Cancer-fighting immune activity boosted by dialing back Treg cell function in animal model

Main Category: Cancer / Oncology
Also Included In: Immune System / Vaccines
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Cancer-fighting immune activity boosted by dialing back Treg cell function in animal model

By carefully adjusting the function of crucial immune cells, scientists may have developed a completely new type of cancer immunotherapy - harnessing the body's immune system to attack tumors. To accomplish this, they had to thread a needle in immune function, shrinking tumors without triggering unwanted autoimmune responses.

The new research, performed in animals, is not ready for clinical use in humans. However, the approach, making use of a key protein to control immune function, lends itself to further study using candidate drugs that employ the same mechanisms.

"This preclinical study demonstrates proof of principle that using a drug to regulate the function of a special, immunosuppressive subset of so-called T-regulatory (Treg) cells safely controls tumor growth," said study leader Wayne W. Hancock, M.D., Ph.D., of the Division of Transplant Immunology at The Children's Hospital of Philadelphia (CHOP). "It really moves the field along towards a potentially major, new cancer immunotherapy."

Hancock and colleagues published the study in Nature Medicine.

"There's a basic paradox in immunology: why doesn't the immune system prevent cancer in the first place?" said Hancock. The answer is complicated, he adds, but much of it involves a delicate balancing act among elements of the immune system: while immunity protects us against disease, an overly aggressive immune response may trigger dangerous, even life-threatening, autoimmune reactions in which the body attacks itself.

In the current study, Hancock focused on a subtype of immune cells called Foxp3+ Tregs, for short. Tregs were already known to limit autoimmunity, but often at the cost of curtailing immune responses against tumors. "We needed to find a way to reduce Treg function in a way that permits antitumor activity without allowing autoimmune reactions," he said.

Hancock's group showed that inhibiting the enzyme p300 can affect the functions of another protein, Foxp3, which plays a key role in controlling the biology of Tregs. By deleting the gene that expresses p300, the researchers safely reduced Treg function and limited tumor growth in mice. Notably, they also achieved the same effects on p300 and Tregs in mice by using a drug that inhibits p300 in normal mice.

Hancock will pursue further investigations into targeting p300 in immunotherapy. The preclinical findings offer encouraging potential for being translated into the clinic, said Hancock, who added that pharmaceutical companies have expressed interest in researching this approach as a possible cancer therapy.

The antitumor study, down-regulating Treg function, is the flip side of another part of Hancock's Treg research. In a 2007 animal study, also in Nature Medicine, he increased Treg function with the goal of suppressing the immune response to allow the body to better tolerate organ transplants. In the current study, decreasing Treg activity permitted the immune system to attack an unwelcome visitor - a tumor. In both cases, he relied on epigenetic processes - using groups of chemicals called acetyl groups to modify key proteins - but in opposite directions. "This is the yin and yang of immune function," he added.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

The National Institutes of Health (grants AI073489, AI095353, and CA158941, all to Hancock) supported this research. In addition to his CHOP position, Hancock is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.

Yujie Liu et al., "Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity," Nature Medicine, published online Aug. 18, 2013. doi:10.1038/nm.3286

Children's Hospital of Philadelphia

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Adding tofacitinib to treatment with DMARDs improves pain and function in patients with active RA

Main Category: Arthritis / Rheumatology
Article Date: 20 Aug 2013 - 1:00 PDT Current ratings for:
Adding tofacitinib to treatment with DMARDs improves pain and function in patients with active RA

Adding tofacitinib to treatment with disease-modifying anti-rheumatic drugs (DMARDs) may help improve symptoms in patients with active rheumatoid arthritis (RA). Nonbiologic DMARDs, including methotrexate, are commonly used to treat RA. However, DMARDs alone do not always adequately treat the disease.

Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. Researchers sought to determine the safety and efficacy of tofacitinib taken in combination with nonbiologic DMRDs.

Patients with inadequately controlled RA (n = 792) despite treatment with nonbiologic DMARDs were randomly assigned to one of four twice-daily treatment sequences: 5 mg of tofacitinib; 10 mg of tofacitinib; placebo advanced to 5 mg of tofacitinib; or placebo advanced to 10 mg of tofacitinib.

