said. "We found an intermediate. We found an immune system that is possessing features of both the innate immune system and the adaptive system."

In their most recent study, UF and USF scientists - including geneticist Gary Litman, of USF's Moffitt Cancer Center - bombarded a highly concentrated, crystallized form of an immune system protein isolated from the fish with X-rays, yielding incredibly high-resolution images of its structure. The lancelet also is known as amphioxus, or by the scientific name Branchiostoma floridae.

"We were surprised not only by how similar the molecules are to our immune response proteins but also that the crystals diffracted to a level of resolution that no one has ever been able to achieve studying these adaptive immune response proteins - atomic resolution," Ostrov said.

That means scientists can actually see where individual hydrogen atoms are positioned in the protein's core, providing clues as to which atoms are participating in key stabilizing interactions.

Doctors often use infusions of antibodies to bolster immune systems weakened by cancer or other conditions, but ironically, these proteins are susceptible to enzymes that break them down. A number of such monoclonal antibody-based drugs are in clinical use, such as Herceptin for breast cancer or Avastin for colorectal cancer.

The lancelet's immune response proteins, however, are resilient. Understanding their essential architecture with such precision could lead to new, improved types of antibody-based therapies that are better able to persist in the body, Ostrov said.

"If we could take advantage of the atomic level structural features that we see, particularly those structural features at the stable core of this molecule, then we expect to design and produce more stable monoclonal antibodies for therapy," he said.

Neil S. Greenspan, M.D., Ph.D., a professor of pathology at Case Western Reserve University School of Medicine, called the study "captivating and thorough."

"However, I expect that further research will be required to corroborate some of the key evolutionary interpretations and to place this study in fuller perspective," Greenspan said. "Should the authors' views prove to be basically correct, the study would offer the prospect of enhancing our understanding of the structural requirements for molecules used by the adaptive immune response to recognize and counter components of invading microbes. If so, it would provide an illustration of the potential for studies of diverse species, even those that at first glance may appear to be of no special interest, to yield information of value in understanding human physiology and of use in facilitating medical advances."


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The study was funded by the National Institute of General Medical Sciences, the National Institute of Allergy, Immunology and Infectious Diseases, the Cure Autism Now Foundation and the U.S. Department of Energy.
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PostPosted: Tue Nov 14, 2006 10:48 am    Post subject: T for two: Scientists show how immune system chooses best wa Reply with quote

Wellcome Trust
14 November 2006

T for two: Scientists show how immune system chooses best way to fight infection

A new study has suggested a novel way of combating diseases related to the immune system, including cancer and autoimmune diseases such as type I diabetes and arthritis. The study, funded by the Wellcome Trust, appears online in the journal Nature.

T cells are produced by the body to fight infection. Scientists previously identified two types of T cell, both produced in the thymus: "effector T cells", which attack infected cells, and "regulatory T cells", which suppress the immune system, protecting the body from inflammatory damage during infection. Regulatory T cells, if given to individuals receiving transplants, may help suppress the rejection response.

Now, a team of researchers has discovered a novel mechanism determining whether a maturing T cell is likely to emerge from the thymus as an effector cell or a regulatory cell. The research suggests that new treatments could be developed to deliberately affect the type of T cells produced, allowing scientists to tackle a number of diseases which are influenced by these different types of T cells.

"Our team has shown that a process known as 'trans-conditioning', which we knew to be involved in T cell development, actually has a profound influence on whether a T cell becomes an effector or a regulatory cell," explains Professor Adrian Hayday of King's College London. "This may be clinically significant; if we can find a way to influence this process, it may be possible to make the body produce effector T cells in a cancer patient or regulatory T cells in someone suffering from autoimmune disease, both of which are caused by the immune system malfunctioning."

Professor Hayday and his team believe that the findings may also answer one of medical research's mysteries: why autoimmune diseases in women commonly go into remission in pregnancy.

"We believe that trans-conditioning is less active during pregnancy," says Professor Hayday. "This means that most T cells emerging at that time will be regulatory. Regulatory T cells prevent an over-active immune system from causing inflammatory damage to the body. This may be one of the key steps in preventing the mother from rejecting the foetus growing inside her."

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The research was carried out at the King's College London School of Medicine at Guy's Hospital and was co-lead by Dr Daniel Pennington, a Wellcome Trust VIP awardee and now at Queen Mary, University of London. Collaborating researchers were based at Faculdade de Medicina de Lisboa, Lisbon; University College, London; Yale University School of Medicine; Institute for Animal Health; and Imperial College London.
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PostPosted: Thu Nov 30, 2006 2:09 pm    Post subject: Healthy bodies help fight disease? Clues to how diet affects Reply with quote

Research Australia
30 November 2006

Healthy bodies help fight disease? Clues to how diet affects the immune system

“This study may help explain the link between dietary fat consumption and inflammation and could be one of the critical links between metabolism and immune responses,” says senior author Professor Charles Mackay, Director of Sydney’s Garvan Institute’s Immunology Program.

Our intake of fats (fatty acids) has changed dramatically over the last thirty years. At the same time there has been an increase in inflammatory diseases in the western world – especially asthma, atherosclerosis, and autoimmune diseases such as rheumatoid arthritis. “We have shown that a subset of white blood cells, called dendritic cells, which initiate immune responses, rely on the fatty acid binding molecule aP2 for their function. It is possible that different fatty acids or their total levels will affect aP2 function in dendritic cells, and hence affect immune responses,” explains Mackay.

Professor Mackay added: “What we want to do now is study whether it is the total levels of fats or the different types of fats that alter dendritic cell function, through their binding to aP2. We know that dietary changes can improve symptoms of rheumatoid arthritis and we believe that a ‘diet hypothesis’ may account for the dramatic changes in inflammatory diseases seen in the western world over the past 30 years -molecules such as aP2 may be one of the clues that will help explain this phenomenon.”

