Archive for the 'Immune System' Category

Are Monoclonal Antibodies A Short-term Therapy For The Long-term Treatment Of Chronic Viral Infections?

June 12th, 2010 -- Posted in Immune System | No Comments »

Monoclonal antibodies are the greatest part prominent class of biotherapeutic drugs. When administered to infected organisms to rough the propagation of pathogenic viruses, they may also induce a long-lasting and affording protection antiviral immune response similar to that achieved through vaccination. These results obtained in mice by the “Oncogen?se et Immunoth?rapie” group at the Institut de G?n?tique Mol?culaire de Montpellier (CNRS/Universit?session Montpellier 1 and 2), be in possession of been published adhering 10 June in PLoS Pathogens. They raise hopes for the handling of indubitable severe and chronic viral infections.

Antibodies (AB) are molecules that are produced by the immune system to defend itself against cancer cells and infective agents. Of these, monoclonal antibodies1 can exist developed and produced at a capacious scale to treat a kind of diseases: cancer, inflammatory or infectious diseases, etc. They thus constitute the largest class of biotherapeutic drugs to age and are being considered with increasing interest on account of the manipulation of acute and chronic viral infections such as HIV (Human Immunodeficiency Virus) or HCV (Hepatitis C Virus), against which current therapies are still unfitted.

Until now, the sole mechanism of operation of antiviral monoclonal antibodies that was really considered by the of the healing art and scientific communities was the neutralization and direct elimination of viruses in infected organisms.

Using a standard of viral leukemia in mice, the “Oncogen?se et Immunoth?rapie” collection at the Institut de G?n?tique Mol?culaire in Montpellier (CNRS/Universit?s Montpellier 1 and 2), headed by Marc Piechaczyk, has recently shown that under the load of never-failing conditions, a very brittle course of treatment (a small in number days) with antiviral monoclonal antibodies can have an adscititious effect similar to that of a vaccine. After three weeks, and even though the injected monoclonal antibodies had disappeared, the researchers indeed detected a potent and long-lasting (more than a year) antiviral immune reply that was sufficient in quest of the mice to forbear death from leukemia.

The team identified an unexpected mechanism enabling the monoclonal antibodies to induce protective antiviral immunity. This machinery is based on their calibre to know again not simply circulating viral particles mete furthermore certain viral proteins expressed at the external part of infected cells. These new tools and materials may help to trigger protective franchise. They should have existence borne in courage by means of the biologists who design and develop curative antiviral monoclonal antibodies.

In mice, a short and early course of curative monoclonal antibodies targeting one as well as the other the viruses and the cells infected by the agency of these viruses in this wise enables permanent recovery from a fatal deep-seated infection. If this annotation be possible to be extrapolated to humans, it will result in a curative benefit not merely for patients but also for company, in that it direct help to significantly reduce the cost of monoclonal antibody therapies, which remains prohibitive in most cases.

1 Monoclonal antibodies are entirely pure antibodies that single recognize one type of antigen. Because of their specificity, which can easily subsist established, they are increasingly root used for therapeutic purposes for the selective havoc of tumor or viral cells and to combat positive inflammatory disease similar as rheumatoid arthritis.

Source: PLoS Pathogens

Gamma Interferon A Wake-Up Call For Stem Cell Response To Infection

June 9th, 2010 -- Posted in Immune System | No Comments »

Most of the time, the corpse’s blood-forming (hematopoietic) stem cells remain latent, with conscientious a few producing blood cells and maintaining a comparison among the different types.

However, invading bacteria can be a call-to-arms, awaking the sleeping stem cells and prompting them to produce immune system cells that battle the foreign organisms. The “bugler” that awakes the stem cells in this contend is gamma interferon, a front-line protein defender against bacterial infection, said researchers from Baylor College of Medicine in a report that appears in the current issue of the diary Nature.

“We are looking at the erect function of pedicel cells,” aforesaid Dr. Margaret Goodell, professor of molecular and sympathetic genetics at BCM and director of the Stem Cells and Regenerative Medicine (STaR) Center. She is the report’s senior author. “One of those is to respond to an infection.”

Goodell and her colleagues knew that cells farther beside in the differentiation process responded to infection, increasing the lengthening of immune cells.

“We were sure in that place was a mechanism by which hematopoietic stem cells respond to infection, mete it was not obvious,” she declared. They started their work with gamma interferon on this account that they knew it played an grave role in bacterial poison.

The collaboration and talents of two researchers in her laboratory – at the outset co-authors Drs. Megan T. Baldridge and Katherine Y. King – facilitated the work with mice that led to this finding, said Goodell. Both are at BCM.

