Brain Birth Defects Successfully Reversed Through Stem Cell Therapy

Scientists at the Hebrew University of Jerusalem have succeeded in reversing brain birth defects in animal models, using stem cells to replace defective brain cells.

The work of Prof. Joseph Yanai and his associates at the Hebrew University-Hadassah Medical School was presented at the Tel Aviv Stem Cells Conference last spring and is expected to be presented and published nest year at the seventh annual meeting of the International Society for Stem Cell Research in Barcelona, Spain.

Involved in the project with Prof. Yanai are Prof. Tamir Ben-Hur, head of the Department of Neurology at the Hebrew University-Hadassah Medical School, and his group, as well as Prof. Ted Slotkin at Duke University in North Carolina, where Prof. Yanai is an adjunct professor.

Neural and behavioral birth defects, such as learning disabilities, are particularly difficult to treat, compared to defects with known cause factors such as Parkinson’s or Alzheimer’s disease, because the prenatal teratogen – the substances that cause the abnormalities -- act diffusely in the fetal brain, resulting in multiple defects.

Prof. Yanai and his associates were able to overcome this obstacle in laboratory tests with mice by using mouse embryonic neural stem cells. These cells migrate in the brain, search for the deficiency that caused the defect, and then differentiate into becoming the cells needed to repair the damage.

Generally speaking, stem cells may develop into any type of cell in the body, however at a certain point they begin to commit to a general function, such as neural stem cells, destined to play a role in the brain/ nervous system. At more advanced developmental stages, the neural stem cells take on an even more specific role as neural or glial (supporting) cells within the brain/ nervous system.

In the researchers’ animal model, they were able to reverse learning deficits in the offspring of pregnant mice who were exposed to organophosphate (a pesticide) and heroin. This was done by direct neural stem cell transplantation into the brains of the offspring. The recovery was almost one hundred percent, as proved in behavioral tests in which the treated animals improved to normal behavior and learning scores after the transplantation. On the molecular level, brain chemistry of the treated animals was also restored to normal.

The researchers went one step further. Puzzled by the stem cells’ ability to work even in those cases where most of them died out in the host brain, the scientists went on to discover that the neural stem cells succeed before they die in inducing the host brain itself to produce large number of stem cells which repair the damage. This discovery, finally settling a major question in stem cell research, evoked great interest and was published earlier this year in one of the leading journals in the field, Molecular Psychiatry.

The scientists are now in the midst of developing procedures for the least invasive method for administering the neural stem cells, which is probably via blood vessels, thus making the therapy practical and clinically feasible.

Normally, stem cells are derived from individuals genetically different from the patient to be transplanted, and therefore the efficacy of the treatment suffers from immunological rejection. For this reason, another important avenue of the ongoing study, toward the same goals, will be to eliminate the immunological rejection of the transplant, which will become possible by taking cells from the patient’s own body -- from a place where they are easily obtained -- by manipulating them to return to their stem cell phase of development, and then transplanting them into the patient’s brain via the blood stream. One important advantage of this approach will be to eliminate the controversial ethical issues involved in the use of embryo stem cells.

The research on the project has been supported by the US National Institutes of Health, the US-Israel Binational Science Foundation and the Israel anti-drug authorities.

Mechanism That Triggers Differentiation Of Embryo Cells Discovered

The mechanism whereby embryonic cells stop being flexible and turn into more mature cells that can develop into specific tissues has been discovered by scientists at the Hebrew University of Jerusalem. The discovery has significant consequences towards furthering research that will eventually make possible medical cell replacement therapy based on the use of embryonic cells.

At a very early stage of human development, all cells of the embryo are identical, but unlike adult cells are very flexible and carry within them the potential to become any tissue type, whether it be muscle, skin, liver or brain.

This cell differentiation process begins at about the time that the embryo settles into the uterus. In terms of the inner workings of the cell, this involves two main control mechanisms. On the one hand, the genes that keep the embryo in their fully potent state are turned off, and at the same time, tissue-specific genes are turned on. By activating a certain set of genes, the embryo can make muscle cells. By turning on a different set, these same immature cells can become liver. Other gene sets are responsible for additional tissues.