The study showed that when used in combination with various nonbiologic DMARDs, tofacitinib, 5 mg and 10 mg twice daily, compared with placebo, rapidly reduced the signs and symptoms of RA and improved physical function. Adverse events included decreases in neutrophil counts, increases in high- and low-density lipoprotein cholesterol level, and small increases in serum creatinine and aminotransaminase levels.

Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis: A Randomized Trial, Joel Kremer, MD; Zhan-Guo Li, MD, PhD; Stephen Hall, MD; Roy Fleischmann, MD; Mark Genovese, MD; Emilio Martin-Mola, MD, PhD; John D. Isaacs, PhD; David Gruben, PhD; Gene Wallenstein, PhD; Sriram Krishnaswami, PhD; Samuel H. Zwillich, MD; Tamas Koncz, MD; Richard Riese, MD, PhD; and John Bradley, MD, Ann Intern Med. 2013;159(4):253-261. doi:10.7326/0003-4819-159-4-201308200-00006

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Where in the body immune cells reach maturity is important for their later function

Main Category: Immune System / Vaccines
Article Date: 16 Aug 2013 - 0:00 PDT Current ratings for:
Where in the body immune cells reach maturity is important for their later function

Regulatory T cells (or "Tregs" for short) play a central role in the human immune system: They guide all of the other immune cells and make sure they are tolerant of the body's own cells and harmless foreign substances. How Tregs become Tregs in the first place has been only incompletely understood - until now. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, along with their colleagues at the Hannover Medical School (MHH) have recently gleaned important new insights into the workings of these cells. As it turns out, origin is key - greater numbers of Tregs are produced within certain lymph nodes than in others. The researchers are now publishing their insights in the scientific journal Mucosal Immunology.

Without regulatory T cells, the human defence system would not work properly. Defender cells would be fiercely fighting off even harmless foreign substances like the parts of certain kinds of food, for example, as the immune system would simply not be "tolerant" towards these harmless substances. This tolerance is mediated through the Tregs - they are "tolerogenic."

They instruct other immune cells as to which intruders really do need to be fought off and which ones do not pose a threat. However, even regulatory T cells have to first acquire this unique skill. What we have known for some time now is that they receive their "training" inside lymph nodes. "Lymph nodes are basically the immune system's meeting points if you will," says Prof. Jochen Hühn, Head of Experimental Immunology at the HZI. "Here, different types of immune cells meet up and also encounter antigen." An antigen is a structure the immune system is able to recognize like component parts of pathogens or foods.

The researchers compared the development of murine T cells obtained from lymph nodes from various locations in the body, like the liver, intestine, and skin. In the process, they learned that more Tregs capable of teaching other cells to be tolerant of food antigens are made inside lymph nodes of the liver and intestine - a property the lymph nodes maintained even when they were transplanted to the skin. Conversely, skin lymph nodes did not become more tolerogenic if transplanted to the intestine. The HZI scientists made these discoveries together with their colleagues from Prof. Oliver Papst's team at the MHH Institute of Immunology.

Based on their observations, the scientists deduced that lymph node location influences the maturation process of the cells they contain. "The cells retained their original skills for weeks following the transplant," says Dr. Sascha Cording, one of the study's first authors. "You might say lymph nodes have something like a location-specific memory."

And this in spite of the fact that all the various types of blood cells within a lymph node, including the immune cells, are constantly replaced, which means the lymph nodes' location memory must be encoded somewhere in its stroma.

Additional experiments allowed the scientists to probe just how lymph nodes obtain their memory: Following birth, both the supply of vitamin A and the intestinal bacterial microflora figure prominently into this process. Without these two influencing factors, the lymph nodes simply forget about their origin and lose their tolerogenic properties.

These findings about lymph node imprinting apply to humans as well: An inadequate supply of vitamin A after birth or meddling with the baby's developing microflora through administration of antibiotics can interfere with the lymph nodes' long-term memory. "At what age this process happens in humans we cannot as of yet pinpoint with any certainty," says Hühn. "Whether we're talking about the first few days, weeks, or months even, is difficult to surmise." The next step will be identifying the potential repercussions interfering with early imprinting of the immune system. Down the line, things like food allergies or autoimmune diseases might be the result.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our immune system / vaccines section for the latest news on this subject.