Over-activation of dendritic cells can trigger inflammatory diseases. This discovery reveals aP2 is key to that process. Fatty acid binding molecules, such as aP2, have already been identified as promising targets for the treatment of metabolic disorders such as type 2 diabetes and atherosclerosis. This new research suggests that medicines directed at aP2 would have great potential in inflammatory as well as metabolic diseases.

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Notes for editors:
This research is published in the December 1 edition of the well-reputed Journal of Immunology. This work was supported in part by grants from the Cooperative Research Centre for Asthma, National Health and Medical Research Council, the National Institutes of Health, and the Sandler Program. Numerous studies have shown that fats such as omega 3, best known for being found in fish, linseed, and sunflower oil, improve clinical outcomes for rheumatoid arthritis.

ABOUT GARVAN
The Garvan Institute of Medical Research was founded in 1963 by the Sisters of Charity. Initially a research department of St Vincent's Hospital in Sydney, it is now one of Australia's largest medical research institutions with approximately 400 scientists, students and support staff. The Garvan Institute’s main research programs are: Cancer, Diabetes & Obesity, Arthritis & Immunology, Osteoporosis, and Neuroscience. It is part of the St Vincent’s Hospital Campus.
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PostPosted: Mon Feb 26, 2007 12:14 pm    Post subject: How T lymphocytes attack Reply with quote

CNRS
26 February 2007

How T lymphocytes attack

Our immune system finds it difficult to eliminate tumours effectively. Deciphering the strategies it implements may increase the immune system's effect on tumour cells and thus improve the clinical perspectives for anticancer immune therapy. At the Institut Curie, INSERM and CNRS researchers have used two-photon microscopy to demonstrate, for the first time in vivo and real-time, how T lymphocytes infiltrate a solid tumour in order to fight it.

These "defenders" methodically encircle the enemy positions and "patrol" until they meet a tumour cell, which they have previously learnt to recognise. They then halt to eliminate it, before resuming their rounds. The rapidity of the advance achieved by T lymphocytes is indicative of either the absence of an adversary, or defeat of the immune system in the battlefield.

This scenario was published in The Journal of Experimental Medicine.

How is a tumour destroyed by T lymphocytes? This scenario has recently been visualised by researchers at the Institut Curie. The original images obtained and assembled in twelve video sequences are the result of close collaboration between a specialist in two-photon microscopy, Luc Fetler, an INSERM scientist in the CNRS/Institut Curie "Physical Chemistry Curie" Unit1, and immunologists, notably Alexandre Boissonnas, in the INSERM "Immunity and Cancer" Unit at Institut Curie.

Our body's defences against an infection or tumour are based on a string of actors, some of them generalists, the others highly specialised. Cytotoxic T lymphocytes belong to the second category. To achieve their task, their cell surface carries a membrane receptor which is complementary to the antigen in the pathological cells to be eliminated. Alerted by the presence of this antigen, the T lymphocytes are activated. Having identified an infectious or tumour cell, they bind to it and target it with a fatal load of enzymes.

When T lymphocytes infiltrate a tumour…

Before this work by Alexandre Boissonnas and Luc Fetler, no-one had ever observed at the cellular scale what happens when activated T cells arrive in a solid tumour. The novel experimental model developed by these Institut Curie scientists reveals the strategy adopted by these cells to destroy the tumour.

Recognition of the tumour antigen determines T lymphocyte behaviour

To arrive at their conclusion, the researchers used an animal model to observe the route followed by T lymphocytes in tumours endowed with a particular antigen, ovalbumin (OVA) and in tumours which served as controls and were devoid of this antigen. When the tumours reached 500 to 1000 mm3, eight to ten days after the injection of tumour cells with or without the antigen, the researchers then injected the mice with a large number of OVA antigen-specific T cells.

What happened after the day of transfer? As expected, only the tumour with the OVA antigen disappeared, after about a week. In the interval, the two-photon microscope (see box) made it possible to examine the scene in situ over the first 150 micrometres of the tumour. Each image provided a photograph of the different cell populations, blood vessels and collagen fibres present. And using a series of successive images, it was possible to reconstitute the trajectory of a T lymphocyte.

Using this method, the researchers thus examined the different protagonists – T lymphocytes and tumour cells – during two distinct periods of tumour development. In the antigen-devoid tumour, T cells "patrolled" at a consistently high rate (approximately 10 micrometres per minute), at all stages of development. However, T lymphocyte behaviour varied in antigen-containing tumour; when the tumour stopped growing because of the lymphocyte injection three or four days previously, the defenders patrolled slowly (4 micrometres per minute) and halted frequently. Their mean rate reached a plateau at 4 micrometres per minute. Then, during later stages when the tumour was regressing, most T lymphocytes resumed their rapid mobility.

To summarise therefore, the T lymphocyte trajectories were confined to regions containing high levels of live tumour cells, while they were broader and fluid in regions littered with dead tumour cells. The Institut Curie scientists concluded that presence of the antigen halted the T lymphocytes which were then occupied by recognising and killing their adversaries.

Furthermore, by analysing the distribution of T lymphocytes throughout the respective tumours, the scientists noted that these defenders were always present at the periphery, but that the presence of the antigen was essential to in-depth penetration, leading to effective tumour elimination.

These results were validated in two types of experimental tumour generated from two lines of cancer cells.

It is now up to the clinicians to verify whether the in-depth infiltration of T lymphocytes could constitute a criterion for a good prognosis.

A clearer understanding of how the immune system functions is essential to optimise one of the most promising options for future cancer treatment: immune therapy.

For many years now, the Institut Curie has been participating actively in the development of innovative strategies in this field. Two clinical studies are currently under way at the Institute: one in patients with choroidal melanoma and the other in women with cervical cancer.