In a recent paper, published in the journal, Nature Structural and Molecular Biology, Professors Yehudit Bergman and Howard Cedar of the Hebrew University-Hadassah Medical School have deciphered the mechanism whereby embryonic cells stop being flexible and turn into more mature cells that can differentiate into specific tissues. Bergman is the Morley Goldblatt Professor of Cancer Research and Experimental Medicine and Cedar is the Harry and Helen L. Brenner Professor of Molecular Biology at the Medical School.

They found in their experiments, using embryos from laboratory mice and cells that grow in culture, that this entire process is actually controlled by a single gene, called G9a, which itself is capable of directing a whole program of changes that involves turning off a large set of genes so that they remain locked for the entire lifetime of the organism, thereby unable to activate any further cell flexibility.

Their studies shed light not only on this central process, but also can have consequences for medical treatment. One of the biggest challenges today is to generate new tissues for replacing damaged cells in a variety of different diseases, such as Parkinson’s disease or diabetes. Many efforts have been aimed at “reprogramming” readily-available adult cells, but scientists have discovered that it is almost impossible to do this, mainly because normal tissues are locked in their fixed program and have lost their ability to convert back to fully potent, flexible, embryonic cells.

Now, with the new information discovered by Bergman and Cedar, the molecular program that is responsible for turning off cell flexibility has been identified, and this may clear the way towards developing new approaches to program cells in a controlled and specific manner.

Artificial Human Bone Marrow Created In A Test Tube

This development could lead to simpler pharmaceutical drug testing, closer study of immune system defects and a continuous supply of blood for transfusions.

The substance grows on a 3-D scaffold that mimics the tissues supporting bone marrow in the body, said Nicholas Kotov, a professor in the U-M departments of Chemical Engineering; Materials Science and Engineering; and Biomedical Engineering.

The marrow is not made to be implanted in the body, like most 3-D biomedical scaffolds. It is designed to function in a test tube.

Kotov, principal investigator, is an author of a paper about the research currently published online in the journal Biomaterials. Joan Nichols, professor from the University of Texas Medical Branch, collaborated on many aspects of the project.

"This is the first successful artificial bone marrow," Kotov said. "It has two of the essential functions of bone marrow. It can replicate blood stem cells and produce B cells. The latter are the key immune cells producing antibodies that are important to fighting many diseases."

Blood stem cells give rise to blood as well as several other types of cells. B cells, a type of white blood cell, battle colds, bacterial infections, and other foreign or abnormal cells including some cancers.

Cancer-fighting chemotherapy drugs can strongly suppress bone marrow function, leaving the body more susceptible to infection. The new artificial marrow could allow researchers to test how a new drug at certain potencies would affect bone marrow function, Kotov said. This could assist in drug development and catch severe side effects before human drug trials.

Bone marrow is a complicated organ to replicate, Kotov said. Vital to the success of this new development is the three-dimensional scaffold on which the artificial marrow grows. This lattice had to have a high number of precisely-sized pores to stimulate cellular interaction.

The scaffolds are made out of a transparent polymer that nutrients can easily pass through. To create the scaffolds, scientists molded the polymer with tiny spheres ordered like billiard balls. Then, they dissolved the spheres to leave the perfect geometry of pores in the scaffold.

The scaffolds were then seeded with bone marrow stromal cells and osteoblasts, another type of bone marrow cell.

"The geometrical perfection of the polymer molded by spheres is very essential for reproducibility of the drug tests and evaluation of potential drug candidates," Kotov said. "The scaffold for this work had to be designed from scratch closely mimicking real bone marrow because there are no suitable commercially products.

"Certain stem cells that are essential for immunity and blood production are able to grow, divide and differentiate efficiently in these scaffolds due to the close similarity of the pores in the scaffold and the pores in actual bone marrow."

The researchers demonstrated that the artificial marrow gives a human-like response to an infectious New Caledonia/99/H1N1 flu virus. This is believed to be a first.

To determine whether the substance behaves like real bone marrow, the scientists implanted it in mice with immune deficiencies. The mice produced human immune cells and blood vessels grew through the substance.

Scientists Probe Limits Of 'Cancer Stem-cell Model'

One of the most promising new ideas about the causes of cancer, known as the cancer stem-cell model, must be reassessed because it is based largely on evidence from a laboratory test that is surprisingly flawed when applied to some cancers, University of Michigan researchers have concluded.

By upgrading the lab test, the U-M scientists showed that melanoma---the deadliest form of skin cancer---does not follow the conventional cancer stem-cell model, as prior reports had suggested.