“I suppose our tools and materials represent an exciting just discovered avenue for studying hematopoiesis,” said King. “By viewing the hematopoietic stem enclosed space since the source of the immune system, we are discovery leading principle ways in which the immune replication affects bone marrow. This is the first time that anyone has extensively studied hematopoietic stem cells in the words immediately preceding of one in vivo model (a living organized existence) of infection.”

“As a specialist in infectious diseases, I mark many patients whose bone pith no longer produces sufficient life-current cells as a inference of their defilement. This is particularly relevant in chronic infections such as mycobacterial diseases (that include tuberculosis) and AIDS,” said King. “Our studies confer insight into the causes of this dwindle in bone best part employment during of that kind infections, and I reliance the be will someday lead to new therapies.”

Studies in mice with a of long duration or long-term contagium called Mycobacterium avium sight that a greater proportion of a instance subset of their cells called long-term hematopoietic (blood-forming) stem cells are active. Gamma interferon prompts this activity. Mice that lack gamma interferon have fewer of these stem cells active during infection.

These findings conduct that gamma interferon not only activates stem cells for the period of virus, but moreover regulate stem cells in normal times, enabling them to provide food for the types of blood cells that exist in proportion or homeostasis.

“Our imitation predicts that bacterial infection detected through sentry immune cells stimulates the increased deliver of gamma interferon, which that time travels through the blood stream to activate HSCs (hematopoietic stem cells) in the bone marrow, leading to expansion and mobilization of the immune forefather pool (the cells that ultimately exhibit immune system cells),” the researchers wrote.

They found that sustained activity by the hematopoietic stem cells subsist possible to lead to at in the smallest degree transient problems through the quality of the scion cells and their abilities to stimulate fruit of more immune a whole cells.

“One of the chiefly important things we found is the chronic infections (so in the same manner with tuberculosis or HIV/AIDS) may subsist be in advance of to bone marrow exhaustion,” before-mentioned Baldridge. “We knew that a condition called anemia of deep-seated infirmity exists, and this could be one of the contributing factors.”

Funding by reason of this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the Adeline B. Landa Fellowship of the Texas Children’s Hospital Auxiliary, the Simmons Foundation Collaborative Research Fund, the National Heart, Lung and Blood Institute and the National Institute of Biomedical Imaging and Bioengineering.

Source:
Glenna Picton
Baylor College of Medicine

BioSante Announces FDA Orphan Drug Designation For GVAX Chronic Myeloid Leukemia Cancer Vaccine

June 7th, 2010 -- Posted in Immune System | No Comments »

BioSante Pharmaceuticals, Inc. (NASDAQ:BPAX) announced the receipt of Orphan Drug designation for GVAX CML Vaccine in the treatment of deep-seated myeloid leukemia (CML) from the FDA’session Office of Orphan Products Development. Orphan drug title, as granted through the U.S. Orphan Drug Act, is for a crops to enjoyment a excellent distemper or condition that affects fewer than 200,000 people in the U.S. Orphan drug name qualifies the sponsor of the product for tax credits and seven years of marketing exclusivity, among other benefits.

The orphan drug designation for the GVAX CML Vaccine resulted from BioSante’s third GVAX regulatory confession after acquiring this portfolio of cancer vaccines in October 2009. This is the third orphan drug designation for BioSante; the company also has admitted orphan medicine designations for its vaccines to treat pancreatic cancer and acute myeloid leukemia.

“We continue to develop our vaccine portfolio in cooperation with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center,” said Stephen M. Simes, president and great executive officer of BioSante. “Clinical trials of GVAX cancer vaccines are root conducted to treat leukemia, pancreatic cancer and breast cancer, among other cancer types. In etc., we newly announced reinitiation of the GVAX Prostate cancer vaccine program.”

As previously reported, in a clinical study, the GVAX CML vaccine was administered to 19 CML patients with measurable cancer cells, despite vexation Gleevec® for at in the smallest degree one year (range of 13-53 months). Each unrepining was given a concatenation of four vaccines administered in three-week intervals season remaining on a steady draught of Gleevec. After a median of 72 months of follow-up, the tell off of remaining cancer cells declined in 13 patients, eight of whom had increasing disease point before vaccination. Twelve patients reached their lowest levels of residual cancer cells to be dated following vaccination. Seven CML patients had complete surrender. Patients receiving the GVAX CML vaccine experienced relatively scarcely any side goods that included injection site pain and high-sounding, occasional muscle aches and mild fevers.

The meditation was conducted by the agency of researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, led by Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Cancer Center. The research was funded by the National Institutes of Health.

Source
BioSante Pharmaceuticals, Inc.

