Switch that Turns On the Allergic Response in People

A new study in human cells has singled out a molecule that specifically directs immune cells to develop the capability to produce an allergic response. The signaling molecule, called thymic stromal lymphopoietin (TSLP), is key to the development of allergic diseases such as asthma, atopic dermatitis (eczema), and food allergy. The study team, led by Yong-Jun Liu, M.D., Ph.D., at the University of Texas M.D. Anderson Cancer Center, Houston, focused on dendritic cells, immune cells that initiate the primary immune response. Dendritic cells come into contact with other immune cells known as T cells, causing them to develop into different subsets of T cells, including helper 1 (Th1) and helper 2 (Th2) cells. These T-cell subsets are involved in protective immune responses, but the Th2 cells can also drive an allergic response. Until now, it was not known how dendritic cells induced T cells to become Th2 cells. The investigators used dendritic cells isolated from the blood of healthy donors and found that the binding of TSLP to these cells activates a distinct set of signaling pathways within the cells. As a result, the dendritic cells produce messenger molecules that act on the T cells, causing them to develop into Th2 cells. The study identifies TSLP as a switch that causes the development of the allergic response in people and suggests that this molecule may be a potential therapeutic target to treat and prevent allergic diseases. Dr. Liu and his colleagues are supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.  The investigators are with the Asthma and Allergic Diseases Cooperative Research Centers program, now in its fourth decade of continuous funding as the cornerstone of NIAID’s asthma and allergy research portfolio.
ARTICLE:		K Arima et al. Distinct signal codes generate dendritic cell functional plasticity.Science Signaling. DOI: 10.1126/scisignal.2000567 (2010).
WHO:		Marshall Plaut, M.D., Chief, Allergic Mechanisms Section, Asthma, Allergy and Inflammation Branch, NIAID Division of Allergy, Immunology and Transplantation, is available to comment on this article.
CONTACT:		To schedule interviews, please contact Julie Wu, 301-402-1663,niaidnews@niaid.nih.gov.

http://www3.niaid.nih.gov/news/newsreleases/2010/TSLPandAllergy.htm

Virus-Like Particle Vaccine Protects Monkeys from Chikungunya Virus

• An experimental vaccine developed using non-infectious virus-like particles (VLP) has protected macaques and mice against chikungunya virus, a mosquito-borne pathogen that has infected millions of people in Africa and Asia and causes debilitating pain, researchers at the National Institutes of Health have found.
• Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) developed the vaccine because there is no vaccine or treatment for chikungunya virus infection. Details about the vaccine were published today in the online version of Nature Medicine.
• “Increases in global travel and trade, and possibly climate change, may be contributing to the spread of disease-carrying mosquitoes into new areas,” says NIAID Director Anthony S. Fauci, M.D. “Finding safe and effective human vaccines for chikungunya virus and other insect-borne pathogens is an important global health priority.”
• To develop the vaccine, scientists in NIAID's Vaccine Research Center (VRC) identified the proteins that give rise to chikungunya VLPs. The VLPs mimic actual virus particles but cannot cause infection, so they can be used safely as a vaccine to elicit immune responses. The researchers immunized rhesus macaques with the VLPs, waited 15 weeks before exposing the animals to chikungunya virus, and observed that the vaccine provided complete protection from infection.
• When the group found that antibodies were responsible for immune protection, they transferred antibody-containing serum from the vaccinated macaques to mice with deficient immune systems. The mice then were exposed to a lethal dose of chikungunya virus, but the immune serum protected them from infection.
• “This virus-like particle vaccine provides a promising way to protect against an emerging infectious disease threat,” says VRC Director Gary Nabel, M.D., Ph.D. “This same approach could possibly extend to viruses related to chikungunya that cause fatal diseases such as encephalitis.” Dr. Nabel says his group plans to seek approval for clinical trials to further evaluate the safety and efficacy of the vaccine in humans.
• There are two VLP vaccines for other diseases approved by the Food and Drug Administration: one for hepatitis B and one for human papillomavirus. This study marks the first time that scientists have used VLPs in a vaccine to protect against chikungunya virus, which is in the genus Alphavirus. The group plans to determine whether VLPs will work against other alphaviruses, such as Western and Eastern equine encephalitis virus found in the United States and o'nyong-nyong virus found in Africa.
• Investigators from Purdue University, the University of Texas Medical Branch at Galveston, and Bioqual Inc., in Rockville, Md., collaborated with NIAID scientists on this study.
• NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
• The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