The findings, to be published as the cover article in the Dec. 4 edition of Nature, also raise questions about the model's application to other cancers, said Sean Morrison, director of the Center for Stem Cell Biology at the U-M Life Sciences Institute.

"I think the cancer stem-cell model will, in the end, hold up for some cancers," Morrison said. "But other cancers, like melanoma, probably won't follow a cancer stem-cell model at all. The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells."

The cancer stem-cell model has steadily gained supporters over the last decade. It states that a handful of rogue stem cells drive the formation and growth of malignant tumors in many cancers. Proponents of the controversial idea have been pursuing new treatments that target these rare stem cells, instead of trying to kill every cancer cell in a patient's body.

But in a series of experiments involving human melanoma cells transplanted into mice, Morrison's team found that the tumor-forming cells aren't rare at all. They're quite common, in fact, but standard laboratory tests failed to detect most of them.

Scientists previously estimated that only one in 1 million melanoma cells has the ability to run wild, exhibiting the kind of unchecked proliferation that leads to new tumors. These aggressive interlopers are the cancer stem cells, according to backers of the model.

But after updating and improving the laboratory tests used to detect these aberrant cells, Morrison's team determined that at least one-quarter of melanoma cells are "tumorigenic," meaning they have the ability to form new tumors. The laboratory tests are known as assays.

"The assay on which the field is based misses most of the cancer cells that can proliferate to form tumors," Morrison said. "Our data suggest that it's not going to be possible to cure melanoma by targeting a small sub-population of cells."

Melanoma kills more than 8,000 Americans each year. The human melanoma cells used in the mouse experiments were provided---with the patients' consent---by a team from the U-M's Multidisciplinary Melanoma Program, one of the country's largest melanoma programs and part of the U-M Comprehensive Cancer Center.

"People were looking to the cancer stem-cell model as an exciting new source for the development of life-saving cures for advanced melanoma," said Dr. Timothy Johnson, director of the U-M melanoma program and a co-author of the Nature paper. "Unfortunately, our results show that melanoma does not strictly follow this model.

"So we'll need to redirect our scientific efforts and remain focused on the fundamental biological processes underlying the growth of melanomas in humans," said Johnson, a cutaneous oncologist. "And as we pursue new treatments for advanced melanoma, we'll have to consider that a high proportion of cancer cells may need to be killed."

Morrison and Johnson stressed that the team's findings do not broadly invalidate the cancer stem-cell model. Cancer stem cells likely do exist in some forms of cancer but are "probably much more common than people have been estimating," Morrison said.

The standard technique used to detect tumor-causing cancer cells in mouse transplants is called the NOD/SCID assay. NOD/SCID mice have defective immune systems. Scientists use the severely immunocompromised mice because the rodents don't reject transplanted human cancer cells the way normal mice would.

However, while the immune system in NOD/SCID mice is impaired, it's not completely inoperative. The mice lack T and B immune cells but still possess natural killer cells, which attack and destroy many of the transplanted human cancer cells.

Morrison's team replaced NOD/SCID mice with mice that lacked T cells, B cells and natural killer cells---and made a few other improvements to the assay. Using the modified assay, they found that about one in four transplanted melanoma cells formed tumors in the mice.

They concluded that previous studies using NOD/SCID mice vastly underestimated the number of tumor-causing melanoma cells, partly because natural killer cells wiped out many of the cancer cells. But once the natural killer cells were eliminated, the "more permissive conditions" allowed many of the transplanted melanoma cells to survive and thrive, the authors wrote.

Co-lead authors of the Nature paper are Life Sciences Institute research fellows Elsa Quintana and Mark Shackleton. In addition to Morrison and Johnson, other co-authors are U-M surgical oncologist Dr. Michael Sabel and U-M dermatopathologist Dr. Douglas Fullen.

The work was supported by the Howard Hughes Medical Institute, the Allen H. Blondy Research Fellowship and the Lewis and Lillian Becker gift.

Breakthrough In Understanding Development Of Type 1 Diabetes

Finnish scientists have reported a breakthrough in understanding the development of type 1 diabetes. They discovered disturbances in lipid and amino acid metabolism in children who later progressed to type 1 diabetes, also known as juvenile diabetes. The alterations preceded the autoimmune response by months to years. The study may prompt new approaches for prediction and prevention of type 1 diabetes in pre-autoimmune phase of the disease.