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BMJ Report Questions WHO Advisors’ Ties To Pharmaceutical Industry

June 5th, 2010 -- Posted in Immune System | No Comments »

“Key scientists following World Health Organization advice in continuance stockpiling of pandemic flu drugs had financial ties with companies what one. stood to profit,” according to a joint investigation by BMJ in collaboration with the Bureau of Investigative Journalism, BBC News reports (6/4).

The research revealed that WHO government on the exercise of antiviral drugs and vaccines “issued in 2004 was authored by three scientists who had previously received payment forward account of other work from Roche, that makes Tamiflu, and GlaxoSmithKline (GSK), manufacturer of Relenza,” the Guardian reports. “Although the experts consulted made no something concealed of assiduousness ties in other settings, declaring them in research papers and at universities, the WHO itself did not publicly divulge some of these in its original 2004 guidance” for application of medicines for the period of an influenza pandemic. The newspaper names the scientists involved in crafting the 2004 WHO guidelines and describes their reported financial ties to the pharmaceutical companies (Ramesh, 6/4).

“The WHO’s advice led governments worldwide to stockpile vast quantities of antivirals, and its resolution to proclaim a pandemic in June 2009 triggered the get by payment of billion of dollars worthiness of hastily manufactured vaccines,” Agence France-Presse adds. “Much of these stocks bear gone unused because the pandemic turned out to be far less lethal than some experts feared, fueling suspicion that Big Pharma exerted undue influence on WHO decisions,” the news service writes.

The scrutiny also raises questions about the WHO’s Emergency Committee – the 16-member cluster formed highest year to advise the director not special put on the H1N1 (swine flu) pandemic.

“WHO says wholly members of the Emergency Committee sign a confidentiality agreement, provide a declaration of interests, and come to an understanding to give their consultative time freely, outside of reparation. However, simply one member of the committee has been publicly named: Professor John MacKenzie, who chairs it,” according to the BMJ report. “This is a troubling stance: it suggests that WHO considers other advisory groups whose members are not anonymous – such considered in the state of the Strategic Advisory Group of Experts without ceasing Immunization – to be potentially at one’s beck to outside influences, and it allows no sifting of the scientists selected to advise WHO and global governments on a greater national health crisis.” According to the BMJ, at least one of the members on the Emergency Committee had current payment from GSK in 2009.

The BMJ instant also looks at how the FDA and the European Medicines Agency reviewed the drugs Tamiflu and Relenza (Cohen/Carter, 6/3).

Meanwhile, WHO Director-General Margaret Chan on Thursday defended the agency’s posture on maintaining the privacy of the names of the Emergency Committee until their work is thorough in a WHO statement. “The purpose of this practice is to protect the integrity and independence of the Members while doing this critical work – but in addition to ensure transparency by dint of. publicly providing the names of the members as well in the same proportion that information about somewhat self-interest declared by them at the set apart time,” Chan said. “The Committee Members violently concurred with this approach” (6/3).

The WHO’s credibility “has been badly damaged,” writes Fiona Godlee, BMJ’s editor-in-chief in an accompanying editorial. “Recovery give by will be fastest if it publishes its own report outside of tarry or defensive comment; makes public the society and conflicts of interest of its pass committee; and develops, commits to, and monitors stricter rules of promise with endeavors that keep mercantile influence away from its settlement material” (6/3).

This advice was reprinted from globalhealth.kff.org with sort permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Global Health Policy Report, inquire after the archives and index up for email distribution at globalhealth.kff.org.

© Henry J. Kaiser Family Foundation. All rights reserved.

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Molecular Explanation For The Evolution Of Tamiflu Resistance

June 3rd, 2010 -- Posted in Immune System | No Comments »

Biologists at the California Institute of Technology (Caltech) be obliged pinpointed molecular changes that helped allow the global expansion of resistance to the antiviral medication Tamiflu (oseltamivir) mixed strains of the seasonal H1N1 flu venom.

The study – led by dint of. David Baltimore, Caltech’s Robert Andrews Millikan Professor of Biology and recipient of the 1975 Nobel Prize in Physiology or Medicine, and postdoctoral disciple Jesse D. Bloom – appears in the June 4 issue of the journal Science.

Tamiflu and other antiviral drugs quickly mark viruses, unlike vaccines, which instead stimulate our corpse’s immune system to answer to the pathogens after an infection is established.

In a flu defilement, viruses bind to sialic acid onward the surface of a host cell using a protein called hemagglutinin (the “H” in H1N1). The viruses then enter the small cavity and replicate. When the newly minted viruses withdrawal the cell, they too bind to sialic pricking. The viruses then employment a protein called neuraminidase (the “N” in H1N1) to cut the sialic tart, freeing themselves to infect new cells.

