Mother's Immune System May Block Fetal Treatments for Blood Diseases

/PRNewswire/ -- Pediatric researchers have resolved an apparent contradiction in the field of prenatal cell transplantation -- a medical approach that holds future promise in correcting sickle cell disease and other serious congenital blood disorders. In a new study in animals, the researchers showed that the mother's immune response interferes with the offspring's earlier ability to tolerate transplanted donor cells.

The study team concludes that focusing on transplant techniques that avoid the maternal immune response may allow scientists to take advantage of fetal tolerance to achieve a long-sought goal of treating blood diseases prenatally.

While cautioning that much work must be done to understand how these animal findings apply to humans, the current findings are "surprising but reassuring," said study leader Alan W. Flake, M.D., of the Children's Center for Clinical Research at The Children's Hospital of Philadelphia.

The study appeared online August 3 in the Journal of Clinical Investigation.

For over 50 years, explained Flake, it has been a fundamental precept of immunology that a fetus tolerates foreign antigens in a window-of-opportunity period before its immune system fully develops the capacity to mount an immune response. Scientists assumed that by carefully introducing donor cells and stimulating a fetus to develop tolerance to those cells, one could set the stage for a later organ or cellular transplant that would not be rejected by a more mature immune system.

As prenatal diagnosis has continued to become available for a greater number of congenital diseases, scientists have considered the possibility of correcting blood disorders such as sickle cell disease or thalassemia. After first transplanting a small number of healthy cells in an early-stage fetus to establish tolerance, a second dose of transplanted cells later in gestation would proliferate, and treat the blood disorder before birth. Researchers use hematopoietic cells -- stem cells that that develop into blood cells -- in this technique, in utero hematopoietic cell transplantation (IUHCT).

However, over the years, Flake's team and other research groups found that IUHCT studies in animal models yielded inconsistent results, ranging from no tolerance to transplants to full tolerance and every degree of tolerance in between. Contrary to the concept of fetal tolerance, an immune barrier seemed to be acting against transplanted cells.

The current study, done in mice, solves the puzzle of an apparent immune barrier. Newborn mice (pups) that received cell transplants in utero were divided into two groups. Mice nursed by their biological mothers lost the transplanted donor cells, while mice nursed by foster mothers retained those donor cells.

The mothers whose fetuses received the donor cells transplants had developed antibodies against those cells, and subsequently transmitted those antibodies to their pups through breast milk. "Those antibodies in the breast milk triggered rejection of the transplanted blood cells in the pups," said Flake. "But in the absence of a maternal immune response, we confirmed that immune tolerance does occur in the early-gestation fetus 100 percent of the time."

Of course, mouse biology is not the same as human biology, and Flake added, "Mouse time is not the same as human time." Because mice have such a brief gestational period, the mother's immune response didn't develop until after the birth of her pups, and was therefore transferred by breastfeeding. In large animals and humans, said Flake, the more likely route of maternal-to-fetal transmission would be through the placenta late in pregnancy, and not through postnatal breastfeeding.

However, it remains an open question whether the mouse findings are applicable to larger mammals and especially to humans. Flake's study team is continuing their investigations in larger animal models.

Looking forward to techniques to avoid maternal immune reactions to prenatal cell transplants, Flake proposed two possibilities. One would be use the mother as a source of donor cells, which would not stimulate an unwanted immune response. Another strategy could involve inducing the generation of increased numbers of T regulatory cells; those cells normally act to prevent the fetus from inappropriately reacting against maternal cells.

The ultimate goal, said Flake, is to develop IUHCT as a prenatal treatment for any congenital blood disorder that may currently be treated with postnatal bone marrow transplants. That would include sickle cell disease, thalassemia, and some inherited immunodeficiency diseases. Currently such postnatal transplants are risky and relatively rare.

"Our current finding is not a clinical breakthrough," added Flake. "But it does offer new potential to the field of cellular transplantation."

Funds from the National Institutes of Health, the Ruth and Tristram C. Colket Jr. Chair of Pediatric Surgery at The Children's Hospital of Philadelphia and the Albert M. Greenfield Foundation supported this study.