The results of the Finnish research team, which consists of scientists from VTT Technical Research Centre of Finland and the Universities of Turku, Oulu and Tampere, have been published on 15 December 2008, in the Journal of Experimental Medicine.

Type 1 diabetes is an autoimmune disease in which the immune system attacks the insulin producing pancreatic beta cells. The gradual loss of beta cells results in life-long dependence on exogenous insulin.

At the moment, the earliest identifiable process in the pathogenesis of type 1 diabetes has been the development of autoimmunity to pancreatic beta cells in the measurable form of islet autoantibodies. Although the autoimmunity usually precedes the clinical disease by months to years, its occurrence may already be too late for therapeutic approaches aimed at preventing progression to overt diabetes. The initiators of the autoimmune response have remained unknown and the mechanisms supporting progression towards beta cell failure have been poorly understood, making discovery of effective prevention a challenge. The results of the SYSDIPP project, which was supported by the Tekes FinnWell Program, bring significant new information for combating the disease.

The SYSDIPP project has made use of metabolomics. Metabolomics systematically studies the chemical fingerprints in cells, tissues and biofluids in a given physiological and environmental context. The metabolic phenotype is sensitive to subtle factors such as age, lifestyle, nutrition and the microbe environment of the intestines. Changes in the concentrations of metabolites may thus reflect both genetic and environmental factors influencing later susceptibility to chronic diseases.

In 1994, an ongoing birth cohort study (DIPP, the Type 1 Diabetes Prediction and Prevention study) was launched in Finland, supported by the Juvenile Diabetes Research Foundation International. Over a period of 14 years, more than 130,000 newborn infants have been screened for genetic risk and over 8000 at-risk children are being regularly followed.

The research team was led by Prof. Matej Orešič from VTT Technical Research Centre of Finland and Prof. Olli Simell from University of Turku. Also Professors Mikael Knip, Jorma Ilonen, and Riitta Lahesmaa together with Dr. Riitta Veijola and Dr.Tuula Simell took part in the study, which investigated metabolic profiles of DIPP children prospectively from birth. The research team has published the results in The Journal of Experimental Medicine on 15 December 2008. The article reports the discovery of metabolic disturbances that precede the autoimmune response in children who later progress to type 1 diabetes.

The investigators found that the individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow-up and increased levels of proinflammatory lysophosphatidylcholines several months prior to autoimmunity to pancreatic beta cells. The metabolic profile was partially normalized following the autoimmune response, suggesting autoimmunity may be a relatively late physiological response to the early metabolic disturbances. The observed lipid changes were not attributable to HLA-associated genetic risk.

Metabolic profiling at early age may therefore aid in determining the risk of type 1 diabetes. The reported findings imply that metabolic or immunomodulatory interventions during the pre-autoimmune period may be used as a new potential strategy for prevention of type 1 diabetes.

The incidence of type 1 diabetes among children and adolescents has increased markedly in the Western countries during recent decades. The incidence has reached record levels in Finland, where currently 1 child out of 120 develops type 1 diabetes before the age of 15 years. The annual incidence is increasing at accelerated rate, with the number of new cases expected to double in the next 15 years.

Biologist Modifies Theory Of Cells' Engines

Biologists have known for decades that cells use tiny molecular motors to move chromosomes, mitochondria, and many other organelles within the cell, but no one has been able to understand what "steers" these engines to their destinations. Now, researchers at the University of Rochester have shed new light on how cells accomplish this feat, and the results may eventually lead to new approaches to fighting pathogens and neurological diseases.

Michael Welte, associate professor of biology, shows in a paper published in the December 11 issue of Cell that the mechanisms that control the molecular motors are quite different from what biologists have previously believed. Before these findings, scientists assumed that the number of motors attached to an organelle determined how far and fast the organelle could travel, but Welte and colleagues have discovered that it is not the number of motors, but yet-to-be-discovered molecules that are likely the master regulators.

"The fact that motor number has nothing to do with regulating transport is extremely surprising, and somewhat unsettling to people working in vitro," says Welte. "It says we're really missing something when we study these motors only in the test tube instead of in a living cell."

