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Posts Tagged ‘immunology

How Smoking Encourages Infection

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Smokers are often more prone to bacterial infections and inflammatory diseases than the rest of us, thanks to hundreds of toxic components in their cigarettes. Next to dry and irritated mucosal linings in mouth and respiratory system due to smoke and nicotine, now new research shows that nicotine affects neutrophils, the short-lived white blood cells that defend against infection, by reducing their ability to seek and destroy bacteria.

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Neutrophils are generated by our bone marrow, which they leave as terminally differentiated cells. Although nicotine is known to affect neutrophils, there has been no study until now of the mechanisms at work when nicotine is present during neutrophil differentiation. David Scott from the Oral Health and Systemic Disease Research Group at the University of Louisville School of Dentistry, Kentucky, USA, along with a team of international colleagues decided to investigate how nicotine influenced the differentiation process.

The authors suggest the processes they observed as contributing to impaired neutrophil function partially explain chronic tobacco users’ increased susceptibility to bacterial infection and inflammatory diseases. A better understanding of this relationship could pave the way for specific therapeutic strategies to treat a number of important tobacco-associated inflammatory diseases and conditions.

The team modeled the neutrophil differentiation process beginning with promyelocytic HL-60 cells, which differentiated into neutrophils following dimethylsulfoxide (DMSO) treatment both with and without nicotine. The researchers found that nicotine increased the percentage of cells in late differentiation phases (metamyelocytes, banded neutrophils and segmented neutrophils) compared to DMSO alone, but did not affect other neutrophil differentiation markers that they examined.

However, the nicotine treated neutrophils were less able to seek and destroy bacteria than nicotine-free neutrophils. The nicotine suppressed the oxidative burst in HL-60 cells, a function that helps kill invading bacteria. Nicotine also increased MMP-9 release, a factor involved in tissue degradation.

BMC Cell Biol. 2008 Apr 15;9(1):19 [Epub ahead of print]
The influence of nicotine on granulocytic differentiation – inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release.

ABSTRACT: BACKGROUND: Neutrophils leave the bone marrow as terminally differentiated cells, yet little is known of the influence of nicotine or other tobacco smoke components on neutrophil differentiation. Therefore, promyelocytic HL-60 cells were differentiated into neutrophils using dimethylsulfoxide in the presence and absence of nicotine (3-(1-methyl-2-pyrrolidinyl) pyridine). Differentiation was evaluated over 5 days by monitoring terminal differentiation markers (CD11b expression and formazan deposition); cell viability, growth phase, kinetics, and apoptosis; assessing cellular morphology and ultrastructure; and conformational changes to major cellular components. Key neutrophil effector functions (oxidative burst, bacterial killing, matrix metalloproteinase release) were also examined. Results: Nicotine increased the percentage of cells in late differentiation phases (metamyelocytes, banded neutrophils and segmented neutrophils) compared to DMSO alone (p < 0.05), but did not affect any other marker of neutrophil differentiation examined. However, nicotine exposure during differentiation suppressed the oxidative burst in HL-60 cells (p < 0.001); inhibited bacterial killing (p < 0.01); and increased the LPS-induced release of MMP-9, but not MMP-2 (p < 0.05). These phenomena may be alpha-7-acetylcholine nicotinic receptor-dependent. Furthermore, smokers exhibited an increased MMP-9 burden compared to non-smokers in vivo (p < 0.05). Conclusions: These findings may partially explain the known increase in susceptibility to bacterial infection and neutrophil-associated destructive inflammatory diseases in individuals chronically exposed to nicotine.

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Written by huehueteotl

April 18, 2008 at 8:56 am

Immune System Needs Food To Function Well

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Researchers studying deer mice have discovered evidence to support what mothers everywhere have long suspected: the immune system needs food to function properly. In a new study Lynn Martin and coauthors find that reduced food intake leads to a decline in immune function in their subjects. The findings could have profound implications for human health.

Immune System Overview

Why immune activity is variable in many wild animals is a question that has long puzzled researchers. “Animals live different lifestyles, so they may use different types of defenses against infection depending on the situation. Perhaps this is why immune defenses vary seasonally in most species; some may be too expensive to use all the time,” Martin said, referring to previous work on Peromyscus and other small mammals and birds.