http://www.nih.gov/news/health/jan2010/niaid-28.htm

Mutations Contribute to Type of Non-Hodgkin Lymphoma

• Researchers have discovered genetic mutations that may contribute to the development of an aggressive form of non-Hodgkin lymphoma—a cancer of white blood cells. The findings provide insight into a mechanism that cancer cells may use to survive, and highlight potential new treatment targets.
• Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, representing about 30% of newly diagnosed cases. DLBCL originates in B cells, which are antibody-producing immune cells and one of the body's key defense mechanisms. Subtypes of DLBCL vary biologically and differ in how patients respond to chemotherapy. The activated B cell-like (ABC) subtype is the least responsive to currently available therapies.
• Previous research suggested that a process called BCR signaling might contribute to the development of lymphomas. When B cells encounter a piece of a virus or other foreign substance, proteins on the cell surface known as B cell receptors (BCRs) activate a stepwise series of biochemical events—called a signaling pathway—that tells the cell to survive and proliferate. Researchers at NIH's National Cancer Institute (NCI), National Institute for Allergy and Infectious Diseases (NIAID) and National Human Genome Research Institute (NHGRI) and their colleagues set out to explore the role of BCR signaling in ABC subtype lymphomas.
• The researchers reported on January 7, 2010, in Nature that they identified critical points in the BCR signaling pathway that affect the survival of lymphoma cells. Interfering with several components of the pathway caused lymphoma cells to die. Thus, ongoing BCR signaling is necessary for ABC subtype DLBCL cells to survive.
• The team then looked for mutations in genes that encode these signaling pathway components in human DLBCL tumors. About one-fifth of ABC subtype tumors, they found, had a critical mutation in a BCR signaling component known as CD79B. The mutation increased BCR signaling by raising the amount of BCRs on the cell surface and by blocking a process that normally turns off the pathway.
• The team tested dasatinib, a drug that is approved for the treatment of chronic myelogenous leukemia in ABC subtype DLBCL cells. They found that the drug turned off BCR signaling by inhibiting the activity of one of the pathway's components, thereby killing the cells.
• "Our data provide important evidence that BCR signaling plays a crucial role in ABC DLBCL," says study senior author Dr. Louis M. Staudt of NCI. The results suggest new therapeutic opportunities for ABC subtype lymphoma.
• More research will be needed to understand how chronic, active BCR signaling begins. "Tests will also need to be developed that can identify patients with cases of DLBCL that depend on chronic, active BCR signaling, so that we can rationally develop clinical trials with agents that inhibit the BCR pathway," Staudt says.

Related Links:

• Non-Hodgkin Lymphoma:
  http://www.cancer.gov/cancertopics/types/non-hodgkins-lymphoma/
• Coiled Protein Region May Play Role in Non-Hodgkin Lymphoma:
  http://www.nih.gov/researchmatters/march2008/03172008protein.htm
• Gene Activity Can Predict Survival Rates of Patients with Lymphoma:
  http://www.nih.gov/researchmatters/december2008/12082008genelymphoma.htm

http://www.nih.gov/researchmatters/january2010/01252010lymphoma.htm

How Light Boosts Migraine Pain

• Most migraine sufferers know that light can intensify headache pain. A new study of blind patients with migraine may help explain why. The finding ultimately may lead to new approaches for calming severe light-induced headaches.
• More than 1 in 10 people nationwide experience recurring headaches known as migraines. They're often described as a pulsing or throbbing in one side of the head. Other symptoms include nausea, vomiting and extreme sensitivity to sound. Exposure to light often triggers or intensifies the pain, but the underlying mechanism has been unclear.
• To gain a better understanding of light's role, Dr. Rami Burstein of Harvard Medical School and his colleagues evaluated 20 migraine sufferers who were also blind. Six participants were unable to detect any light, either because their optic nerves had been damaged or their eyes removed due to disease. The remaining 14 were unable to perceive images, but their eyes could detect some light, even if they were not aware of it. Their sleep-wake cycles were normal, whereas the other 6 had disrupted sleep patterns. The study was supported by NIH's National Institute of Neurological Disorders and Stroke (NINDS) and by Research to Prevent Blindness.
• As reported in the January 10, 2010, online edition of Nature Neuroscience, the researchers found that light exposure intensified migraine pain in the 14 people with some light detection but not in the remaining 6 who were totally blind. The researchers concluded that the optic nerve, which carries light signals to the brain, must be key to light-induced migraine. But because the 14 had faulty rods and cones—the main light-detecting and image-producing cells in the eye—the scientists suspected that some other type of light-detecting cell must contribute to light-sensitive pain.
• The scientists turned to rats to gain a better sense of the brain pathways that might be involved. They focused on rare light-sensing cells in the eye called intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells, discovered only a decade ago, are crucial for maintaining sleep-wake cycles and for pupil response to light, but play no role in image formation.
• The researchers traced the path of ipRGC signals through rat optic nerves, where they later converged on brain cells that transmit pain. Exposure to light rapidly activated the ipRGCs and the pain-transmitting cells, which previously had been linked to migraine pain. When the light was removed, the brain cells remained activated for several minutes.
• "This helps explain why patients say that their headache intensifies within seconds after exposure to light, and improves 20 to 30 minutes after being in the dark," says Burstein.
• The findings point to a non-imaging-forming pathway for light-induced migraines, although the scientists note that additional mechanisms may be involved. "Clinically, this research sets the stage for identifying ways to block the pathway so that migraine patients can endure light without pain," Burstein says.