###
For more information

The two-photon microscope, plunging into living tissues

For several years, the Institut Curie has been placing particular emphasis on imaging techniques to decipher the intimate mechanisms of life. Two-photon microscopy (M2P) has been helping the work of Institut Curie biologists for ten years. Its ability to illuminate an site situated at a depth of up to 0.5 mm can avoid a time-consuming succession of sections and samples within the thickness of a fixed tissue. The principle of M2P is based on the excitation of molecules which are intrinsically fluorescent in cells, or fused with a protein such as GFP or CFP (green- or cyan-fluorescent protein). The infrared laser used to excite these molecules emits ultra-short impulses (100 femtosecondes3, 80 million times a second) which are so intense that the two photons can be absorbed simultaneously by a molecule. This absorption of photon pairs only occurs at the focal point, thus enabling the generation of clear, penetrating images and the direct and real-time filming of cell movements in a living tissue.

T lymphocyte tactics in tumours

The scientists injected mice with tumour cells expressing a green fluorescent molecule: some cells were endowed with an antigen, ovalbumin, while the others (which served as controls) were devoid of this antigen. When the tumours reached 500 to 1000 mm3, eight to ten days later, the scientists injected the mice with a large number of antigen-specific T lymphocytes. On these two-photon microscopy photographs we can see, left, that the tumour expresses the antigen and the tumour cells (in green) are few in number as they have been destroyed by T lymphocytes. On the right, the tumour is devoid of the antigen and the tumour cells have not been destroyed. The blue labelling corresponds to collagen fibres and the red labelling to blood vessels.

1 UMR 168 CNRS/Institut Curie "Physical Chemistry Curie", headed by Jean-François Joanny 2 INSERM Unit 653Institut Curie "Immunity and Cancer", headed by Sebastian Amigorena

© A. Boissonnas, L. Fetler/Institut Curie References « In vivo imaging of cytotoxicT cell infiltration and elimination of a solid tumor » Alexandre Boissonnas1,3, Luc Fetler2,3, Ingrid S. Zeelenberg1, Stephanie Hugues1 and Sebastian Amigorena1

1 Unité Inserm 653, Immunité et Cancer, Pavillon Pasteur, Institut Curie, 26 rue d'Ulm, F-75245 Paris cedex 05.

2 CNRS UMR 168, Laboratoire de Physico-Chimie Curie, Institut Curie, 26 rue d'Ulm, F-75245 Paris cedex 05.

3 Auteurs en contribution équivalente

The Journal of Experimental Medicine, February 19, 2007
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PostPosted: Sat Apr 14, 2007 7:11 am    Post subject: Microbes start immune response by sneaking inside cells Reply with quote

University of Michigan Health System
13 April 2007

Microbes start immune response by sneaking inside cells

New insights could lead to better vaccines, treatments for rheumatoid arthritis, study suggests
Immune cells that are the body’s front-line defense don’t necessarily rest quietly until invading bacteria lock onto receptors on their outside skins and rouse them to action, as previously thought. In a new paper, University of Michigan scientists describe their findings that bacteria can barge inside these guard cells and independently initiate a powerful immune response.

The study, published online ahead of print in the April issue of the journal Immunity and accompanied by a special commentary, adds important new details to an emerging picture of how the body recognizes invading bacteria and responds. The work of the U-M team and researchers elsewhere — now taking place in laboratory animal studies — offers a different way of thinking about how best to design future human vaccines, as well as drugs that could more precisely target the body’s inflammatory response in rheumatoid arthritis and some other autoimmune diseases.

“In our study, the presence of bacterial microbes inside the cell is what triggers the immune response. That creates a new perspective for developing new drugs,” says senior author Gabriel Nunez, M.D., the Paul H. de Kruif professor of pathology at the U-M Medical School and a member of the U-M Comprehensive Cancer Center.

For years, scientists have believed that when bacteria invade the body, they set off alarms in the immune system by interacting with receptors on a cell’s surface. But, now new studies are revealing that bacteria can also plunge inside immune system cells and trigger the immune response there. In the new study, Nunez’ team sheds light on one major pathway in which this process occurs.

When invading bacteria enter immune system cells, a protein called cryopyrin, present in the fluid inside the cells, responds and activates a key pathogen-fighting molecule, Nunez’ team reported last year in Nature. Cryopyrin is implicated in the development of several inflammatory syndromes characterized by recurrent fever, skin rash and arthritis.

Cryopyrin triggers a key enzyme involved in the body’s inflammatory response, capsase-1, which in turn causes production of IL-1beta, a powerful molecule which signals the immune system to attack pathogens and induces fever to help the body fend off infection. IL-1beta plays an important role, too, in excessive immune system activity in inflammatory diseases.

The researchers report in the new paper how cryopyrin is activated to start the process. In experiments that exposed mouse immune cells called macrophages to bacteria, Thirumala-Devi Kanneganti, Ph.D., a U-M research investigator in pathology, and Mohamed Lamkanfi, Ph. D, a U-M research fellow, the study’s co-first authors, find that cryopyrin’s call to action inside the cells occurs without requiring a well-known set of cell-surface receptors called Toll-like receptors or TLRs. ”We prove that these TLRs are not required to activate cryopyrin. That is a major step,” says Nunez.

Instead, bacteria were able to enter the cells through a pore in the cell membrane, and stimulate the cryopyrin-initiated immune response without activating TLRs. The researchers discovered that a protein called pannexin-1 creates the pore, like a devious undersea diver drilling a hole in a ship hull.

The team’s work joins a growing body of research revealing the importance of recently discovered receptors such as cryopyrin inside cells, known collectively as NOD-like receptors. Knowledge about NOD-like receptors is moving forward rapidly and will contribute to a fuller understanding of the human immune system, say the U-M researchers.
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PostPosted: Thu May 24, 2007 11:43 am    Post subject: How plague-causing bacteria disarm host defense Reply with quote

University of California - San Diego
24 May 2007

How plague-causing bacteria disarm host defense

Effector proteins are the bad guys that help bacterial pathogens do their job of infecting the host by crippling the body's immune system. In essence, they knock down the front door of resistance and disarm the cell's alarm system.

