HIV Immune

ScienceDaily (Feb. 11, 2010) ? Current research suggests that pandemic H1N1 influenza of swine origin has distinct means of transmission from the seasonal flu, yet does not result in the pathogenic severity of avian flu viruses.

Pandemic H1N1 influenza of swine origin is a novel influenza strain that causes a generally mild respiratory illness, but results in severe disease or death in vulnerable individuals. The World Health Organization reports that “as of 17 January 2010, worldwide more than 209 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including at least 14142 deaths.” High risk groups include the very young and old, people with compromised immune systems, and pregnant women.

Unlike seasonal flu, which only infects cells located in the nose and the throat, pandemic H1N1 can replicate efficiently in cells deeper in the lung, similar to the more pathogenic H5N1 ‘bird flu’. Researchers led by Drs. Michael C.W. Chan and Joseph S.Malik Peiris at Queen Mary Hospital, Hong Kong SAR, China compared the cell infection pattern and immune responses of pandemic H1N1 to seasonal flu as well as to highly pathogenic avian influenza strains. They found that in contrast to seasonal flu, pandemic H1N1 and highly pathogenic avian flu could infect the conjunctiva, a membrane that lines the eyelids and covers the white part of the eye, suggesting an additional route of transmission as well as differences in receptor binding profile. However, pandemic H1N1 did not differ from seasonal flu either in replication in nose, throat, and lung cells or in induction of an inflammatory immune response, which is dysregulated in high pathogenic avian flu infections. Taken together, these results are consistent with epidemiological data that suggest that while pandemic H1N1 has subtle differences in transmissibility and pathogenesis from seasonal flu, it does not induce as severe disease as bird flu viruses.

Chan et al conclude that “the pandemic [H1N1 virus] (but not the seasonal virus) infects conjunctival epithelium, suggest[ing] that the eye may be an important route for acquiring infection with [pandemic H1N1] as compared with seasonal influenza viruses. Furthermore, this observation implies important differences in receptor preference and tissue tropism between the pandemic H1N1 and seasonal influenza viruses, which may have relevance in pathogenesis. … [However,] the 2009 pandemic H1N1 influenza virus is comparable with seasonal influenza in inducing host innate responses and does not have the intrinsic properties of cytokine dysregulation possessed by [the highly pathogenic avian influenza] virus or the 1918 pandemic H1N1 influenza virus.” “While generally mild in the majority of cases, the pandemic H1N1 virus is not just another seasonal flu virus and has subtle peculiarities of its own.” Future studies using host-gene expression profiling of virus infected respiratory cells using microarrays are in progress to further investigate the pathogenesis of this virus.

This work was supported by a Research Fund for Control of Infectious Disease grant (Ref: LAB-15, RFCID commissioned study on human swine influenza virus and RFCID grant, reference no: 06060552, 08070842) from the Research Fund for Control of Infectious Disease, Health, Welfare, and Food Bureau, Hong Kong SAR Government, and the General Research Fund (HKU 7612/08M and 7610/09M to M.C.W.C., HKU 7530/06M to L.L.M.P and HKU 7735/07M to J.M.N), Research Grants Council, Hong Kong SAR Government; Small project funding (reference no: 200907176007 to R.W.Y.C), The University of Hong Kong; National Institutes of Health (NIAID contract HHSN266200700005C) and AoE Funding (AoE/M-12/06) from the Area of Excellence Scheme of the University Grants Committee, Hong Kong SAR Government. This work was also supported by the National Institutes of Health Grant AI59429 and by a grant from the Infectious Disease Science Center.

Adapted from materials provided by American Journal of Pathology, via EurekAlert!, a service of AAAS.

1. Chan et al. Tropism and Innate Host Responses of the 2009 Pandemic H1N1 Influenza Virus in ex Vivo and in Vitro Cultures of Human Conjunctiva and Respiratory Tract. American Journal Of Pathology, 2010; DOI: 10.2353/ajpath.2010.091087

ScienceDaily (Feb. 14, 2010) ? Biologists at UC San Diego have identified the specific region in vertebrates where adult blood stem cells arise during embryonic development.

Their discovery, which appears in a paper in this week’s early online edition of the journal Nature, is a critical first step for the development of safer and more effective stem cell therapies for patients with leukemia, multiple myeloma, anemia and a host of other diseases of the blood or bone marrow.