While it is known that the immune system expends energy when it gears up to fight a virus or an infection–a fever, for example–the researchers found that restricting their subjects’ diet by 30% significantly decreased the amount of available B cells, which produce antibodies and maintain immune memory. Without these cells, the immune system must relearn how to fight a threat if it reappears.

Research on the relationship between food and the immune system could have profound implications for humans. Martin and fellow researchers cite previous studies that have found that infections are “more frequent and tend to be chronic in malnourished children.” Vaccines, in order to work effectively, must provoke B cells to produce sufficient antibodies for immune memory.

Previous studies have found that vaccines such as those for measles have a significantly lower rate of efficacy among the malnourished. “A 30% restriction in food intake doesn’t affect body mass and only minimally reduces activity in deer mice, but it eliminates the long-term immune protection provided by antibodies. One wonders whether similar moderate food restriction has comparable immune effects in humans,” Martin asked. Although other variables may be at work, the authors propose that for both wild animals and humans, food availability impinges on immunity and future research should determine what specific components of a diet (calories, protein, micronutrients) are responsible.

Physiological and Biochemical Zoology. Volume 81, Issue 3, Page 366–372, May 2008

Food Restriction Compromises Immune Memory in Deer Mice (Peromyscus maniculatus) by Reducing Spleen‐Derived Antibody‐Producing B Cell Numbers

Lynn B. Martin II, Kristen J. Navara, Michael T. Bailey, Chelsea R. Hutch, Nicole D. Powell, John F. Sheridan, and Randy J. Nelson

Abstract

Immune activity is variable in many wild animals, despite presumed strong selection against immune incompetence. Much variation may be due to changes in prevalence and abundance of pathogens (and/or their vectors) in time and space, but the costs of immune defenses themselves may also be important. Induction of immune activity often increases energy and protein expenditure, sometimes to the point of compromising fitness. Whether immune defenses are expensive to maintain once they are generated, however, is less well appreciated. If so, organisms would face persistent challenges of allocating resources between immunity and other expensive physiological processes, which would mandate trade-offs. Mild food restriction (70% ad lib. diet) reduces secondary antibody responses in deer mice (Peromyscus maniculatus), functionally representing a cost of immune memory. In this study, we asked whether compromised immune memory was mediated by a decrease in size of the B cell population responsible for producing antibodies (i.e., spleen-derived B lymphocytes producing immunoglobulin G [IgG]). Two weeks of food restriction reduced total splenocytes, total splenic B lymphocytes (B220+ cells), and splenic B lymphocytes producing IgG (B220+/IgG+ cells) but did not affect body mass or two circulating antibody subclasses (IgG1 and IgG2a) in deer mice. These results further indicate that maintenance of immune memory is expensive and may be subject to trade-offs with other physiological processes.

Written by huehueteotl

April 4, 2008 at 8:23 pm

Neural Progenitor Cells As Reservoirs For HIV In The Brain

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Impaired brain function is a prominent and still unsolved problem in AIDS. Shortly after an individual becomes infected with HIV, the virus can invade the brain and persist in this organ for life. Many HIV-infected individuals experience disturbances in memory functions and movement, which can progress to serious dementia. How the virus causes brain disease is still unclear.


HI-Virus leaving a cell. (Credit: NIH)

Dr. Ruth Brack-Werner and her team at the Institute of Virology of the German Research Center for Environmental Health previously demonstrated that HIV invades not only brain macrophages but also astrocytes. Astrocytes are the most abundant cells in the brain. They perform many important activities which support functions of nerve cells and protect them from harmful agents. HIV-infected astrocytes normally restrain the virus and prevent its production. However, various factors can cause astrocytes to lose control over the virus, allowing the virus to replicate and to reach the brain. There HIV can infect other brain cells as well as immune cells that patrol the brain and may carry the virus outside the brain.

Thus astrocytes form a reservoir for HIV in infected individuals and represent a serious obstacle to elimination of the virus from infected individuals. Whether this also applies to other types of brain cells was unclear until now. In a study recently published in AIDS, Dr. Brack Werner, together with Ina Rothenaigner and colleagues present data indicating that neural progenitor cells can also form HIV reservoirs in the brain. Neural progenitor cells are capable of developing into different types of brain cells and have an enormous potential for repair processes in the brain.