Now, researchers at the University of California, San Diego (UCSD) School of Medicine have identified a novel molecular target for an effector protein called YpkA, one of several effectors of the bacteria Yersinia – the pathogen responsible for the Middle Ages' "Black Death" and a virulent form of food poisoning today. Their study will be published online in the May 25 issue of Molecular Cell.

YpkA targets a host protein called Gaq, the messenger that transmits extracellular signals ("we are under attack!") into the host cell, so that it can mount a defense.

"The alarm signal sent by Gaq is intercepted by YpkA, which sets up a roadblock along several cellular pathways that Gq uses to deliver the alarm," said lead author Lorena Navarro, Ph.D., post-doctoral researcher in the lab of the study's principle investigator, Jack E. Dixon, Ph.D., professor of Pharmacology and Cellular and Molecular Medicine at the UCSD School of Medicine.

Identifying this new target is the first step to developing effective strategies for preventing disease, including means to fight antibiotic-resistant strains of Yersinia that could be used in biological warfare, according to Navarro.

The genus Yersinia includes three species of bacteria that are pathogenic to humans: Y. pestis is perhaps the most infamous, being responsible for the bubonic plague (also known as the Black Death), which killed more than 200 million people in the Middle Ages.

"This bacterial species could still be a threat today," said Navarro, adding that scientists had isolated an antibiotic-resistant strain of this species. In addition Y. pseudotuberculosis and Y. enterocolitica are big words for nasty, little bugs that cause what's commonly known as food poisoning. All three bacteria species find their way past the body's immune system through a sophisticated invasion system that injects the effector proteins directly into the host cell's cytoplasm.

"More than a decade after its discovery, our understanding of YpkA is still incomplete," Navarro said. "But Yersinia has maintained YpkA over millions of years, so it must be doing something important." The researchers speculate that YpkA plays an important role in disabling the body's immune system beyond its previously known role of disrupting the host cell's normal structure, which interferes with the cell's innate ability to engulf and destroy invading bacteria. "The question now becomes, why is Gaq targeted by YpkA""


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Additional investigators for the study include Antonius Koller and Susan Taylor, Ph.D., UCSD professor of chemistry and biochemistry; and Roland Nordfelth and Hans Wolf-Watz of Umeå University in Sweden.

Funding for the research was provided in part by the National Institutes of Health and a University of California President's Postdoctoral Fellowship.
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PostPosted: Tue Jun 12, 2007 9:34 am    Post subject: Newly discovered antibody may be body's natural defense agai Reply with quote

New York- Presbyterian Hospital/Columbia University Medical Center
11 June 2007

Newly discovered antibody may be body's natural defense against Alzheimer's

Human antibodies in blood potentially could act as specific protection against toxic form of beta amyloid
NEW YORK & WASHINGTON (June 11, 2007) -- In an important advance in the battle against Alzheimer's disease, physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center have identified naturally occurring antibodies in human blood that may help to defend against this form of dementia as well as other neurodegenerative diseases.

The newly found antibodies selectively target aggregates of beta amyloid proteins called "oligomers" that are toxic to brain cells, while ignoring the benign single-molecule forms of the same proteins. The existence of such antibodies was predicted by animal studies, but they were never previously demonstrated to be present in substantial quantities in blood from normal humans.

Lead researcher Dr. Norman Relkin, a behavioral neurologist and neuroscientist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, will present the findings on Monday, June 11, at 3:30 pm, at the "2nd Alzheimer's Association International Conference on Prevention of Dementia," in Washington, DC.

Dr. Relkin is director of the Memory Disorders Program at NewYork-Presbyterian/Weill Cornell and associate professor of clinical neurology at Weill Cornell Medical College.

Dr. Relkin's team has been testing an antibody-based immunotherapy called Intravenous Immunoglobulin (IVIG) as a potential new treatment for Alzheimer's. IVIG is made from the blood of healthy donors and was previously reported to contain small quantities of antibodies against beta amyloid.

"The effects of IVIG in lowering beta amyloid levels in Alzheimer's patients in our Phase I clinical trial were much more profound than we expected," Dr. Relkin explains. "We couldn't readily explain this based on the low levels of anti-amyloid antibodies known to be present in IVIG. We suspected there might be another, unseen player."

His laboratory studies demonstrated that IVIG initially bound very little single-molecule ("monomer") beta amyloid in a test tube. However, it gathered up much more of the protein when the amyloid was "aged" in a way that allowed soluble aggregates to form.

These beta amyloid "oligomers" can grow into insoluble "fibrils" that cluster around brain cells and are a hallmark of Alzheimer's disease. While monomers are produced from birth and appear to be relatively benign, oligomers have been implicated as potent toxins responsible for Alzheimer's-linked memory loss and brain cell death. This has led many scientists to speculate that oligomers may be the main culprit in Alzheimer's and therefore a prime target for a new generation of disease-modifying treatments.

To further confirm that these natural antibodies bind with oligomers, Dr. Relkin and his colleagues collaborated with Drs. Charles Glabe and Rakez Kayed from the University of California at Irvine, who had previously created anti-oligomer antibodies in rabbits. Using techniques pioneered by Dr. Glabe's group, the NewYork-Presbyterian/Weill Cornell scientists were able to measure and extract the human version of anti-oligomer antibodies from IVIG and then demonstrate that these antibodies are present in the blood of normal individuals.

The basis for the selective recognition of oligomers by these antibodies appears to be their capacity to recognize the oligomer's misfolded shape.

"That was a surprise, because most antibodies work by recognizing some aspect of the chemical structure of their target -- not their shape," explains Weill Cornell Medical College molecular biologist and study co-author, Dr. Paul Szabo. "That means that even though beta amyloid monomers and oligomers have the same fundamental chemical makeup, human anti-oligomer antibodies can distinguish between them. The antibodies recognize a particular shape that proteins assume only when they become these toxic aggregates."

The ability of the antibodies to recognize toxic proteins based on their shape may have important implications for immune therapy of other neurologic disorders, the researchers explain.