Intracellular transport is crucial to a cell's health, says Welte. For instance, during cell division, one copy of each of the cell's chromosomes migrates to one side of the cell while the other copy moves to the other side. If this movement is disturbed, it could cause an imbalance of chromosomes in the daughter cells, which might die or become cancerous. Similarly, neurons, some of which are as much as three feet in length, manufacture proteins and organelles at one end and then must move that precious cargo all the way to the far end where they'll be used. This is an enormous task, says Welte, and defects in this transport are thought to cause a number of neurological diseases.

Given the difficulty of investigating these tiny motors acting within the cell, biologists have performed basic experiments on them outside of the cell in a carefully controlled environment. This led them to believe that the speed and distance an organelle could be transported depended on how many motors were pulling it, says Welte. Thus, the scientists reasoned, perhaps the cell simply attaches the right number of motors to an organelle to send it the right distance. Although this "multi-motor" hypothesis is very simple and elegant, says Welte, whether it actually holds true within living cells had never been tested.

Welte's graduate student, Susan Tran, decided to perform that test. She created fruit-fly eggs lacking a type of molecular motor called kinesin and found that certain organelles stopped moving—strong evidence that kinesin is responsible for their transport. Tran then made another type of mutant eggs, this time ones that produced only about half the number of kinesin motors of a regular egg. In both types of eggs, organelles were transported with the same speed and the same distance.

Welte needed to know if this equality was because the normal egg was simply utilizing only half the available kinesin motors, or if some master regulator was controlling the organelle's progress, regardless of the number of motors moving it. To do this, Welte turned to Steven Gross, associate professor of developmental and cell biology at the University of California. Gross' group uses an apparatus called "optical tweezers" that employs laser light to measure the tiny forces the motors generate. The team found that organelles in regular cells are pulled with twice the force of Tran's mutant, low-kinesin cells.

"That clinched it for us," says Welte. "Yes, there are multiple motors moving organelles around, but exactly how many doesn't matter. There is something else in the cell that's controlling all the motors. That opens up a big area for research—find what's driving these motors and maybe we can control them all by controlling one thing."

Welte and his team are now looking at where in the cell this signal comes from and how it influence the motors. Although Welte's team studied fruit fly eggs, the motors moving the organelles are present in all animals and employed for many tasks, including transport in human neurons.

Welte also points out that viruses, including HIV, make use of the same kind of motors to move about the cell, first to get from the site of penetration to the nucleus, where they multiply, and then to get progeny viruses back to the cell surface. If Welte and others can figure out how cells normally control these motors, it may be possible to prevent HIV from taking control of the motors and thus to keep it, and other intracellular pathogens, at the edge of the cell where they can do little harm.

This research was funded by the National Institutes of Health, and includes researchers from the University of Rochester, the University of California Irvine, and University of Texas at Austin

Toothbrushing Can Prevent Hospital-borne Pneumonia

Hospital-borne infections are a serious risk of a long-term hospital stay, and ventilator-associated pneumonia (VAP), a lung infection that develops in about 15% of all people who are ventilated, is among the most dangerous. With weakened immune systems and a higher resistance to antibiotics, patients who rely on a mechanical ventilator can easily develop serious infections — as 26,000 Americans do every year.

Thanks to a proven new clinical approach developed by Tel Aviv University nurses, though, there is a new tool for stopping the onset of VAP in hospitals.

This new high-tech tool? An ordinary toothbrush.

Three Times a Day Keeps Pneumonia Away

“Pneumonia is a big problem in hospitals everywhere, even in the developed world,” says Nurse Ofra Raanan, the chief researcher in the new study and a lecturer at Tel Aviv University’s Department of Nursing. “Patients who are intubated can be contaminated with pneumonia only 2 or 3 days after the tube is put in place. But pneumonia can be effectively prevented if the right measures are taken.”

Raanan, who works at the Sheba Academic School of Nursing at The Chaim Sheba Medical Center, collaborated with a team of nurses at major medical centers around Israel. The nurses found that if patients — even unconscious ones — have their teeth brushed three times a day, the onset of pneumonia can be reduced by as much as 50%.

A Pioneering Study with Measurable Effects

It’s difficult to quantify the effects precisely, the researchers say. “While the research shows a definite improvement in reducing the incidence of hospital-borne pneumonia, it’s hard to say by exactly how much toothbrushing prevents VAP,” says Raanan, but the published evidence shows a direct correlation for intubated patients.