The researchers say their time-lapse imaging of the process, by which primitive embryonic tissues first produce the parent stem cells that produce all adult blood cells over the life of an individual, should help guide future efforts to repair and replace this cell population for therapeutic purposes.

Current transplantation therapies rely on the infusion of donor stem cells into a patient’s bone marrow to generate new, healthy blood cells without disease. But that procedure is often risky and can result in fatal complications, due in part to “graft-versus-host disease,” in which transplanted cells react against foreign tissues of the recipient. One means of circumventing this immune rejection problem would be to generate hematopoietic stem cells, or HSCs, using the patient’s own precursor cells. Such cells would be perfectly genetically matched, but in order to generate such cells, scientists must first understand the molecular processes that underlie specification of HSCs.

“If we could generate healthy HSCs from patients and transplant them back into their own bone marrow, it would eliminate many complications,” said David Traver, an assistant professor of biology who headed the research team.

“Our findings are an important step toward this goal because they provide a better understanding of how HSCs, the cell type responsible for the clinical benefits of bone marrow transplants, are first specified during development,” he said. “This improved understanding will aid efforts to instruct pluripotent embryonic stem cells (ESCs), the stem cells that can produce all types of tissue-specific stem cells in the body, to make HSCs; something that is not currently possible. In other words, we are one step closer now to understanding how to clinically generate HSCs for cellular replacement therapies from ESCs.”

Traver and his colleagues, who included Julien Bertrand, a postdoctoral fellow in his laboratory, Neil Chi, an assistant professor of medicine at UCSD and Didier Stainier, a professor of biochemistry at UC San Franscisco, made their discoveries in zebrafish, a model laboratory organism for geneticists in which embryos are transparent, allowing the researchers to observe and track individual stem cells with a microscope.

A number of earlier studies using indirect observation had led to the idea that a particular region of the embryo surrounding the dorsal aorta, an early blood vessel, produced the first HSCs, but until now no one had been able to directly visualize the process in living animals.

“Indeed a number of conflicting studies had proposed different or earlier sites of origin, making the exact location where HSCs develop controversial,” said Traver. “Using zebrafish embryos with fluorescently labeled tissues, we were able to demonstrate that HSCs arise directly from cells lining the floor of the dorsal aorta by imaging the process in living embryos.”

The UCSD researchers also documented the stepwise formation of HSCs from “hemogenic” aortic endothelium and showed, by expressing a permanent fluorescent marker in these cells, that all adult blood and immune cell types derive from aortic endothelium of the early embryo.

“Our studies suggest that transition through a hemogenic endothelial intermediate is a requisite step for hematopoietic stem cell formation,” said Traver. “Based upon the high degree of evolutionary similarity in the regulation of HSC formation and later blood maturation in other vertebrates, this finding almost certainly applies to the development of HSCs in humans. These findings should, together with recent breakthroughs in making induced pluripotent stem cells (iPSCs), the functional equivalent of patient-specific ESCs, in principle allow the generation of replacement HSCs from unrelated adult tissues. This would enable repopulation of a patient’s hematopoietic system with his own, disease-free HSCs to avoid immune rejection.”

Other researchers involved in the study included Buyung Santoso and Shutian Teng of UCSD. The study was supported by grants from the National Institutes of Health and the California Institute for Regenerative Medicine.

Adapted from materials provided by University of California – San Diego, via EurekAlert!, a service of AAAS.

ScienceDaily (Feb. 13, 2010) ? As if there are not enough reasons for obese people to lose weight, a new research report published online in The FASEB Journal adds several more. In a study involving rats, researchers from Duke University found that obesity in mothers causes cellular programming in utero that predisposes offspring to inflammation-related disorders (such as Alzheimer’s, Parkinson’s, type 2 diabetes, stroke, heart disease, and more) from the day that they are born, regardless of whether or not the offspring are obese themselves.

“We hope these data will eventually lead to treatments for obesity-associated problems, by the identification of novel targets within the immune system,” said Staci D. Bilbo, Ph.D., co-author of the study, from the Department of Psychology and Neuroscience at Duke University in Durham, N.C. “Our hope is also that these data will lead people to consider the consequences of their dietary intakes not only for their own health, but also for their children’s health, and potentially even their grandchildren’s health.”