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FDA Advises Public of Serious Adverse Event with Psoriasis Drug Raptiva

The U.S. Food and Drug Administration today issued a public health advisory concerning three confirmed, and one possible report of progressive multifocal leukoencephalopathy (PML), a rare brain infection, in patients using the psoriasis drug Raptiva (efalizumab). Three of those patients have died. All four patients were treated with the drug for more than three years. None of the patients were receiving other treatments that suppress the immune system.

The FDA is reviewing this latest information. The agency will take appropriate steps to:

* ensure that the risks of Raptiva do not outweigh its benefits;
* that patients prescribed Raptiva are clearly informed of the signs and symptoms of PML; and
* that health care professionals carefully monitor patients for the possible development of PML.

PML is caused by a virus that affects the central nervous system. PML usually occurs in people whose immune systems have been severely weakened. It leads to an irreversible decline in neurologic function and death. Symptoms may include unusual weakness, loss of coordination, changes in vision, difficulty speaking and personality changes. There is no known effective prevention or treatment.

Psoriasis is a chronic disease, for which a number of effective therapeutic options are available, including four other approved biologic agents, ultraviolent light therapy, and the drugs cyclosporine, acitretin, and methotrexate. Generally, treatment for psoriasis patients involves a rotation of therapies.

In October 2008, the product labeling for Raptiva was revised to highlight in a boxed warning the risks of life-threatening infections, including PML. At that time, the FDA directed Genentech, the manufacturer, to develop a risk evaluation and mitigation strategy (REMS) to include a medication guide to educate patients about the drug’s risks.

The FDA strongly recommends that health care professionals carefully monitor patients on Raptiva, as well as those who have discontinued the drug, for any signs or symptoms of neurologic disease, and that they periodically reassess the benefits of continued treatment. Patients should be aware of the symptoms of PML and contact their health care professionals immediately if they experience any such symptoms.

Raptiva is a once-weekly injection approved for adults with moderate to severe plaque psoriasis who are candidates for systemic (whole body) therapy or phototherapy. The drug works by suppressing T-cells (blood cells that help fight infection) in the immune system. These cells, when activated, migrate to the skin and cause inflammation which results in the red, inflamed and scaly patches of skin, which is associated with psoriasis. By suppressing T-cells, Raptiva decreases the function of the immune system which increases a patient’s susceptibility to infections.

Health care professionals and consumers may report serious adverse events (side effects) or product quality problems with the use of this product to the FDA's MedWatch Adverse Event Reporting program online, by regular mail, fax or phone.

--Online: www.fda.gov/MedWatch/report.htm
--Regular Mail: use postage-paid FDA form 3500 available at: www.fda.gov/MedWatch/getforms.htm and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
--Fax: (800) FDA-0178
--Phone: (800) FDA-1088

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Flu Season is Tea Time

/PRNewswire/ -- January is National Hot Tea Month and is also the height of the dreaded "cold and flu season". The CDC estimates that there will be more than 200,000 Americans affected by the cold and flu this year, which leads to missing work, school and even social gatherings. So what can one do to avoid the cold and flu?

The CDC strongly recommends an annual flu vaccine as the best way to reduce the chances that you will get the flu. In addition, drinking hot tea may also help you stay healthy during the cold and flu season.

Published research from Brigham and Women's Hospital and Harvard University indicates that theanine, an ingredient found naturally in tea, supports the immune system. A cup of tea contains an average of 20-25 mg of theanine. Drinking tea throughout the day may strengthen the immune system which is something important to do during the cold and flu season.

Drinking five cups of Black Tea a day for two to four weeks boosted the body's immune defense system by four times, according to the results of a human clinical trial. According to this study, the data suggests that drinking Black Tea boost's the body's natural resistance to infection.(1)

Tea also contains flavonoids, which are naturally occurring compounds known for their antioxidant properties. Antioxidants work to neutralize free radicals, which scientists believe damage elements in the body, such as genetic material and lipids, and contribute to many chronic diseases.

The CDC states that healthy adults have a 30% chance of contracting the flu even with an annual flu vaccination, and the vaccine may be somewhat less effective for children and the elderly. And while drinking tea may not keep you from getting sick this season, it can help your odds of staying healthy.

So why not do something good for your body while having a hot beverage ... help stay healthy this cold and flu season and drink your tea every day! For more information about the role of tea in a healthy diet and lifestyle, please visit www.TeaUSA.org.