“Sometimes, however, doctors and nurses do everything right and the patient still gets pneumonia. But this approach will certainly improve the odds for survival.”

Normally, the teeth and oral cavity in a healthy mouth maintain a colony of otherwise harmless bacteria. Infection takes root when a breathing tube allows free passage of the “good” bacteria into the lower parts of the lung. The bacteria travel in small water droplets through the tube and colonize the lung. Once there, the bacteria take advantage of a patient’s weakened immune system and multiply. A regular toothbrushing kills the growth and subsequent spread of the bacterium that leads to VAP.

Augmenting the Preventative Routine

There are additional steps for preventing the onset of VAP. Today, nurses typically use a mechanical suction device to remove secretions from the mouth and throat. They also put patients in a seated position and change the position every few hours. Toothbrushing, say Tel Aviv University nurses, should be added to the routine.

Although nurses in some American hospitals already practice toothbrushing on ventilated patients, these new results may convince medical centers around the world to invest more resources in this routine practice, thereby saving lives.

The research and recommendations are scheduled for publication in a leading nursing journal.

Mouse Model For Mesothelioma Reproduces Human Disease

Scientists have established a mouse model for human malignant mesothelioma that will provide valuable insight into cancer development and progression along with new directions for design of therapeutic strategies. The research, published by Cell Press in the March issue of Cancer Cell, may eventually lead to a substantially improved outlook for patients with this devastating disease.
Scientists have established a mouse model for human malignant mesothelioma that will provide valuable insight into cancer development and progression along with new directions for design of therapeutic strategies. The research, published by Cell Press in the March issue of Cancer Cell, may eventually lead to a substantially improved outlook for patients with this devastating disease.

New Strategy For Broad Spectrum Anti-viral Drugs Developed

Bavituximab, an anti-viral drug developed by UT Southwestern Medical Center researchers, shows promise as a new strategy to fight viral diseases, including potential bioterrorism agents.
In a study appearing in the December issue of Nature Medicine, groups of guinea pigs infected with a virus similar to Lassa fever virus recovered from the fatal disease when treated with bavituximab alone or in combination with a common anti-viral medication. Bavituximab treatment also cured mice infected with cytomegalovirus, an opportunistic infection that afflicts transplant and AIDS patients.

Dr. Philip Thorpe, professor of pharmacology at UT Southwestern and senior author of the study, proposed that phosphatidylserine, a lipid molecule that is normally positioned on the internal surface of a cell, flips to the outside of the cell when the cell is infected by a virus. His laboratory developed bavituximab, which binds to phosphatidylserine on the infected cells. Dr. Thorpe, holder of the Serena S. Simmons Distinguished Chair in Cancer Immunopharmacology, predicted that this interaction would muster the body's immune cells to attack and destroy the infected cells before the virus has a chance to replicate.

"When injected into the bloodstream, bavituximab circulates in the body until it finds these inside-out lipids and then binds to them," said Dr. Thorpe. "In the case of virus infection, the binding raises a red flag to the body's immune system, forcing the deployment of defensive white blood cells to attack the infected cells."

In the study, half of the guinea pigs infected with a virus similar to the Lassa fever virus were cured when bavituximab was administered alone. This is the first report of a therapeutic treatment being effective against advanced Lassa-like fever infections in animals. Lassa fever is an endemic disease in portions of West Africa, where the Lassa virus is carried by rats. As a hemorrhagic fever virus, Lassa is listed as a Category A bioterrorism agent – the same class as the Ebola and Marburg viruses – by the Centers for Disease Control and Prevention.

In a second experiment, researchers administered both bavituximab and the anti-viral medication ribavirin. Ribavirin works by a different mechanism than bavituximab; it stops virus replication in the cell. With this combination therapy, 63 percent of guinea pigs survived.

Dr. Melina Soares, instructor of pharmacology at UT Southwestern and lead author of the Nature Medicine study, said, "As viruses mutate, they become more resistant to existing anti-viral drug therapies. Using bavituximab to attack a lipid target could prove to be a new and effective strategy for treating virus infections."

Dr. Thorpe said that because phosphatidylserine on virus-infected cells is host-derived and independent of the virus, drug-resistance should be less problematic.