"We were able to confirm that the antibodies we found not only recognize oligomers of beta amyloid but also unhealthy forms of other proteins that accumulate in a wide variety of diseases, such as Parkinson's, Lewy body dementia and Prion disease (the human form of ‘Mad Cow' disease), to name a few," says Dr. Relkin.

Since beta amyloid oligomers are much less abundant in the body than the single-molecule variety, the relatively high amount of oligomer-specific antibody found in human blood suggests that the immune system recognizes these aggregates to be a particularly noxious threat.

"This could be part of an innate defense mechanism against Alzheimer's and other age-related neurodegenerative disorders," comments Dr. Marc Weksler, The Irving Wright Sherwood Professor of Geriatrics and professor of medicine at Weill Cornell Medical College, and senior investigator in the Phase I IVIG study that led to this discovery.

However, the clear demonstration of the relationship of these scientific findings to clinical benefit in patients requires much more study, the experts say.

NewYork-Presbyterian/Weill Cornell is currently leading a six-month Phase II study of IVIG in 24 patients with mild and moderate Alzheimer's disease, which is planned to be complete later this year. While this study may provide a signal of the effect of IVIG therapy to clinical outcomes, further investigation in larger controlled and longer-term trials will be needed to definitively demonstrate whether IVIG is useful in treating Alzheimer's.

Still, this discovery substantially boosts our understanding of Alzheimer's and other neurodegenerative illnesses, the experts say.

###
This work was funded by grants from Baxter Healthcare, which developed and produces GAMMAGARD IVIG; the Citigroup Foundation; and private philanthropy.

Other collaborators on the "Alzheimer's Association Prevention Conference" presentation include Drs. Marc Weksler, Diana Mujalli, Sushila Shenoy and Basia Adamiak -- all of NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

For more information, patients may call (866) NYP-NEWS.

NewYork-Presbyterian Hospital/Weill Cornell Medical Center

New York-Presbyterian Hospital/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital New York-Presbyterian and its academic partner, Weill Cornell Medical College. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, research, education and community service. New York-Presbyterian, which is ranked sixth on the U.S. News & World Report's list of top hospitals, also comprises NewYork-Presbyterian Hospital/Columbia University Medical Center.
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PostPosted: Thu Jun 21, 2007 7:39 am    Post subject: Invertebrate immune systems are anything but simple, confere Reply with quote

21. June 2007 11:00
Invertebrate immune systems are anything but simple, conference finds
Author: Professor Paul Schmid-Hempel


A hundred years since Russian microbiologist Elie Metschnikow first discovered the invertebrate immune system, scientists are only just beginning to understand its complexity. Presenting their findings at a recent European Science Foundation (ESF) conference, scientists showed that invertebrates have evolved elaborate ways to fight disease.



By studying starfish, Metschnikow was the first to see cells digesting bacteria, a process he called phagocytosis (the eating of cells by other cells). Phagocytosis, it turns out, is an important immune defence in all living things. Since Metschnikow’s work, scientists have studied the immune systems of simpler organisms (such as invertebrates) in the hope of understanding the immune systems of more complex organisms, like us.



However, invertebrates’ immune systems are more elaborate than we expected. “We have underestimated the complexity of invertebrate immunity,” says Dr. Paul Schmid-Hempel, an evolutionary ecologist at the ETH Zurich in Switzerland. By studying the immune systems of fruit flies, mosquitoes and other invertebrates (including bed bugs, moths, crustaceans, worms, sponges and bees), scientists are finding new molecules involved in defences against pathogens (microbes that cause disease).



One molecule found in fruit flies, Dscam, is capable of folding itself in 18,000 different ways. Computer models that predict the structure of this molecule have led scientists to suggest that this folding creates different shapes, each capable of binding to different structures on the pathogen’s surface. “These molecules can be used very flexibly by assembling their components in many ways,” says Schmid-Hempel. Until now, this ability to recognize specific pathogens was thought to be limited to vertebrates.



In another exciting area of research, scientists showed the sophisticated ways that invertebrates manage their immune systems. “Insects recognise peptidoglycan [a component of bacterial cell wall] and this triggers a rapid immune response” explains Schmid-Hempel. However, once the bacteria have been killed, molecules digest peptidoglycans and therefore dampen down the immune response. Regulating the immune response in this way is important because immune systems, if left unchecked, can harm an individual by mistakenly attacking cells in the body.



In humans, the failure of the body to recognise itself results in autoimmune diseases. For example, Crohn’s disease is the failure of the body to recognize intestinal cells, resulting in an immune response against these cells. Understanding these autoimmune processes in invertebrates might help us to better engineer drugs to tackle these debilitating diseases in humans.



Insects can also boost their immune systems ready for a pathogen invasion. Female bedbugs, which are often wounded during mating, enhance their immune system prior to mating in anticipation of pathogen invasion. Similarly, bumblebees maintain their immune systems in an enhanced state following a pathogen attack to counter future infections. “This can even cross generations, with mothers transferring immunity to their offspring” says Schmid-Hempel. This delicate management of immune responses has until now been regarded as a characteristic of vertebrates.



Schmid-Hempel thinks that the molecular mechanisms found in invertebrate immune systems may rival those seen in the vertebrate world. He says: “Insects use different cells and molecules, but follow very similar principles for detecting pathogens as vertebrates.”



And scientists are only beginning to understand the elaborate ways that invertebrates respond to pathogens. As they discover new molecules, the invertebrate immune system could turn out to be much more like that of vertebrates — making it an even better model for the study of our own immune system.