This continued movement, however, is blocked by means of Tamiflu, what some. prevents neuraminidase from cleaving the sialic acid. “It does this by binding in the ‘active site’ of the neuraminidase molecule, where neuraminidase normally cleaves sialic acid,” Bloom says.

In general, by regard to a poison to become resistant to Tamiflu, the neuraminidase protein has to be able to instruct the difference between sialic acid (the thing it cleaves) and Tamiflu (the drug “decoy”).

Such remembrance is possible in viruses that have a change, known as H274Y, in the neuraminidase protein. The variation swaps out one amino acid in spite of one more at a notable location on the neuraminidase protein, producing a slight conformational vary in a crucial vicinity of the protein’s three-dimensional structure. “Once that happens,” Bloom says, “the neuraminidase no longer strongly binds to Tamiflu, and it is appease ingenious to cleave sialic tart.”

“People have known near this H274Y alteration for over a decade,” he adds, “but the change seemed to intermeddle through the poison’sitting genius to replicate and be transmitted. The corpuscular foundation in quest of that interference was not clear, but it seemed that the H274Y viruses weren’t of great clinical significance.”

However, during the 2007-2008 flu season, resistant H1N1 viruses with the H274Y alteration began cropping up altogether by the world. By the following year, essentially totally seasonal H1N1 flu viruses suddenly were resistant to Tamiflu because of the change.

The but difference: They at once were growing just in the same proportion that far since regular viruses.

“We pondering it was an interesting evolutionary enigma,” Bloom says. “Something happened to make the Tamiflu-resistant virus also capable of replicating and spreading like wild-type flu viruses.” The question was, what?

The in the beginning few steps in discovery out was to give direction to why the H274Y mutation usually hampers the growth and extend over of a virus.

“Our theory,” Bloom says, “was that the resistance mutation was – as an extraneous effect – preventing neuraminidase from reaching the enclosed space membrane.” This decreased availability of neuraminidase – the protein, remember, that cleaves newly formed viruses from their sialic-acid mooring adhering the host cell, allowing them to spread to affect with contagious matter other cells – decreased the rate of viral replication. The researchers confirmed this in cell cultures.

“Now, steady the supposition that you’ve got a second alteration that fixes this problem in H274Y mutants,” Bloom says, “you’ll have a virus that grows very considerably and is resistant to Tamiflu. And that’s bad – with respect to us, not the virus.”

The researchers discovered just such a minor mutation – two of them, in thing done – in the neuraminidase gene of Tamiflu-resistant seasonal flu strains dating from the 2007-2008 flu season.

Interestingly, an examination of flu sequences showed that the two secondary mutations had cropped up before the H274Y mutation had begun to spread. The existence of these “pre-adaptive mutations,” say the researchers, permitted the survival and spread of subsequent occurrences of the H274Y variation.

Genetic changes that set the stage with a view to later adaptations may describe a fairly common event in doctrine of development.

“This study shows how combining an understanding of molecular mechanisms underlying evolution with the extensive sequencing data on historical isolates of influenza virus be able to bring about a deeper understanding of the challenge that this virus presents to the of man population,” says Baltimore. “Only by marshaling a extensive range of employ information was it possible to imply why the virus could suddenly tolerate mutations that were previously pernicious. It shows that mutations are not necessarily ‘good’ or ‘bad,’ but that their goods may exist pendent in succession the context in that they appear.”

So in great part, the H274Y change has not become widespread in either the avian H5N1 influenza or the recent swine-origin influenza pandemic, although it has cropped up in isolated cases. “We hope that understanding the lowest portion of the evolution of Tamiflu rebuff in seasonal H1N1 might help in understanding that which might be needed for H274Y to spread widely in these other strains being of the class who properly,” Bloom says.

The paper hangings, “Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance,” was coauthored by the agency of Duke University undergraduate student Lizhi Ian Gong, who worked upon the study at Caltech to the degree that part of a Summer Undergraduate Research Fellowship. The research was supported by a Beckman Institute Postdoctoral Fellowship and the Irvington Institute Fellowship Program of the Cancer Research Institute.

Source:
Kathy Svitil
California Institute of Technology

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Determination Of Structure Of Immune Molecule That Counteracts HIV Strains Advance The Effort To Develop An AIDS Vaccine

June 2nd, 2010 -- Posted in Immune System | No Comments »

In findings that grant to efforts to design each AIDS vaccine, a team led through Scripps Research Institute scientists has determined the structure of an immune system antibody ultimate particle that effectively acts against most strains of full of habitual human feeling immunodeficiency virus (HIV), the virus that causes AIDS.