"This approach reduces the ability of the virus to escape attack by a drug," he said. "Viruses often dodge drugs by mutating into a different form that the drug is ineffective against. Host cells are a more immutable target."

Bavituximab is currently in clinical trials to treat patients with hepatitis C. The trials have shown that treatment is safe for patients, and researchers are reporting a reduction in their blood-virus load.

UT Southwestern researchers have found that phosphatidylserine flipping occurs in cells infected with influenza, the herpes simplex virus and viruses in the families of the small pox and rabies viruses. Other researchers have shown that this also occurs in HIV.

"It could very well be that this is a generic feature of enveloped viruses," Dr. Soares said. "It could lead to a new, broad spectrum anti-viral treatment."

Peregrine Pharmaceuticals has exclusively licensed bavituximab from UT Southwestern and has a sponsored research agreement to develop the drug further. Dr. Thorpe is a consultant to and has an equity interest in the company.

The research was funded by the National Institutes of Health and Peregrine.

Cell Receptor Identified As Target For Anti-inflammatory Immune Response

Invading pathogens provoke a series of molecular heroics that, when successful, muster an army of antibodies to neutralize the threat. Like with any close-quarter combat, however, an aggressive immune response runs the risk of friendly fire accidents. For the last decade, immunologists have intensively studied mechanisms evolved by the immune system to avoid these accidents by shutting off the immune response once the invaders have been eliminated.
Now the discovery of a new role for a specialized cell receptor has revealed aspects of how the immune system prevents a harmful overreaction to a foreign threat. Researchers at The Rockefeller University found that a receptor known to shield HIV and Hepatitis C from an effective immune response is also essential to the therapeutic effects of a common anti-inflammatory drug, intravenous immunoglobulin (IVIG). The finding opens up new possibilities for developing drugs to suppress the inflammation caused by autoimmune diseases such as rheumatoid arthritis and lupus.

“I see the implications as quite immediate,” says Jeffrey Ravetch, Theresa and Eugene M. Lang Professor and head of Rockefeller’s Laboratory of Molecular Genetics and Immunology. “We can develop new classes of anti-inflammatory molecules that can exploit this pathway. These findings also explain why certain pathogens like the HIV virus and Hepatitis C have usurped this pathway with their own mechanisms for evading host response.”

The research further demystifies the workings of IVIG, which have baffled scientists for years. Essentially, IVIG is a very high dose of the same class of antibodies — immunoglobulin cells called IgG — that perpetrate autoimmune diseases in the first place. Ravetch and colleagues in his lab partially solved this paradox in earlier work that identified a single sugar molecule called sialic acid at the tail end of some IgG molecules. When present, the sugar gives IgG molecules anti-inflammatory activity. If absent, the IgG molecules lose their protective qualities and become pro-inflammatory agents. Building on that finding, Ravetch in April published research in Science explaining how to engineer a molecule of sialylated IgG that — when given to arthritic mice — was 30 times more effective than standard IVIG treatment.

The latest findings, to be published as Ravetch’s inaugural paper in the Proceedings of the National Academy of Sciences, pushes this research further to define a special cell receptor that is required for IVIG to work. In mice, this receptor — SIGN-R1 — is found in a group of cells in the spleen that regulate the immune response in part by recognizing that special sugar found on some IgG molecules. “This recognition of and binding with the sialylated IgG cells seems to be the first step that is triggered by IVIG to suppress inflammation,” Ravetch says.

Ravetch and his colleagues homed in on the spleen by breeding transgenic mice lacking in key types of immune cells, dosing them with IVIG, and measuring whether it protected them from an arthritis-inducing agent that they were then exposed to. They found that mice were not protected when certain types of immune cells common to the spleen were deleted. A series of biochemical tests on the different receptors within those cells identified SIGN-R1 as the one that bound specifically to the molecules that help along the anti-inflammation response, sialylated IgG.

The findings should apply to humans, too. Ravetch and his colleagues identified a receptor in human cells — DC-SIGN — that behaves exactly as the SIGN-R1 found in mice. In our case, the receptors are found on dendritic cells, a prominent cell-type of the human immune system.

Now that he knows both the protein and receptor that initiate the immune response, Ravetch wants to develop molecules that can regulate that response. He also wants to know what, exactly, the sialylated IgG causes to happen that ultimately leads to the anti-inflammatory response. “It’s exciting to have this new pathway to dissect,” Ravetch says