The impact on innate immunity: at the defence frontier – the biology of innate immunity conference was organised by the ESF Research Conferences Scheme and was attended by 90 immunologists and evolutionary ecologists. It was held at the University of Innsbruck Conference Centre in Obergurgl, Ötz Valley, Austria on 19-24 May 2007. The conference appealed to an international audience, drawing scientists from mainland Europe (Kenneth Söderhäll, Uppsala University, Sweden), Britain (Andrew Read, University of Edinburgh, Scotland), and the Canada (Shelley Adamo, Dalhousie University, Nova Scotia, CA). This conference was organised by ESF in partnership with the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich (FWF) and the Leopold-Franzens-Universität Innsbruck (LFUI).
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PostPosted: Sun Aug 05, 2007 1:01 pm    Post subject: Study identifies source of fever Reply with quote

Beth Israel Deaconess Medical Center
5 August 2007

Study identifies source of fever

Findings explain key factor in illness, inflammation
BOSTON – With the finding that fever is produced by the action of a hormone on a specific site in the brain, scientists have answered a key question as to how this adaptive function helps to protect the body during bacterial infection and other types of illness.

Reported by researchers at Beth Israel Deaconess Medical Center (BIDMC), the study results appear today in Nature Neuroscience’s Advance Online Publication.

“This study shows how the brain produces fever responses during infections,” explains senior author Clifford Saper, MD, PhD, Chairman of the Department of Neurology at BIDMC and James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School. “Our laboratory identified the key site in the brain at which a hormone called prostaglandin E2 (PGE2) acts on a target, called the EP3 receptor, on neurons to cause the fever response.”

During periods of inflammation, such as when the body is fighting an infection or illness, the body produces hormones known as cytokines. The cytokines, in turn, act on blood vessels in the brain to produce PGE2.

“PGE2 then enters the brain’s hypothalamus, causing fever, loss of appetite, fatigue and general feelings of sickness and achiness,” says Saper, explaining that these common symptoms of illness function as an adaptive response to enable the body to better fight infection.

“When body temperature is elevated by a few degrees, white blood cells can fight infections more effectively. Also, individuals tend to become achy and lethargic. Consequently,” he adds, “they tend to take it easy, thereby conserving their energy so that they can better fight the infection. That is why so many different types of illness result in more or less the same sickness behaviors.”

To this point, the specific neurons on which PGE2 was acting to produce fever were unknown. Saper and his colleagues created a knockout mouse in which the gene for the EP3 receptor – which registers the presence of PGE2 – could be removed in one part of the brain at a time.

“This was the first time that anyone has been able to remove the receptor at a single spot in the brain,” says Saper. “As a result, we are able to definitively say that this particular site in the brain – only a little bigger than the head of a pin – is where prostaglandins work to cause the fever response.

“We think that the other aspects of sickness behavior, such as the achiness caused by increased sensitivity to pain, also come from specific sites in the brain,” he adds. “We plan to use this same approach to dissect the brain’s response to inflammation, and find out why people feel the way they do when they are ill.”


###
This study was funded by grants from the U.S. Public Health Service.

In addition to Saper, coauthors include BIDMC investigators Michael Lazarus, PhD(lead author), Kyoko Yoshida, PhD, Takatoshi Mochizuki, PhD, Bradford Lowell, MD, PhD, and Roberto Coppari, PhD; and Caroline Bass, PhD, of Wake Forest University, North Carolina.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu
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PostPosted: Wed Sep 05, 2007 1:21 pm    Post subject: A German-American research collaboration discovers how the i Reply with quote

September 4th, 2007
Max Planck Society

Dangerous Liaisons

A German-American research collaboration discovers how the immune system can drive the formation of new species

Plant geneticists and animal breeders alike know the problem: single individuals or entire broods will not thrive, some die early, or remain, even if they survive, the runts of the litter and thus not useful for continued breeding programs. What is annoying for the breeder, fascinates geneticists and molecular biologists. The unfit offspring are an example that genetic material cannot always be combined at will. Apparently there are reproductive barriers that not only prevent the exchange of genes between well established species, but also between varieties of one and the same species. How these barriers arise is of central importance if one wants to understand the origin of biodiversity. A research team led by Detlef Weigel from the Max Planck Institute of Developmental Biology in Germany and Jeff Dangl from the University of North Carolina has now shown that a mis-regulated immune system can establish reproductive barriers and might be a first step toward speciation. The international collaboration studied a genetic incompatibility known as hybrid necrosis, using thale cress, Arabidopsis thaliana.

For the full article:

http://www.mpg.de/english/illu.....e20070904/
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PostPosted: Wed Sep 19, 2007 1:06 pm    Post subject: Their immune cells, fighting your cancer Reply with quote

New Scientist
19 September 2007

Their immune cells, fighting your cancer

IMMUNE cells from “cancer-resistant” people are to be injected into those with cancer to help fight the disease. Zheng Cui at Wake Forest University of Medicine in Winston-Salem, North Carolina, and his colleagues have received permission from the US Food and Drug Administration (FDA) to screen people for their ability to ward off cancer. Immune cells from the best cancer fighters will be given to cancer patients, after being matched for blood type. All of us have some ability to fight cancer, via immune cells called NK cells which can identify and kill tumour cells, although the extent of these cells’ influence is not known. But Cui has now discovered that a much larger population of immune cells called granulocytes can also kill cancer and that the effectiveness of these cells varies from person to person.

For the full article:

http://www.eurekalert.org/pub_.....091907.php
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PostPosted: Thu Oct 04, 2007 1:20 pm    Post subject: Agent that triggers immune response in plants is uncovered Reply with quote

Cornell University News Service
4 October 2007

Agent that triggers immune response in plants is uncovered

Although plants lack humans' T cells and other immune-function cells to signal and fight infection, scientists have known for more than 100 years that plants still somehow signal that they have been attacked in order to trigger a plantwide resistance. Now, researchers at the Boyce Thompson Institute for Plant Research (BTI) on the Cornell campus have identified the elusive signal in the process: methyl salicylate, an aspirin-like compound that alerts a plant's immune system to shift into high gear.

This phenomenon is called systemic acquired resistance and is known to require movement of a signal from the site of infection to uninfected parts of the plant.

The findings are published in the Oct. 5 issue of Science.

"By finally identifying a signal that moves from an infection site to activate defenses throughout the plant, as well as the enzymes that regulate the level of this signal, we may be in a position to alter the signal in a way that enhances a plant's ability to defend itself," said BTI senior scientist Daniel F. Klessig, an adjunct professor in plant pathology at Cornell, who conducted the work with Sang-Wook Park and other BTI colleagues.