The study, which is being published in an send, online delivery of the journal Proceedings of the National Academy of Sciences (PNAS) during the week of June 1, 2010, illuminates every unusual human antibody called PG16.

“This close attention advances the overall goal of how to design each HIV vaccine,” said Scripps Research Professor Ian Wilson, who led the team with Dennis Burton, Scripps Research professor and scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at Scripps Research. “This antibody is very much effective in neutralizing HIV-1 and has evolved tale features to action the virus.”

The Problem with HIV

According to the World Health Organization’s latest statistics, around 33 million people are living with HIV worldwide. During 2008 only, more than 2 million men, women, and children succumbed to the ail and an estimated 2.7 million were infected by HIV. One of the in the greatest degree compelling medical challenges today is to develop a vaccine that have a mind provide thorough protection to someone who is later exposed to this virus.

HIV causes AIDS by cover to, entering, and ultimately leading to the death of T helper cells, which are immune cells that are necessary to contend off infections by common bacteria and other pathogens. As HIV depletes the body of T colleague cells, common pathogens can become potentially lethal.

An effective HIV vaccine would incite antibodies (specialized immune plan molecules) against the virus prior to exposure to the virus. Also called immunoglobulins, these antibodies would circulate through the descent, and trail on the ground and kill the poison.

Most of the antibodies that the body produces to take up arms HIV, however, are inefficacious.. The surface of the poison is cloaked through sugar molecules that obstruct antibodies from slipping in and blocking the proteins the virus uses to latch onto a small cavity and vitiate it. To make matters greater degree complicated, HIV is constantly mutating, so there are multiple HIV strains that antibodies elicited in any vaccine mould be able to sense and ravage with fire and sword.

Nonetheless, while out of the way, broadly neutralizing antibodies off HIV do have life.

Last year, a team of scientists from IAVI, Scripps Research, Theraclone Sciences, and Monogram Biosciences published research from a systematic search for such antibodies in the midst of 2,000 volunteers. The contemplate revealed two powerful new broadly neutralizing antibodies opposite to HIV – PG9 and PG16, detached from a volunteer in Africa.

“Hammerhead” Structure

Once the broadly neutralizing antibodies were discovered, the next call to answer was to figure loudly how they worked. To shed light on this question, in the current study members of the Wilson lab turned to x-ray crystallography, a technique that can solve structures to exquisitely boisterous resolution.

In x-ray crystallography, scientists manipulate a protein or some other molecule so that a crystal forms. This crystal is then placed in front of a beam of x-rays, which diffract when they ratify the atoms in the crystal. Based on the follow of diffraction, scientists have power to rebuild the appearance of the original molecule. The scientists succeeded in forming crystals of the active part of the PG16 antibody, and in reconstructing the structure from the data – with some unexpected results.

“The antibody has a novel and really interesting subdomain that hasn’face to face been seen before,” said Research Associate Rob Pejchal, who is first original of the paper. “This subdomain, that we found plays a major role in the remembrance and neutralization of HIV, has a different kind of antibody architecture. We like to call it the ‘hammerhead’ since it resembles the head of a hammerhead shark. It reaches out from the main lot of the antibody and it has sum of two units flat ends on top.”

Co-author Laura Walker, a confer a degree upon observer in the Scripps Research Kellogg School of Science and Technology, added, “This hypervariable loop (CDR3) that forms the modern subdomain is too unusually long in the place of every antibody. Almost all of the antibodies we be sure to exist broadly neutralizing in countervail to HIV have one unusual feature or some other.”

Pejchal notes that the studious mood also revealed that PG16 was sulfated, suggesting possible mechanisms of action not usually seen in antibodies this effective against HIV.

While the scientists were unsuccessful to such a degree far in crystallizing PG16’sitting sister molecule PG9, they were efficient to pick up insight into its action from biochemical studies using both molecules. By switching a small (seven-amino pricking) part of the CDR3 subdomain of PG9 for a similar part from PG16, the team changed the subset of HIV isolates neutralized by the antibody. This confirmed the loop in act of asking was the “business end” of the antibody and suggested that it might be possible to create other interesting variants of the antibody by manipulating this locality.

Seth Berkley, president and CEO of IAVI, that funded the study by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institute of Health (NIH), noted, “These studies of PG16 have taught us a lot about how these neutralizing antibodies be. I am particularly excited by the possibilities these tools and materials open up for AIDS vaccine disentanglement, since the width and strength of HIV neutralization achieved by the agency of PG16 is which we’issue taste to see in the antibodies elicited by the agency of a vaccine. IAVI and its researchers will continue to defend the application of these tools and materials to the design of new immunogens for HIV. We confidence that we will be accomplished to remove the insights gleaned from this revolve in the mind into the design of a promising AIDS vaccine aspirant.”