—by Vicki Contie

Related Links:

• Eye Cells Are Out of Sight:
  http://www.nih.gov/researchmatters/january2009/01122009eyecells.htm
• What Makes Your Head Hurt?
  http://newsinhealth.nih.gov/2008/June/docs/01features_02.htm
• Migraine Information Page:
  http://www.ninds.nih.gov/disorders/migraine/migraine.htm
• Headache: Hope Through Research:
  http://www.ninds.nih.gov/disorders/headache/detail_headache.htm

http://www.nih.gov/researchmatters/january2010/01252010migraine.htm

Gene Involved in Brittle Bone Disease

• Researchers discovered a third gene that accounts for previously unexplained forms of osteogenesis imperfecta, a genetic condition that weakens bones, results in frequent fractures and is sometimes fatal.
• Osteogenesis imperfecta affects between 20,000 and 50,000 Americans. About 85% of all cases are caused by mutations in the genes needed to make the protein collagen. Collagen functions as a molecular scaffolding that holds together bone, skin and other tissues.
• Dr. Joan Marini at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her colleagues had earlier found that osteogenesis imperfecta could also be caused by defects in the protein complex that modifies collagen before it is secreted from cells to become a part of bone. Mutations in the genes for 2 proteins in this complex—cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1)—could result in severe and sometimes fatal forms of osteogenesis imperfecta.
• The new study involved a collaboration between researchers at NICHD, led by Marini, and at the Hospital for Special Surgery in New York City, led by Dr. Cathleen Raggio. Scientists at the University of Washington in Seattle and NIH's National Institute of Human Genome Research (NHGRI) also took part. Additional support came from other NIH institutes.
• The researchers diagnosed a 12-year-old boy and his 4-year-old sister as having a novel form of osteogenesis imperfecta, as described in the online edition of theNew England Journal of Medicine on January 20, 2010. The children's parents were immigrants from Senegal living in New York. Although the children's bones were brittle and highly susceptible to fracturing, they did not have shortening of the upper portion of limbs seen in children with mutations in CRTAP and P3H1.
• The researchers analyzed the children's DNA and found that they had a mutation in a gene coding for Cyclophilin B that causes a complete lack of the protein. Cyclophilin B is part of the same complex with CRTAP and P3H1. Like the mutations in those genes, the mutation in Cyclophilin B is recessive, requiring 2 defective copies to cause the disorder.
• A previous study found that Cyclophilin B was essential for folding collagen into its final form. Marini and her colleagues, however, discovered that collagen from the 2 children was folded into its usual configuration. Cyclophilin B, then, must not be the only protein to have this role in collagen folding.
• Marini notes that additional research is needed to determine why, despite the seemingly normal collagen folding, the children developed osteogenesis imperfecta.
• "The discovery provides insight into a previously undescribed form of osteogenesis imperfecta," says NICHD Acting Director Dr. Alan E. Guttmacher. "The advance also provides new information on how collagen folds during normal bone formation, which may also lead to greater understanding of other bone disorders."