Their approach, using gene technology to enhance plant immunity, could have wide consequences, boosting crop production and reducing pesticide use.

Methyl salicylate is a modified form of salicylic acid (SA), which has been used for centuries to relieve fever, pain and inflammation, first through the use of willow bark and, since 1889, with aspirin, still the most widely used drug worldwide.

In the 1990s, Klessig's research group reported that SA and nitric oxide are two critical defense-signaling molecules in plants, as well as playing important roles in human health. Then, in 2003 and 2005, the group reported in the Proceedings of the National Academy of Sciences that an enzyme, salicylic acid-binding protein 2 (SABP2), is required for systemic acquired resistance and converts methyl salicylate (which is biologically inactive as it fails to induce immune responses) into SA, which is biologically active.

After plants are attacked by a pathogen, the researchers had previously found, they produce SA at the infection site to activate their defenses. Some of the SA is converted into methyl salicylate, which can be converted back into SA by SABP2.

Using plants in which SABP2 function was either normal, turned off or mutated in the infected leaves or the upper, uninfected leaves, Klessig's group showed that SABP2 must be active in the upper, uninfected leaves for systemic acquired resistance to develop properly. By contrast, SABP2 must be inactivated in the infected leaves by binding to SA.

"This inactivation allows methyl salicylate to build up," explained Klessig. "It then flows through the phloem (or food-conducting "tubes") to the uninfected tissue, where SABP2 converts it back into active SA, which can now turn on the plant's defenses."

Klessig said that it is unclear why plants send this hormone to uninfected tissue in an inactive form, which then must be activated by removal of the methyl group.

"This research also provides insight into how a hormone like SA can actively regulate its own structure -- and thereby determine its own activity -- by controlling the responsible enzyme," noted Park, the lead author of the paper.
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PostPosted: Thu Oct 18, 2007 12:04 pm    Post subject: Immune cells fighting chronic infections become progressivel Reply with quote

The Wistar Institute
18 October 2007

Immune cells fighting chronic infections become progressively 'exhausted,' ineffective

Potential interventions to restore disease-fighting capability outlined

(PHILADELPHIA) – A new study of immune cells battling a chronic viral infection shows that the cells, called T cells, become exhausted by the fight in specific ways, undergoing profound changes that make them progressively less effective over time.

The findings also point to interventions that would reverse the changes, suggesting that novel therapies could be developed to reinvigorate T cells that become depleted in their struggle against a virus. Alternatively, strategies that would intentionally trigger the immune-dampening mechanisms explored in the study could prove useful in countering autoimmune disorders in which the immune system is inappropriately activated.

Although the experiments were conducted in mice, the problem of T-cell exhaustion has also been identified in HIV, hepatitis B, and hepatitis C infections in humans, as well as some cancers, such as melanoma. A report on the study results appears in the current issue of Immunity, published online October 18.

“We knew that T cells responding to chronic infections become progressively compromised in many of their functional properties,” says E. John Wherry, Ph.D., an assistant professor in the Immunology Program at The Wistar Institute and lead author on the Immunity study. “Put simply, the T cells become exhausted as time passes. What we wanted to learn in our study was what the specific problems were with these cells and whether their depleted state could be reversed.”

Using a technique called gene-expression profiling, Wherry and his colleagues identified 490 genes whose activity in T cells is altered during a chronic viral infection. Closer study at different time points using a 22-gene subset of the larger group of genes provided molecular signatures of progressive T-cell exhaustion. Only a few changes in the activity of the 22 genes were seen at the end of the first week of infection, increasing to 9 differences at two weeks, 18 differences at one month, and 21 differences at two months. At the end of two months, T cells contending with a chronic infection were sluggish metabolically and immunologically unresponsive to stimulus.

One gene identified as playing a central role in this process is called PD-1, which codes for an inhibitory receptor on the surface of the T cells. By blocking PD-1 in vivo, the researchers found they could alleviate T-cell exhaustion, get more functional T cells, and control the infection better.

“Blocking this one pathway partially reverses T-cell exhaustion in some settings, suggesting that we may be able to intervene to reinvigorate depleted immune cells,” says Wherry. “The T cells undergo many changes during chronic infections, however, so that it will be important to learn how to treat them for multiple problems.”

Wherry notes that the mechanisms involved in T-cell exhaustion also have important upsides.

“The flip side of this process is that the immune system has developed an effective way to turn off its response to a stimulus – which is exactly what one wants to do in the case of autoimmunity,” he says.

He points out, too, that the energy outlay during the acute phase of the immune system’s response to an infection is enormous – and fundamentally unsustainable.

“In the first week of an immune response to a virus, T cells can divide every four to six hours, as fast as any other mammalian cell at any time during development,” Wherry says. “In terms of their rate of division, T cells are in the same category as cells in the earliest stages of embryonic development. The energy involved in doing this is extraordinary, and the body can’t keep that up for an extended period of time.”


###
Wherry is the lead author on the Immunity study, as well as the corresponding author. The senior author was Rafi Ahmed at the Emory University School of Medicine. The co-authors on the study are; Sang-Jun Ha, Surojit Sarkar, Vandana Kalia, and Shruti Subramaniam at Emory; Susan M. Kaech at Yale University Medical School; W. Nicholas Haining at the Dana-Farber Cancer Institute; Joseph N. Blattman at the Fred Hutchinson Cancer Research Center; and Daniel L. Barber at National Institutes of Health.