(1) Kamath AB, Wang L, Das H, Li L, Reinhold VN, Bukowski JF. Antigens in tea-beverage prime human Vgamma 2Vdelta 2 T cells in vitro and in vivo for memory and nonmemory antibacterial cytokine responses. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6009-14. Epub 2003 Apr 28.

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Drinking Milk to Ease Milk Allergy?

HHH Note: This study is promising. It does, however, come with the warning NOT to try this at home.

Giving children with milk allergies increasingly higher doses of milk over time may ease, and even help them completely overcome, their allergic reactions, according to the results of a study led by the Johns Hopkins Children’s Center and conducted jointly with Duke University.

Despite the small number of patients in the trial – 19 – the findings are illuminating and encouraging, investigators say, because this is the first-ever double-blinded and placebo-controlled study of milk immunotherapy. In the study, the researchers compared a group of children receiving milk powder to a group of children receiving placebo identical in appearance and taste to real milk powder. Neither the patients nor the investigators knew which child received which powder, a rigorous research setup that minimizes the chance for error and bias.

The findings of the study are reported online ahead of print, Oct. 28, in the Journal of Allergy & Clinical Immunology

“Our findings suggest that oral immunotherapy gradually retrains the immune system to completely disregard or to better tolerate the allergens in milk that previously caused allergic reactions,” says Robert Wood, M.D., senior investigator on the study and director of Allergy & Immunology at Hopkins Children’s. “Albeit preliminary and requiring further study, these results suggest that oral immunotherapy may be the closest thing yet to a ‘true’ treatment for food allergy.”

Currently, food allergy management involves complete avoidance of the trigger foods, waiting for the child to outgrow the allergy or treating allergic reactions if and when they occur. The latter could be dangerous, investigators say, because these common foods are difficult to avoid and some reactions can be severe and even life-threatening.

In a report released Oct. 22, the Centers for Disease Control and Prevention estimates that food allergies are on the rise with three million children in the United States now having at least one food allergy, an 18 percent jump from 10 years ago. Milk allergy is the most prevalent type of food allergy.

“Given that the quality of life of a child with a food allergy is comparable to the quality of life of a child with diabetes, we urgently need therapies that go beyond strict food avoidance or waiting for the child to outgrow the allergy,” Wood says.

Researchers followed allergic reactions over four months among 19 children with severe and persistent milk allergy, 6 to 17 years of age. Of the 19 patients, 12 received progressively higher doses of milk protein, and seven received placebo. At the beginning of the study, the children were able to tolerate on average only 40 mg (.04 ounces or a quarter of a teaspoon) of milk.

At the end of the four-month study, both groups were given milk powder as a “challenge” to see what dose would cause reaction after the treatment. The children who had been receiving increasingly higher doses of milk protein over a few months were able to tolerate a median dose of 5, 140 mg (over 5 ounces) of milk without having any allergic reaction or with mild symptoms, such as mouth itching and minor abdominal discomfort. Those who had been getting the placebo remained unable to tolerate doses higher than the 40 mg of milk powder without having an allergic reaction. In the group receiving milk protein, the lowest tolerance dose was 2, 540 mg (2.5 ounces) and the highest was 8,140 mg (8 ounces). Lab tests showed the children who regularly drank or ate milk had more antibodies to milk in their blood, yet were able to better tolerate milk than those who took the placebo. Researchers say, tolerance in children treated with milk continued to build over time, and recommend that these children continue to consume milk daily to maintain their resistance. The researchers caution that it remains unclear whether the children would maintain their tolerance once they stop consuming milk regularly. “It may very well be that this tolerance is lost once the immune system is no longer exposed to the allergen daily,” Wood says.

The Hopkins group is currently studying oral immunotherapy in children with egg allergy to determine whether increasingly higher doses of egg protein can help resolve their allergy, and have recently started another study of milk immunotherapy.

Wood emphasizes the findings require further research and advises parents and caregivers not to try oral immunotherapy without medical supervision.

Other Hopkins investigators in the study: Justin Skripak, M.D., Hannah Rowley, R.D., Nga Brereton, R.D., Susan Oh, R.D., Robert Hamilton, M.D., Elizabeth Matsui, M.D. M.H.S.

Duke University co-investigators: Scott Nash, M.D., and A. Wesley Burks, M.D.

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

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