Related Links:

• Osteogenesis Imperfecta:
  http://health.nih.gov/topic/OsteogenesisImperfecta
• Second Gene Discovered for Form of Brittle Bone Disease:
  http://www.nih.gov/researchmatters/february2007/02192007bone.htm

http://www.nih.gov/researchmatters/january2010/01252010brittlebone.htm

Best Ways to Prevent Mother-to-Child HIV

New Study Examines Best Ways to Prevent Mother-to-Child HIV Transmission and

Preserve Maternal and Infant Health

• An estimated 430,000 children worldwide became infected with HIV in 2008, mostly through birth or breastfeeding from an HIV-infected mother. Many regions of the world are gaining increased access to complex antiretroviral drug regimens for preventing HIV transmission from a mother to her child. However, these strategies have not yet been directly compared with simpler antiretroviral drug regimens in terms of their safety, efficacy, feasibility and cost-effectiveness.
• On January 15, a large, multinational clinical trial began to determine how best to reduce the risk of HIV transmission from infected pregnant women to their babies during pregnancy and breastfeeding while preserving the health of these children and their mothers.
• The PROMISE (“Promoting Maternal-Infant Survival Everywhere”) study aims to enroll 7,950 HIV-infected women who are pregnant or have recently given birth and 5,950 HIV-exposed infants of these women. The participants will come from as many as 18 countries whose levels of resources range from high to low. The International Maternal Pediatric Adolescent AIDS Clinical Trials network is conducting the study with funding from the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, both part of the National Institutes of Health. Led by protocol chair Mary Glenn Fowler, M.D., M.P.H., of the Makerere University–Johns Hopkins University Research Collaboration in Kampala, Uganda, the study team expects results in five to six years.
• The HIV-infected women eligible to participate in PROMISE do not yet qualify for treatment—that is, their CD4+ T cell count, a measure of immune health, exceeds the level (350 cells per cubic millimeter of blood) at which highly active antiretroviral therapy (HAART)  generally is recommended. HAART consists of a potent combination of three or more antiretroviral drugs.
• The study addresses four distinct research questions. Most volunteers will participate in multiple components of the study to answer these questions. The first component will examine which of two proven strategies is safer and more effective at preventing mother-to-child HIV transmission before and during delivery: giving HIV-infected pregnant women a three-antiretroviral-drug regimen beginning as early as 14 weeks of gestation, or giving them the antiretroviral drug zidovudine beginning as early as 14 weeks of pregnancy and a single dose of the antiretroviral drug nevirapine during labor. The regimen of zidovudine and nevirapine is the standard of care in many countries for women who do not yet require treatment for their HIV infection. Some 4,400 women will be assigned at random to receive either one of these two interventions. 
• The second component of the PROMISE study will compare the safety and efficacy of two methods of preventing mother-to-child HIV transmission during breastfeeding. The study team will assign 4,650 mother-infant pairs at random either to receive a daily dose of infant nevirapine or to have the mothers take a three-antiretroviral-drug regimen throughout breastfeeding.
• The third component of the PROMISE study will examine the effects of short-term use of a three-antiretroviral-drug regimen during pregnancy and breastfeeding to prevent mother-to-child HIV transmission on the health of HIV-infected mothers who do not yet need treatment. For such women, it remains unclear whether stopping the three-drug regimen after giving birth or ceasing to breastfeed would compromise their health. Although past studies have shown that interrupting treatment with antiretroviral drugs has a negative effect, the conditions in those studies are different enough from the conditions of the PROMISE study to make extrapolating the results difficult, according to the study investigators.
• The 4,675 women participating in this third component of PROMISE will be assigned at random either to stop the three-antiretroviral-drug regimen after giving birth or weaning, or to continue the drug regimen indefinitely. The health of these two groups will be compared. In addition, the women who receive the time-limited three-drug regimen will be compared with the women who participated in the first component of PROMISE and did not receive the three-drug regimen, but rather took zidovudine during pregnancy and single-dose nevirapine during labor.
• The last component of the PROMISE study involves protecting the health of HIV-exposed but uninfected infants. In resource-limited settings, it is standard to give the antibiotic cotrimoxazole once daily to infants exposed to HIV at birth until the infant has stopped breastfeeding and is known to be HIV-uninfected. While cotrimoxazole prophylaxis improves the survival rate of HIV-infected infants, it is not known whether continuing to administer the drug after weaning similarly would benefit HIV-exposed but uninfected children.
• In this fourth component of the PROMISE study, nearly 2,290 HIV-exposed but uninfected, weaned infants under one year old will be assigned at random either to continue receiving cotrimoxazole or to receive a placebo through age 18 months. Neither the mothers of the infants nor the study team will know which infants are in which group. The study will determine whether continuing cotrimoxazole prophylaxis in HIV-exposed, uninfected infants from the time they stop breastfeeding through age 18 months decreases their risk of illness and death without causing side effects or generating bacterial resistance to cotrimoxizole.

Media inquiries can be directed to the NIAID Office of Communications at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.  For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visithttp://www.nih.gov.

http://www3.niaid.nih.gov/news/newsreleases/2010/PROMISE.htm