Funding for the research was provided by the National Institutes of Health, the Foundation for NIH, the Bill and Melinda Gates Foundation, the Elizabeth Glaser Pediatric AIDS Foundation, the Cancer Research Institute, and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. Discoveries at Wistar led to the creation of the rubella vaccine that eradicated the disease in the United States, human rabies vaccines used worldwide, and a new rotavirus vaccine approved in 2006. Today, Wistar is home to preeminent research programs studying skin cancer, lung cancer, and brain tumors. Wistar Institute Vaccine Center scientists are creating new vaccines against pandemic influenza, HIV, and other diseases threatening global health. The Institute works actively to transfer its inventions to the commercial sector to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the web at www.wistar.org
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PostPosted: Wed Oct 24, 2007 2:13 pm    Post subject: Scientists discover a direct route from the brain to the imm Reply with quote

North Shore-Long Island Jewish (LIJ) Health System
24 october 2007

Scientists discover a direct route from the brain to the immune system

– It used to be dogma that the brain was shut away from the actions of the immune system, shielded from the outside forces of nature. But that’s not how it is at all. In fact, thanks to the scientific detective work of Kevin Tracey, MD, it turns out that the brain talks directly to the immune system, sending commands that control the body’s inflammatory response to infection and autoimmune diseases. Understanding the intimate relationship is leading to a novel way to treat diseases triggered by a dangerous inflammatory response.

Dr. Tracey, director and chief executive of The Feinstein Institute for Medical Research, will be giving the 2007 Stetten Lecture on Wednesday, Oct. 24, at the National Institutes of Health in Bethesda, MD. His talk – Physiology and Immunology of the Cholinergic Anti-inflammatory Pathway – will highlight the discoveries made in his laboratory and the clinical trials underway to test the theory that stimulation of the vagus nerve could block a rogue inflammatory response and treat a number of diseases, including life-threatening sepsis.

With this new understanding of the vagus nerve’s role in regulating inflammation, scientists believe that they can tap into the body’s natural healing defenses and calm the sepsis storm before it wipes out its victims. Each year, 750,000 people in the United States develop severe sepsis, and 215,000 will die no matter how hard doctors fight to save them. Sepsis is triggered by the body’s own overpowering immune response to a systemic infection, and hospitals are the battlegrounds for these potentially lethal conditions.

The vagus nerve is located in the brainstem and snakes down from the brain to the heart and on through to the abdomen. Dr. Tracey and others are now studying ways of altering the brain’s response or targeting the immune system itself as a way to control diseases.

Dr. Tracey is a neurosurgeon who came into research through the back door of the operating room. More than two decades ago, he was treating a young girl whose body had been accidentally scorched by boiling water and she was fighting for her life to overcome sepsis. She didn’t make it. Dr. Tracey headed into the laboratory to figure out why the body makes its own cells that can do fatal damage. Dr. Tracey discovered that the vagus nerve speaks directly to the immune system through a neurochemical called acetylcholine. And stimulating the vagus nerve sent commands to the immune system to stop pumping out toxic inflammatory markers. “This was so surprising to us,” said Dr. Tracey, who immediately saw the potential to use vagus stimulation as a way to shut off abnormal immune system responses. He calls this network “the inflammatory reflex.”

Research is now underway to see whether tweaking the brain's acetylcholine system could be a natural way to control the inflammatory response. Inflammation is key to many diseases - from autoimmune conditions like Crohn's disease and rheumatoid arthritis to Alzheimer's, where scientists have identified a strong inflammatory component.

Dr. Tracey has presented his work to the Dalai Lama, who has shown a great interest in the neurosciences and the mind-body connection. He has also written a book called “Fatal Sequence,” about the double-edge sword of the immune system.


###
About The Feinstein Institute for Medical Research

Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org or http://feinsteininstitute.type.....einweblog/
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PostPosted: Sat Nov 17, 2007 6:53 am    Post subject: Superbug: What makes one bacterium so deadly Reply with quote

Week of Nov. 17, 2007; Vol. 172, No. 20 , p. 307

Superbug: What makes one bacterium so deadly
Sarah C. Williams

Some of the most aggressive antibiotic-resistant staph infections gain their advantage with a molecule that punctures the immune cells trying to fight off the bacteria, scientists have discovered. Understanding the role of this molecule in methicillin-resistant Staphylococcus aureus (MRSA) could lead to new therapies for the notoriously hard-to-treat, and sometimes fatal, skin infection.

For the full article:

http://sciencenews.org/articles/20071117/fob1.asp
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PostPosted: Tue Dec 04, 2007 3:07 pm    Post subject: Exercising our immune system Reply with quote

Research Australia
3 December 2007

Exercising our immune system

Elite athletes - often perceived as the epitome of health and fitness – may be more susceptible to common illness and are therefore proving useful in helping scientists understand more about the immune system.

Nic West, a PhD candidate at Griffith University, has enlisted elite rowers to help him study the role of salivary proteins that act as a barrier to infectious agents such as respiratory viruses.

He said salivary proteins such as lactoferrin and lysozyme act to prevent microbes from infecting the body and typically increase as the body fights off infection. They have a direct antimicrobial effect and also help modulate other aspects of the body’s immune response.

“We want to understand the mucosal immune system better and the factors that increase a person’s susceptibility to illness.”

An initial observational study comparing elite rowers with sedentary individuals over five months clearly showed that exercise was associated with a significant reduction in the concentration of lactoferrin.

“Theoretically, exercise is a stress on the body and leads to a greater susceptibility to illness. The decrease in salivary proteins, one of the body’s first lines of defence against infection, may help explain this.”

However a second study comparing the concentration of salivary proteins in rowers at rest, after moderate exercise, and after high intensity exercise, showed that exercise increased rather than decreased lactoferrin and lysozymes in the short term.

“Salivary proteins increased by about 50 per cent following exhaustive exercise which may be a transient activation response that increases protection in the immediate post-exercise period,” he said.

His research over the next 18 months will test the effectiveness of a nutritional intervention in ameliorating the effects of hard physical activity on the immune system.

“There is some research to indicate that probiotics and resistant starches are useful in boosting mucosal barrier function.”

Mr West said the beauty of the immune system was that it had a natural ‘redundancy’ – with overlapping components in the event of any one protective mechanism failing.

“So we also have mechanical barriers against infection such as the cilia in our nose, and immunity led by cells such as lymphocytes.”
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