The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes

Sascha Cording, Benjamin Wahl, Devesha Kulkarni, Himprya Chopra, Jörn Pezoldt, Manuela Buettner, Annegret Dummer, Usri Hadis, Markus Heimesaat, Stefan Bereswill, Christine Falk, Ulrike Bode, Alf Hamann, Diana Fleissner, Jochen Huehn, Oliver Pabst

Mucosal Immunology, 2013, DOI: 10.1038/mi.2013.54

Helmholtz Centre for Infection Research

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New mechanism in the function of a nearly universal biological structure will impact fundamental biology, design of pharmaceuticals

Main Category: Biology / Biochemistry
Also Included In: Pharma Industry / Biotech Industry
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
New mechanism in the function of a nearly universal biological structure will impact fundamental biology, design of pharmaceuticals

Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular environment, atom for atom, University of Chicago scientists have revealed this new mechanism in the function of a nearly universal biological structure, with implications ranging from fundamental biology to the design of pharmaceuticals. Their findings were published online in Nature.

"Our research clarifies the nature of this previously mysterious inactivation state. This gives us better understanding of fundamental biology and should improve the rational design of drugs, which often target the inactivated state of channels" said Benoît Roux, PhD, professor of biochemistry and molecular biology at the University of Chicago.

Potassium channels, present in the cells of virtually living organisms, are core components in bioelectricity generation and cellular communication. Required for functions such as neural firing and muscle contraction, they serve as common targets in pharmaceutical development.

These proteins act as a gated tunnel through the cell membrane, controlling the flow of small ions into and out of cells. After being activated by an external signal, potassium channels open to allow ions through. Soon after, however, they close, entering an inactive state and are unable to respond to stimuli for 10 to up to 20 seconds.

The cause of this long recovery period, which is enormously slow by molecular standards, has remained a mystery, as structural changes in the protein are known to be almost negligible between the active and inactivated states - differing by a distance equivalent to the diameter of a single carbon atom.

To shed light on this phenomenon, Roux and his team used supercomputers to simulate the movement and behavior of every individual atom in the potassium channel and its immediate environment. After computations corresponding to millions of core-hours, the team discovered that just 12 water molecules were responsible for the slow recovery of these channels.

They found that when the potassium channel is open, water molecules quickly bind to tiny cavities within the protein structure, where they block the channel in a state that prevents the passage of ions. The water molecules are released slowly only after the external stimulus has been removed, allowing the channel to be ready for activation again. This computer simulation-based finding was then confirmed through osmolarity experiments in the laboratory.

"Observing this was a complete surprise, but it made a lot of sense in retrospect," Roux said. "Better understanding of this ubiquitous biological system will change how people think about inactivation and recovery of these channels, and has the potential to someday impact human health."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

The work was supported by grants from the National Institutes of Health. Computation resources were provided by Oak Ridge National Laboratory, the National Resource for Biomedical Supercomputing and the Pittsburgh Supercomputing Center.

University of Chicago Medical Center

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Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes

Main Category: Liver Disease / Hepatitis
Also Included In: Stem Cell Research
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes

Researchers have generated functional hepatocytes from human stem cells, transplanted them into mice with acute liver injury, and shown the ability of these stem-cell derived human liver cells to function normally and increase survival of the treated animals. This promising advance in the development of cell-based therapies to treat liver failure resulting from injury or disease relied on the development of scalable, reproducible methods to produce stem cell-derived hepatocytes in bioreactors, as described in an article in Stem Cells and Development, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Stem Cells and Development website.

Massoud Vosough and coauthors demonstrate a large-scale, integrated manufacturing strategy for generating functional hepatocytes in a single suspension culture grown in a scalable stirred bioreactor. In the article "Generation of Functional Hepatocyte-Like Cells from Human Pluripotent Stem Cells in a Scalable Suspension Culture" the authors describe the method used for scale-up, differentiation of the pluripotent stem cells into liver cells, and characterization and purification of the hepatocytes based on their physiological properties and the expression of liver cell biomarkers.