Dr. Brack-Werner’s team used a multi-potent neural progenitor cell line, which can be grown and developed to different types of brain cells in the laboratory, for their studies. After exposing these neural progenitor cells to HIV, they examined the cultures for signs of virus infection for 115 days. HIV was found to persist in these cultures during the entire observation period.

The cultures released infectious HIV particles for over 60 days and contained information for production of HIV regulatory proteins- Tat, Rev and Nef- for even longer. Dr. Brack-Werner and her team also examined neural progenitor cell populations cells with persisting HIV for differences from uninfected cells. They found that HIV persistence had an influence on the expression of selected genes and on cell morphology, but did not prevent their development to astrocytes. Thus HIV persistence has the potential to change neural progenitor cells.

Dr. Brack-Werner’s summarizes, “Our study indicates that neural progenitor cells are potential reservoirs for HIV and that HIV persistence has the potential to change the biology of these cells.” In future studies the researchers are planning to investigate the influence of HIV infection on important functions of neural progenitor cells. These include migration to diseased regions of the brain and development of different types of brain cells. Subsequently they will investigate how HIV changes neural progenitor cells and, importantly, how to protect neural progenitor cells from harmful effects of the virus in HIV infected individuals.

AIDS. 2007 Nov 12;21(17):2271-81.
Long-term HIV-1 infection of neural progenitor populations.
Rothenaigner I, Kramer S, Ziegler M, Wolff H, Kleinschmidt A, Brack-Werner R.

GSF–National Research Center for Environment and Health, Institute of Molecular Virology, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.

BACKGROUND: HIV can reside in the brain for many years. While astrocytes are known to tolerate long-term HIV infection, the potential of other neural cell types to harbour HIV is unclear. OBJECTIVE: To investigate whether HIV can persist in neural progenitor cell populations. DESIGN: A multipotent human neural stem cell line (HNSC.100) was used to compare HIV infection in neural progenitor and astrocyte cell populations. METHODS: Expression of cellular genes/proteins was analysed by real-time reverse transcriptase PCR, Western blot, immunocytochemistry and flow cytometry. Morphological properties of cells were measured by quantitative fluorescent image analysis. Virus release by cells exposed to HIV-1IIIB was monitored by enzyme-linked immunosorbent assay for Gag. Proviral copy numbers were determined by real-time PCR and early HIV transcripts by reverse transcriptase PCR. Rev activity was determined with a fluorescent-based reporter assay. RESULTS: Progenitor populations differed from astrocyte populations by showing much lower glial fibrillary acidic protein (GFAP) production, higher cell-surface expression of the CXCR4 chemokine receptor, higher Rev activity and distinct cell morphologies. HIV-exposed progenitor cultures released moderate amounts of virus for over 2 months and continued to display cell-associated HIV markers (proviral DNA, early HIV transcripts) during the entire observation period (115 days). Differentiation of HIV-infected progenitor cells to astrocytes was associated with transient activation of virus production. Long-term HIV infection of progenitor populations led to upregulation of GFAP and changes in cell morphology. CONCLUSION: These studies suggest that neural progenitor populations can contribute to the reservoir for HIV in the brain and undergo changes as a consequence of HIV persistence.

Written by huehueteotl

March 7, 2008 at 12:56 pm

Posted in HIV

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Aromatherapy Feels Good, But It Won’t Make You Well

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Bach is better than sex – applies to the composer rather than the inventor of the same named flowers. One of the most comprehensive investigations done to date on aromatherapy failed to show any improvement in either immune status, wound healing or pain control among people exposed to two often-touted scents.

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While one of two popular aromas touted by alternative medicine practitioners – lemon – did appear to enhance moods positively among study subjects, the other – lavender – had no effect on reported mood, based on three psychological tests.

Neither lemon nor lavender showed any enhancement of the subjects’ immune status, nor did the compounds mitigate either pain or stress, based on a host of biochemical markers. In some cases, even distilled water showed a more positive effect than lavender.

The study, published online in the journal Psychoneuroendocrinology, looked for evidence that such aromas go beyond increasing pleasure and actually have a positive medical impact on a person’s health.  While a massive commercial industry has embraced this notion in recent decades, little, if any, scientific proof has been offered supporting the products’ health claims.