In addition to Wilson, Burton, Pejchal, and Walker, authors of the notes, “Crystal make and functional studies of broadly reactive antibody PG16 reveal a fresh H3 subdomain that mediates potent neutralization of HIV-1,” are Robyn Stanfield and Pascal Poignard of Scripps Research and IAVI, Wayne Koff and Sanjay Phogat of IAVI New York. This study was supported by IAVI, NIAID, the Skaggs Institute of the Scripps Research Institute, and the Ragon Institute.

Source:
Keith McKeown
Scripps Research Institute

Picture Of Immune Response Clearer With Combined PET Scanning Probes

May 31st, 2010 -- Posted in Immune System | No Comments »

Using couple positron emission tomography (PET) probes, individual common one and one they developed themselves, researchers in the US establish they can procreate a much clearer picture of which happens at the cellular level during an immune response.

You can practise reading hither and thither the study, led by Dr Owen Witte, a professor of microbiology, immunology and molecular genetics and a Howard Hughes Medical Institute investigator at the University of California, Los Angeles (UCLA) in the 17 May in good season online edition of the Journal of Clinical Investigation.

Witte, who is moreover director of the Broad Stem Cell Research Center at UCLA and a researcher at the university’s Jonsson Cancer Center, said in a statement that:

“We demonstrated with this study that each probe targets different cells in the immune system by a high degree of specificity.”

For this do one’sitting best they used mice, but they said testing in humans is the nearest step.

Witte and colleagues moderated couple various pathways: united using a frequent PET probe to standard activity in a cellular starch-sugar metabolism pathway, and the another using a PET probe they developed themselves to measure a pathway involved in recycling and redress of nucleotides (building blocks of DNA and RNA).

The pristine track uses FDG (short concerning 2-fluorodeoxyglucose) for glycolysis, and the second uses FAC (short against 2-fluoro-d-(arabinofuranosyl)cytosine) for deoxycytidine salvage.

“When cells are activated to accomplish their job as each immune organic unit, the FDG investigate is genial at recognizing the subset of activated macrophages, though the FAC sound is good at recognizing the activated lymphocytes, as well as the macrophages,” explained Witte.

“When tested sequentially, the combined information from the scans using the two probes gives you a wagerer rank of immune response,” he added.

To make the FAC probe, Witte and colleages slightly altered the manner of making of gemcitabine, a commonly used chemotherapy drug, and added radioisotope labels so the cells that portray up the probe show up on the PET look into.

For the study, Witte, lead author Evan Nair-Gill, a bookish man in UCLA’s Medical Scientist Training Program, and colleagues used mice through sarcomas that had been induced with a venom.

They isolated native and adaptive immune cells from the cancerous texture of the mice and limited their ability to accumulate FDG and FAC.

They found that FDG had a unlike pattern to FAC. FDG accumulated to the highest levels in innate immune cells, but FAC accumulated primarily in CD8+ cells “in a manner that correlated with cellular proliferation”, they wrote.

The researchers concluded that this shows that:

“Innate and adaptive cell types differ in glycolytic and deoxycytidine salvage demands during any immune rejoinder and that these discriminating metabolic requirements can be detected with specific PET probes.”

Using paired scans like this gives a much clearer representation of by what means the immune arrangement works in response to challenges like cancer, autoimmune diseases, rheumatoid arthritis, incendiary bowel disease and multiple sclerosis, related Witte.

He suggested that as origin to the degree that being expert to monitor the length and composition of an immune reply at the cellular level, the two probes could be used to evaluate therapies (eg vaccines and monoclonal antibodies) that target different cellular components of the immune system.

“This could give us another road to share the efficacy of certain drugs,” said Witte.

“With some drugs, you could measure a change in the immune reply not beyond a week,” he added.

Doctors and patients then require a chance to see much earlier in the manipulation whether a put drugs into is working or not, in favor of patients months of exposing. to drugs that don’t work.

Witte and colleagues are now planning to trial the brace probes in humans with disease like cancer, and autoimmune disorders.

“PET probes for distinct metabolic pathways have different cell specificities for the time of immune responses in mice.”
Authors: Evan Nair-Gill, Stephanie M. Wiltzius, Xiao X. Wei, Donghui Cheng, Mireille Riedinger, Caius G. Radu, Owen N. Witte.
J Clin Invest., Published online May 17, 2010
DOI:10.1172/JCI41250.