To make this discovery, Bilbo and colleagues placed rats on one of three diets (low-fat, high-saturated fat, and high-trans fat) four weeks prior to mating and throughout pregnancy and lactation. The high-fat diets rendered the mice clinically obese. Researchers analyzed the brains of the newborn pups after challenge by inflammatory stimuli. Offspring born to mothers on the high-fat diets showed increased immune cell activation and release of injurious products (cytokines). This overshoot was already apparent on the day after birth. When the scientists continued to analyze the pup brains through their juvenile and adult years, and even after the rats were put on healthy low-fat diets, this hyper-response to inflammation remained dramatically increased compared to rats born to normal-weight mothers.

“If there ever was a maternal hex, obesity might be it,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal, “and as it turns out, even after the weight comes off, the biggest loser isn’t a mother, but her child.”

Adapted from materials provided by Federation of American Societies for Experimental Biology, via EurekAlert!, a service of AAAS.

1. Bilbo et al. Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. The FASEB Journal, 2010; DOI: 10.1096/fj.09-144014

ScienceDaily (Feb. 15, 2010) ? Scientists have discovered a molecular pathway that works through the immune system to regenerate damaged kidney tissues and may lead to new therapies for repairing injury in a number of organs systems.

The findings, reported in this week’s Proceedings of the National Academy of Sciences (PNAS), come from collaborative research led by Cincinnati Children’s Hospital Medical Center and the Brigham & Women’s Hospital of Harvard Medical School.

The study may have significant medical ramifications as currently there are no effective treatments for acute kidney injury — a growing problem in hospitals and clinics, according to the study’s senior co-authors, Richard Lang, Ph.D., a researcher in the divisions of Pediatric Ophthalmology and Developmental Biology at Cincinnati Children’s, and Jeremy Duffield, M.D., Ph.D., a researcher at Brigham and Women’s Hospital. Acute kidney injury is a significant cause of kidney disease, cardiovascular complications and early death, affecting as many as 16 million children and adults in the United States.

The new molecular repair pathway involves white blood cells called macrophages — part of the immune system — that respond to tissue injury by producing a protein called Wnt7b. Scientists identified the macrophage-Wnt7b pathway during experiments in mice with induced kidney injury. Wnt7b is already known to be important to the formation of kidney tissues during embryonic organ development. In this study the scientists found the protein helped initiate tissue repair and regeneration in injured kidneys.

“Our findings suggest that by migrating to the injured kidney and producing Wnt7b, macrophages are re-establishing an early molecular program for organ development that also is beneficial to tissue repair,” said Dr. Lang. “This study also indicates the pathway may be important to tissue regeneration and repair in other organs.”

Wnt7b is part of the Wnt family of proteins, which are known to help regulate cells as they proliferate, grow and become specific cell types for the body. Wnt proteins have also been linked to the regulation of stem cells in bone marrow and skin, which suggested to researchers of the current study that Wnt might have a role in tissue regeneration.

The researchers conducted a number of experiments of kidney injury in mice to identify the repair pathway, finding that:

• Silencing macrophage white blood cells through a process called ablation reduced the response level of Wnt proteins to injured kidney cells.
• Deleting the Wnt7b protein from macrophages diminished normal tissue repair functions in injured kidneys.
• Injecting into the injured kidneys a protein calked Dkk2, which interacts with and is known to help regulate the Wnt pathway during embryonic development, enhanced the macrophage-Wnt7b repair process. It also restored epithelial surface cells that line internal kidney surfaces and suggested a therapeutic potential for the pathway.

Drs. Lang and Duffield said the repair pathway may benefit other injured organs because macrophages act somewhat like a universal emergency responder in the body, rushing to injured tissues wherever damage occurs. Another factor is the central role the Wnt pathway plays in cell regulation and function throughout the body.

Other collaborating institutions in the study include: the Department of Structural Biology , St, Jude Children’s Hospital, Memphis, Tenn.; the departments of Internal Medicine and Molecular Biology, University of Texas Southwest Medical Center; Department of Molecular and Developmental Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y.; Department of Molecular and Cellular Biology, Harvard University; the Visual Systems Group in the division of Pediatric Ophthalmology at Cincinnati Children’s; and the Department of Ophthalmology, University of Cincinnati.

Funding support came from the National Institutes of Health, the American Society of Nephrology Gottschalk Award, the Genzyme Renal Initiatives Program, a National Taiwan Merit Award, and the Abrahamson Pediatric Eye Institute Endowment at Cincinnati Children’s.

Adapted from materials provided by Cincinnati Children’s Hospital Medical Center, via EurekAlert!, a service of AAAS.