“We all know that the placebo effect can have a very strong impact on a person’s health but beyond that, we wanted to see if these aromatic essential oils actually improved human health in some measurable way,” explained Janice Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State University and lead author of the study.

The researchers chose lemon and lavender since they were two of the most popular scents tied to aromatherapy.  Recently, two other studies focused on these same two scents.

For the study, Kiecolt-Glaser; Ronald Glaser, a professor of molecular virology, immunology and medical genetics, and William Malarkey, professor of internal medicine, assembled a group of 56 healthy volunteers.  These men and women were screened beforehand to confirm their ability to detect standard odors.  Some were proponents of the merits of aromatherapy while others expressed no opinion on its use.

Each person took part in three half-day sessions where they were exposed to both scents.  Participants were monitored for blood pressure and heart rate during the experiments, and the researchers took regular blood samples from each volunteer.

Researchers taped cotton balls laced with either lemon oil, lavender oil or distilled water below the volunteers’ noses for the duration of the tests.

The researchers tested volunteers’ ability to heal by using a standard test where tape is applied and removed repeatedly on a specific skin site.  The scientists also tested volunteers’ reaction to pain by immersing their feet in 32-degree F water.

Lastly, volunteers were asked to fill out three standard psychological tests to gauge mood and stress three times during each session.   They also were asked to record a two-minute reaction to the experience which was later analyzed to gauge positive or negative emotional-word use.

The blood samples were later analyzed for changes in several distinct biochemical markers that would signal affects on both the immune and endocrine system.  Levels of both Interleukin-6 and Interleukin-10 – two cytokines – were checked, as were stress hormones such as cortisol, norepinephrine and other catacholomines.

While lemon oil showed a clear mood enhancement, lavender oil did not, the researchers said.  Neither smell had any positive impact on any of the biochemical markers for stress, pain control or wound healing.

“This is probably the most comprehensive study ever done in this area, but the human body is infinitely complex,” explained Malarkey.  “If an individual patient uses these oils and feels better, there’s no way we can prove it doesn’t improve that person’s health.

“But we still failed to find any quantitative indication that these oils provide any physiological effect for people in general.”

The wound healing experiments measured how fast the skin could repair itself, Glaser said.  “Keep in mind that a lot of things have to take place for that healing process to succeed.  We measured a lot of complex physiological interactions instead of just a single marker, and still we saw no positive effect,” he said.

The project was supported in part by the National Center for Complementary and Alternative Medicine at the National Institutes of Health.  Kiecolt-Glaser, Glaser and Malarkey are all members of Ohio State’s Institute for Behavioral Medicine Research.

Psychoneuroendocrinology. 2008 Apr;33(3):328-39.
Olfactory influences on mood and autonomic, endocrine, and immune function.

Department of Psychiatry, The Ohio State University, 1670 Upham Drive, Columbus, OH 43210, USA; The Ohio State Institute for Behavioral Medicine Research, 2175 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.

Despite aromatherapy’s popularity, efficacy data are scant, and potential mechanisms are controversial. This randomized controlled trial examined the psychological, autonomic, endocrine, and immune consequences of one purported relaxant odor (lavender), one stimulant odor (lemon), and a no-odor control (water), before and after a stressor (cold pressor); 56 healthy men and women were exposed to each of the odors during three separate visits. To assess the effects of expectancies, participants randomized to the “blind” condition were given no information about the odors they would smell; “primed” individuals were told what odors they would smell during the session, and what changes to expect. Experimenters were blind. Self-report and unobtrusive mood measures provided robust evidence that lemon oil reliably enhances positive mood compared to water and lavender regardless of expectancies or previous use of aromatherapy. Moreover, norepinephrine levels following the cold pressor remained elevated when subjects smelled lemon, compared to water or lavender. DTH responses to Candida were larger following inhalation of water than lemon or lavender. Odors did not reliably alter IL-6 and IL-10 production, salivary cortisol, heart rate or blood pressure, skin barrier repair following tape stripping, or pain ratings following the cold pressor.