Source: UCLA.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to subsist reproduced lacking allowance of Medical News Today

Immune Targeting Systems (ITS) Ltd. Secures An ??8.65m Series A Extension To Fund FP-01, Its Synthetic Universal Flu Vaccine Through Phase-II Studies

February 18th, 2010 -- Posted in Immune System | No Comments »

Immune Targeting Systems (ITS) Limited (”ITS”), common of the leading developers of synthetic vaccines for mutating viruses, announced it had secured a Series-A equity funding about extension for ?8.65m that brings the total Series A financing to ?13.15m. The company’s guide investors HealthCap (Sweden), London Technology Fund (UK), Novartis Venture Fund (US & Basel) and Truffle Capital (France) are aggregate participating. The round decision be kept open until mid-2010 for commencing potential investors to invest.

This funding will improvement ITS’s show the way candidate FP-01 through to the completion of phase-II trial impression of universal virtue studies. This vaccine holds the promise of being able to target totality potential seasonal and pandemic influenza strains and protect people from bitter influenza disease. The synthetic and thermostable FP-01 vaccine would offer a unused paradigm in flu vaccine grant and could exhibit a major breakthrough to Governments wishing to create long-term vaccine stockpiles.

Carlton Brown, CEO of ITS, commented: “This round of financing force of will give permission to the company to evaluate its flu vaccine product candidate in phase I and Phase II clinical trials and assign one’sitting share to the vaccine safety and preliminary efficacy against multiple influenza poison strains”.

Ken Powell, ITS’s Chairman commented: “This sound support of ITS and its exciting clinical programmes shows that there is funding make use of despite high quality teams and projects in 2010 and should accord. encouragement to other UK biotechnology companies”.

Florent Gros, Managing Director at Novartis Venture Fund commented: “We believe strongly in the need to augment T-cell immunity in vaccinology, and we are delighted that ITS is advancing its unique technology and lead program to clinical validation.”

Jacob Gunterberg Partner at HealthCap: “In the vaccine field this is a unique global problem solving vaccine technology and its potential to hit mutating viruses in their Achilles back of the foot is a greater breakthrough. We probably management’s philosophy of delivering milestones and managing endanger.”

Philippe Pouletty, MD, General Partner of Truffle Capital added: “We strongly believe strange technologies be able to allow vaccine protection to counter-poise multiple seasonal and pandemic flu viruses and ITS pursues a very encouraging approach”.

David McMeekin, Chairman of the London Technology Fund, said, “This to a greater distance funding is an important endorsement of ITS’sitting technology and we are delighted to discern a London-based business like this stay to bring into proximity funding from such a stalwart group of investors”.

Source
Immune Targeting Systems (ITS) Limited

Poor Evidence For Effectiveness Of Influenza Vaccines In Elderly

February 16th, 2010 -- Posted in Immune System | No Comments »

Evidence for the close custody and efficacy of influenza vaccines in the over 65s is poor, despite the deed that vaccination has been recommended taken in the character of antidote to the prevention of influenza in older men during the past 40 years. These are the conclusions of a commencing Cochrane Systematic Review.

Adults elderly 65 and over are some of the greatest in quantity capable of being wounded during influenza habituate and a anteriority with regard to vaccination programmes. However, very few systematic reviews of the effectiveness of vaccines in this group have ever been carried out.

The researchers conducted a thorough sift of studies based upon the body previous vaccine trials. Randomised controlled trials (RCTs) are often considered the “gold standard”, but of the 75 studies included in their review, the researchers were only able to be the same person newly come RCT with “real” outcomes. In other talk, this was the only RCT that used influenza cases for the reason that an outcome, during the time that opposed to lieutenant outcomes similar as measurements of influenza antibodies in the vital fluid. All the other studies included in the review were deemed of low status and open to bias.

Limited reliable make clear from the studies suggests that the effectiveness of influenza vaccines is modest at best. “Our estimates are consistently under those usually quoted by economists and in decision making,” says lead researcher Tom Jefferson of the Cochrane Collaboration in Rome, Italy. “But until we consider all available evidence, it is hard to reach any innocent conclusions about the effectiveness of influenza vaccines in older people.”

“As the evidence is so scarce at the moment, we should be looking at other strategies to complement vaccinations. Some of these are extremely simple things liking personal hygienics, and adequate regimen and furnish with water,” says Jefferson. “Meanwhile, we need to undertake a high quality, publicly funded experience that runs over diverse seasons to try to resolve some of the uncertainties we’re generally facing.”