ScienceDaily (Mar. 11, 2010) ? Diabetics, under the gun to better manage their disease by controlling their food intake and weight, may find themselves in the sticky wicket of needing treatment that makes them hungry, researchers said.

Attempts to maintain healthy blood sugar levels and prevent weight gain may suggest an eating disorder when the disease and its treatment are to blame, said Dr. Deborah Young-Hyman, pediatric psychologist at the Medical College of Georgia’s Georgia Prevention Institute.

“You can’t use the same criteria to diagnose eating disorders that you use in non-diabetic populations because what we actually prescribe as part of diabetes treatment is part of disordered eating behavior. Food preoccupation is one example,” she said.

Preoccupation with food, in fact, is required for optimal disease management. Questions like “What are you putting in your mouth? Did you know that was going to raise your blood sugar?” are a part of life, Dr. Young-Hyman said. Young women, and increasingly young men, also are not immune from societal pressures to be thin, she noted.

Side-by-side comparisons of young people with and without diabetes are needed to answer fundamentals such as the incidence of eating disorders among diabetics, who is at risk and whether treatment can be modified to reduce the risk, researchers report in a review article in the March issue of Diabetes Care.

Answers could include better methods of insulin delivery and new therapies that address hunger-related hormones, which also become dysregulated in type 1 diabetes.

Dr. Young-Hyman and her colleagues extensively reviewed related literature enabling them to connect the dots between the disordered eating behavior reported by some diabetics with the dysregulation of hunger-related hormones and/or inadequate management of insulin therapy.

In type 1 diabetes, the immune system attacks the insulin producing cells of the pancreas complicating food metabolism. The treatment — insulin by injection or pump — spurs hunger. If the insulin dose isn’t exactly calibrated with food intake, blood sugar levels rise and require more insulin which could drop the blood sugar levels and increase hunger even more.

The cycle of inexact insulin dosing can cause weight gain which increases insulin requirements and resistance.

And there’s another factor at work: the insulin producing-cells attacked by the disease also make amylin which works with other appetite regulating hormones such as leptin to regulate the sensation of fullness. The resulting difficulty of diabetics to determine whether they are full has been documented in anorexia.

Interestingly, most type 1 diabetics lose a lot of weight before diagnosis because they excrete rather than metabolize calories. For a period of months, they may be able to eat large amounts of food and not gain weight. When they start taking insulin to “control” their disease, they can gain a lot of weight quickly. “It’s not hard to see how the treatment of the disease can lead to disordered eating behavior to control weight gain,” Dr. Young-Hyman said.

As a psychologist, Dr. Young-Hyman has treated many type 1 diabetics diagnosed with an eating disorder. In fact, one patient she describes as accomplished, funny and discouraged by her inability to control how much she ate and her subsequent weight gain, helped inspire Dr. Young-Hyman to learn more about eating disorders in patients with diabetes.

The conundrum expressed by this patient can lead, particularly for young women, to unhealthy behavior such as skipping or reducing insulin doses or binging-purging in an effort to avoid weight gain. The behaviors create immediate risks such as hypoglycemia or extreme high blood sugar levels, and are associated with long-term complications of diabetes such as eye, nerve and heart damage.

Controversy persists about whether type 1 patients have increased rates of diagnosable eating disorders or disordered eating behavior; incidence projections range from as low as 3.8 percent to up to 40 percent in young females when skipping or reducing an insulin dose is considered.

“We need to document that these patients are experiencing dysregulation in satiety and that it’s not only connected with factors one usually associates with disordered eating behaviors such as societal pressure, anxiety and depression,” Dr. Young-Hyman said. “It’s also associated with having diabetes.”

Studies that chronicle disordered eating behavior in type 1 diabetics could aid in prevention, including developing potential new treatments, Dr. Young-Hyman said.

She is completing an American Diabetes Association-funded study that might answer some of the questions. She and colleagues at Harvard and Emory universities are following 90 children, age 10-17, newly diagnosed with diabetes or transitioning to an insulin pump. They are documenting pertinent issues such as treatment patterns, weight, psychological adjustment and attitudes about weight and eating, including changes in eating patterns and blood sugar levels in response to insulin dosing.

Adapted from materials provided by Medical College of Georgia.

1. Deborah L. Young-Hyman, Catherine L. Davis. Disordered Eating Behavior in Individuals With Diabetes: Importance of context, evaluation, and classification. Diabetes Care, 2010; 33 (3): 683 DOI: 10.2337/dc08-1077