Written by huehueteotl

March 5, 2008 at 1:25 pm

HIV Breakthrough: Protein That Fights Immunodeficiency Identified

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A Canada-U.S. research team has solved a major genetic mystery: How a protein in some people’s DNA guards them against killer immune diseases such as HIV. In an advance online edition of Nature Medicine, the scientists explain how the protein, FOX03a, shields against viral attacks and how the discovery will help in the development of a HIV vaccine.

 

Computer model of AIDS virus (HIV). (Credit: Produced by Richard Feldmann; courtesy of NIH/National Institute of Allergy and Infectious Diseases)

“HIV infection is characterised by the slow demise of T-cells, in particular central memory cells, which can mediate lifelong protection against viruses,” said lead researcher Rafick-Pierre Sékaly, a Université de Montréal professor and a researcher at the Centre Hospitalier de l’Université de Montréal and the French Institut national de la santé et de la recherche médicale (Inserm).

“Our group has found how the key protein, FOX03a, is vital to the survival of central memory cells that are defective in HIV-infected individuals even if they are treated,” added Dr. Sékaly, who produced his study with CHUM and Inserm colleagues including Elias El Haddad and Julien van Grevenynghe. Collaborators also included Jean-Pierre Routy, a McGill University Health Centre researcher and professor at McGill University and Robert S. Balderas, Vice-President of Research and Development at BD Biosciences of San Diego, CA.

Public support for the research came through Genome Canada and Génome Québec, among others, while private contributions came via a segment of BD (Becton, Dickinson and Company). “Public-private collaborations such as this play an important role in advancing medical research,” Robert S. Balderas. “BD Biosciences was pleased to provide powerful research instruments, reagents and technical expertise to support this breakthrough research.”

The breakthrough emerged by studying three groups of men: One HIV-negative sample, a second HIV-positive group whose infection was successfully controlled through tritherapy and a third group whose HIV did not show any symptoms. Called elite controllers, this third group fended off infection without treatment because their immune system, which would normally be attacked by HIV, maintained its resilient immune memory through the regulation of the FOX03a protein.

“Given their perfect resistance to HIV infection, elite controllers represent the ideal study group to examine how proteins are responsible for the maintenance of an immune system with good anti-viral memory,” said Dr. Haddad. “This is the first study to examine, in people rather than animals, what shields the body’s immune system from infection and to pinpoint the fundamental role of FOX03a in defending the body.”

Beyond HIV treatment, Dr. Sékaly said his team’s discovery offers promise for other immune diseases. “The discovery of FOX03a will enable scientists to develop appropriate therapies for other viral diseases that weaken the immune system,” he said, citing cancer, rheumatoid arthritis, hepatitis C, as well as organ or bone marrow transplant rejection.

Paul L’Archevêque, president and CEO of Génome Québec, lauded Dr. Sékaly’s team for their breakthrough and the people who volunteered for the study. “This discovery, the first such study in humans, is a major step forward in the understanding of how our immune system responds to life-threatening infections such as HIV. This advance stems directly from research co-financed by Génome Québec, which demonstrates the impact that genomic research can have in improving healthcare.”

This research was made possible by public and private institutions across Canada, the United States and France: the Université de Montréal, CHUM, Inserm, MUHC, Genome Canada, Génome Québec, Fonds de la recherche en santé du Québec, Canadian Institutes of Health Research, National Institutes of Health and BD Biosciences.

 

Nature Medicine Published online: 2 March 2008 | doi:10.1038/nm1728
Transcription factor FOXO3a controls the persistence of memory CD4+ T cells during HIV infection

Julien van Grevenynghe, Francesco A Procopio, Zhong He, Nicolas Chomont, Catherine Riou, Yuwei Zhang, Sylvain Gimmig, Genevieve Boucher, Peter Wilkinson, Yu Shi, Bader Yassine-Diab, Elias A Said, Lydie Trautmann, Mohamed El Far, Robert S Balderas, Mohamed-Rachid Boulassel, Jean-Pierre Routy, Elias K Haddad & Rafick-Pierre Sekaly

The persistence of central memory CD4+ T cells (TCM cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of TCM cell decline predicts HIV disease progression. In this study, we show that TCM cells and effector memory CD4+ T cells (TEM cells) from HIV+ elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to TCM and TEM cells from aviremic successfully treated (ST) subjects or from HIV donors. We show that persistence of TCM cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of TCM cells from ST subjects to a length of time similar to that of TCM cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.