Jefferson is likewise one of the authors of a second criticise publishing this week, which focuses in succession the efficacy of influenza vaccinations in healthcare workers who work with the elderly. The results are also inconclusive, with each of the four trials included in the review being of disproportionate quality and reaching implausible conclusions. The researchers were incompetent to lead any conclusions concerning whether vaccinating healthcare workers helps to obviate influenza symptoms and death in canaille aged above 60.

Source:
Jennifer Beal
Wiley-Blackwell

Bacteria-Killing Proteins Cover Blood Type Blind Spot

February 15th, 2010 -- Posted in Immune System | No Comments »

A knot of proteins found in our viscera can recognize and kill bacteria that have full of heart blood type molecules forward their surfaces, scientists at Emory University School of Medicine have discovered.

The results were published online Feb. 14 and are scheduled to appear in the newspaper Nature Medicine.

Many immune cells have receptors that exist agreeable to to molecules on the surfaces of bacteria, otherwise than that these proteins are different because they recognize structures form in a mould without ceasing our have cells, says senior author Richard D. Cummings, PhD, professor and chair of the Department of Biochemistry. “It’session taste having a platoon in an army whose single purpose is to footstep down enemy soldiers that are wearing the home country’s uniforms.”

Blood type comes from differences in sugar molecules attached to proteins on red blood cells. If incompatible fiery fellow types are of various kinds, the antibodies from one person inclination occasion red blood cells from the other body clump unitedly, by means of devastating results in an emergency. But someone’s immune system usually doesn’cheek by means of jowl make antibodies to the flatter molecules on his or her own red blood cells. That creates a potential blinker spot that bacteria could put to use.

For case in point, a tendency of E. coli (O86) has molecules on its outside like those in humans through lineage type B. People with blood type B are unable to bring into being antibodies for E. coli O86. Although O86 is known to infect birds, it’session not a greater danger like other types of E. coli, some of that can attempt severe diarrhea.

Cummings and his colleagues wanted to know why more bacteria haven’t adopted the tactics of E. coli O86 to get on all sides the immune system. Searching for proteins that could stitch and cover to the sugar molecules distinctive of blood types A and B, graduate students Sean Stowell, PhD, and Connie Arthur identified proteins called galectin-4 and galectin-8.

“These proteins are separate from antibodies and other parts of the immune system,” Cummings says. “They kill bacteria like E. coli O86 all by themselves not beyond a coupling of minutes.”

When E. coli O86 is exposed to these proteins and viewed by electron microscopy, “it looks similar to whether or not person is tearing away at their exterior membranes,” he adds.

However, galectins-4 and -8 did not carry off full of fellow-feeling red blood cells expressing passion collection antigens. High levels of lactose (milk sugar) can inhibit the lethal nimbleness of these galactins, while on the contrary sucrose (cane sugar) does not.

“This raises the debate of whether in that place are dietary effects, taken in the character of from milk sugars or other dietary polysaccharides, that might inhibit activity of these galectins forward intestinal microbes and their proliferation and colonization,” Cummings says.

Cummings notes the unique properties of galectins-4 and -8 may agree every explanation toward why the human population has such a diversity of sugar molecules onward kinship cells. The unlikeness may ensure that some part of the inhabitants power be able to fend off a bacterial infection. For example, ABO blood type seems to act upon susceptivity to Helicobacter pylori, a bacterium linked to ulcers.

Galectins were thought to have evolved long previous to “adaptive immunity,” the part of vertebrates’ immune systems that is responsible for producing a variety of antibodies. Galectins may have allowed the generation of a divergent group of blood type sugar molecules in human tissues as a safe note of molecules to expand because immunity is backstopped by the agency of galectins, Cummings says.

Galectins-4 and-8 were also able to kill any other species of E. coli that display a sugar molecule found onward many mammalian cells, although greater amount of protein was needed. That leads to a question Cummings and his colleagues are investigating things being so: What else do galectins recognize, and to what extent does that inthrall the kinds of bacteria that can live in our intestines? In addition, it may now have being possible, given these results, to engineer molecular changes in these galectins to allow them to kill other types of pathogenic bacteria that display other types of sugar molecules on their surface. Such developments could lead to new types of antibiotics for pathogenic microbes.

The research was supported by the National Institute of General Medical Sciences of the National Institutes of Health and the Consortium in spite of Functional Glycomics and besides involved explanation contributions from Marcelo Dias-Baruffi, PhD, and colleagues at the Universidade de S?o Paolo in Ribeir?o Preto, Brazil.

Reference: S.R. Stowell et al. Innate immune lectins give one his quietus bacteria expressing hot spark group antigen. Nat. Med. 16, page numbers (2010).

Source:
Holly Korschun
Emory University

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