Written by huehueteotl

March 4, 2008 at 4:33 pm

Gene Can Block The Spread Of HIV

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A team of researchers at the University of Alberta has discovered a gene that is able to block HIV, and in turn prevent the onset of AIDS. Stephen Barr, a molecular virologist in the Department of Medical Microbiology and Immunology, says his team has identified a gene called TRIM22 that can block HIV infection in a cell culture by preventing the assembly of the virus.

“When we put this gene in cells, it prevents the assembly of the HIV virus,” said Barr, a postdoctoral fellow. “This means the virus cannot get out of the cells to infect other cells, thereby blocking the spread of the virus.”

Barr and his team also prevented cells from turning on TRIM22 – provoking an interesting phenomenon: the normal response of interferon, a protein that co-ordinates attacks against viral infections, became useless at blocking HIV infection.

“This means that TRIM22 is an essential part of our body’s ability to fight off HIV. The results are very exciting because they show that our bodies have a gene that is capable of stopping the spread of HIV.”

One of the greatest challenges in battling HIV is the virus’ ability to mutate and evade medications. Antiretroviral drugs introduced during the late 1990s interfere with HIV’s ability to produce new copies of itself – and even they are beneficial, the drugs are unable to eradicate the virus. Barr and his team have discovered a gene that could potentially do the job naturally.

“There are always newly emerging drug-resistant strains of HIV so the push has been to develop more natural means of blocking the virus. The discovery of this gene, which is natural in our cells, might provide a different avenue,” said Barr. “The gene prevents the assembly of the virus so in the future the idea would be to develop drugs or vaccines that can mimic the effects of this gene.”

“We are currently trying to figure out why this gene does not work in people infected with HIV and if there is a way to turn this gene on in those individuals,” he added. “We hope that our research will lead to the design of new drugs, or vaccines that can halt the person-to-person transmission of HIV and the spread of the virus in the body, thereby blocking the onset of AIDS.”

The researchers are now investigating the gene’s ability to battle other viruses.

The Interferon Response Inhibits HIV Particle Production by Induction of TRIM22.

Barr SD, Smiley JR, Bushman FD (2008)

Abstract

Treatment of human cells with Type 1 interferons restricts HIV replication. Here we report that the tripartite motif protein TRIM22 is a key mediator. We used transcriptional profiling to identify cellular genes that were induced by interferon treatment and identified TRIM22 as one of the most strongly up-regulated genes. We confirmed, as in previous studies, that TRIM22 over-expression inhibited HIV replication. To assess the role of TRIM22 expressed under natural inducing conditions, we compared the effects of interferon in cells depleted for TRIM22 using RNAi and found that HIV particle release was significantly increased in the knockdown, implying that TRIM22 acts as a natural antiviral effector. Further studies showed that TRIM22 inhibited budding of virus-like particles containing Gag only, indicating that Gag was the target of TRIM22. TRIM22 did not block the release of MLV or EIAV Gag particles. Inhibition was associated with diffuse cytoplasmic staining of HIV Gag rather than accumulation at the plasma membrane, suggesting TRIM22 disrupts proper trafficking. Mutational analyses of TRIM22 showed that the catalytic amino acids Cys15 and Cys18 of the RING domain are required for TRIM22 antiviral activity. These data disclose a pathway by which Type 1 interferons obstruct HIV replication.

Written by huehueteotl

March 3, 2008 at 4:02 pm

Posted in HIV

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Dramatic Boost To Immune Response With Engineered Artificial ‘Cells’

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Using artificial cell-like particles, Yale biomedical engineers have devised a rapid and efficient way to produce a 45-fold enhancement of T cell activation and expansion, an immune response important for a patient’s ability to fight cancer and infectious diseases, according to an advance on line report in Molecular Therapy.

Stimulatory particles (red) bound to activated T-cells (blue) as seen by fluorescence microscopy. Scale bar = 10 µm (Credit: Fahmy-Steenblock/Yale)

The artificial cells, developed by Tarek Fahmy, assistant professor of biomedical engineering at Yale and his graduate student Erin Steenblock, are made of a material commonly used for biodegradable sutures. The authors say that the new method is the first “off-the-shelf” antigen-presenting artificial cell that can be tuned to target a specific disease or infection.

“This procedure is likely to make it to the clinic rapidly,” said senior author Fahmy. “All of the materials we use are natural, biodegradable already have FDA approval.”

Cancer, viral infections and autoimmune diseases have responded to immunotherapy that boosts a patient’s own antigen-specific T cells. In those previous procedures, a patient’s immune cells were harvested and then exposed to cells that stimulate the activation and proliferation of antigen-specific T-cells. The “boosted” immune cells were then infused back into the patient to attack the disease.

Limitations of these procedures include costly and tedious custom isolation of cells for individual patients and the risk of adverse reaction to foreign cells, according to the Yale researchers. They also pointed to difficulty in obtaining and maintaining sufficient numbers of activated T-cells for effective therapeutic response.

In the new system, the outer surface of each particle is covered in universal adaptor molecules that serve as attachment points for antigens — molecules that activate the patient’s T-cells to recognize and fight off the targeted disease — and for stimulatory molecules. Inside of each particle, there are slowly released cytokines that further stimulate the activated T-cells to proliferate to as much as 45 times their original number.

“Our process introduces several important improvements,” said lead author Steenblock. “First, the universal surface adaptors allow us to add a span of targeting antigen and co-stimulatory molecules. We can also create a sustained release of encapsulated cytokines. These enhancements mimic the natural binding and signaling events that lead to T-cell proliferation in the body. It also causes a fast and effective stimulation of the patient’s T-cells — particularly T-cells of the cytotoxic type important for eradicating cancer.”

“Safe and efficient T-cell stimulation and proliferation in response to specific antigens is a goal of immunotherapy against infectious disease and cancer,” said Fahmy. “Our ability to manipulate this response so rapidly and naturally with an “off the shelf” reproducible biomaterial is a big step forward.”

Fahmy was recently awarded a five-year National Science Foundation (NSF) Career Award for work on this process and ways of engineering biomaterials to manipulate immune responses to fight cancer and other diseases. His approach incorporates signals important for T-cell stimulation in biocompatible polymer particulates, and integrates all the signals needed for efficient T-cell stimulation.

According to the NSF, devices as such these offer ease and flexibility in targeting different types of T-cells, and is expected to lead to state of the art improvements in the preparation of a new generation of therapeutic systems.

 

Molecular Therapy (2008); doi:10.1038/mt.2008.8

Mechanisms of Immunization Against Cancer Using Chimeric Antigens

Manuel E Engelhorn1, José A Guevara-Patiño2, Taha Merghoub1, Cailian Liu1, Cristina R Ferrone3, Gabriele A Rizzuto1, Daniel H Cymerman1, David N Posnett1, Alan N Houghton1 and Jedd D Wolchok1

  1. 1The Swim Across America Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  2. 2Section of Surgery and Committee on Immunology, University of Chicago, Chicago, Illinois, USA
  3. 3Division of General Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Jedd D Wolchok, Melanoma-Sarcoma Service, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room Z-1462, New York, New York 10021, USA. E-mail: wolchokj@mskcc.org

Received 29 October 2007; Accepted 28 December 2007; Published online 26 February 2008.

Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy. Here we explore nine different chimeric vaccine designs, in which the antigen of interest is expressed as an in-frame fusion with polypeptides that impact antigen processing or presentation. In DNA immunization experiments in mice, three of nine fusions elevated relevant CD8+ T-cell responses and tumor protection relative to an unfused melanoma antigen. These fusions were: Escherichia coli outer membrane protein A (OmpA), Pseudomonas aeruginosa exotoxin A, and VP22 protein of herpes simplex virus-1. The gains of immunogenicity conferred by the latter two are independent of epitope presentation by major histocompatibility complex class II (MHC II). This finding has positive implications for immunotherapy in individuals with CD4+ T-cell deficiencies. We present evidence that antigen instability is not a sine qua non condition for immunogenicity. Experiments using two additional melanoma antigens identified different optimal fusion partners, thereby indicating that the benefits of fusion vectors remain antigen specific. Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines.

Written by huehueteotl

February 27, 2008 at 10:28 am