David C. Hay, MRC Centre for Regenerative Medicine, University of Edinburgh, U.K., comments on the importance of Vosough et al.'s contribution to the scientific literature in his editorial in Stem Cells and Development entitled "Rapid and Scalable Human Stem Cell Differentiation: Now in 3D." The researchers "developed a system for mass manufacture of stem cell derived hepatocytes in numbers that would be useful for clinical application," creating possibilities for future "immune matched cell based therapies," says Hay. Such approaches could be used to correct mutated genes in stem cell populations prior to differentiation and transplantation, he adds.

"The elephant in the room for stem cell therapy rarely even acknowledged let alone addressed in the literature is that of scalable production of cells for translational application," says Editor-in-Chief Graham C. Parker, PhD, research professor, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine. "Baharvand's groups' landmark publication not only demonstrates but exquisitely describes the methodology required to scale up stem cell populations for clinical application with a rigor to satisfy necessary manufacturing standards."

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New mechanism in the function of a nearly universal biological structure will impact fundamental biology, design of pharmaceuticals

Main Category: Biology / Biochemistry
Also Included In: Pharma Industry / Biotech Industry
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
New mechanism in the function of a nearly universal biological structure will impact fundamental biology, design of pharmaceuticals

Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular environment, atom for atom, University of Chicago scientists have revealed this new mechanism in the function of a nearly universal biological structure, with implications ranging from fundamental biology to the design of pharmaceuticals. Their findings were published online in Nature.

"Our research clarifies the nature of this previously mysterious inactivation state. This gives us better understanding of fundamental biology and should improve the rational design of drugs, which often target the inactivated state of channels" said Benoît Roux, PhD, professor of biochemistry and molecular biology at the University of Chicago.

Potassium channels, present in the cells of virtually living organisms, are core components in bioelectricity generation and cellular communication. Required for functions such as neural firing and muscle contraction, they serve as common targets in pharmaceutical development.

These proteins act as a gated tunnel through the cell membrane, controlling the flow of small ions into and out of cells. After being activated by an external signal, potassium channels open to allow ions through. Soon after, however, they close, entering an inactive state and are unable to respond to stimuli for 10 to up to 20 seconds.

The cause of this long recovery period, which is enormously slow by molecular standards, has remained a mystery, as structural changes in the protein are known to be almost negligible between the active and inactivated states - differing by a distance equivalent to the diameter of a single carbon atom.

To shed light on this phenomenon, Roux and his team used supercomputers to simulate the movement and behavior of every individual atom in the potassium channel and its immediate environment. After computations corresponding to millions of core-hours, the team discovered that just 12 water molecules were responsible for the slow recovery of these channels.

They found that when the potassium channel is open, water molecules quickly bind to tiny cavities within the protein structure, where they block the channel in a state that prevents the passage of ions. The water molecules are released slowly only after the external stimulus has been removed, allowing the channel to be ready for activation again. This computer simulation-based finding was then confirmed through osmolarity experiments in the laboratory.

"Observing this was a complete surprise, but it made a lot of sense in retrospect," Roux said. "Better understanding of this ubiquitous biological system will change how people think about inactivation and recovery of these channels, and has the potential to someday impact human health."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

The work was supported by grants from the National Institutes of Health. Computation resources were provided by Oak Ridge National Laboratory, the National Resource for Biomedical Supercomputing and the Pittsburgh Supercomputing Center.

University of Chicago Medical Center

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Discovery of gene function may help prevent kidney stones

Main Category: Genetics
Also Included In: Urology / Nephrology
Article Date: 26 Jul 2013 - 2:00 PDT Current ratings for:
Discovery of gene function may help prevent kidney stones

The discovery of a gene's function in E. coli and other bacteria might lead to a probiotic to prevent the most common type of kidney stone, according to a Purdue University study.

Human cells can't metabolize oxalate, an acidic chemical found in nearly all plants we eat, so any oxalate we absorb from food must be excreted from the body. Calcium-oxalate urinary stones can form when oxalate reaches a high concentration in the kidneys. About 80 percent of kidney stones are composed of insoluble calcium oxalate.

T. Joseph Kappock, assistant professor of biochemistry, and his research team made the discovery during a study of genes in Acetobacter aceti, a harmless bacterium that is typically used to convert wine to vinegar. Acetobacter aceti, which normally lives on plant tissue, thrives in acidic conditions that easily kill most other bacteria, Kappock said.

The researchers were searching for other acids in addition to acetic acid, the acid present in vinegar, that the bacterium can metabolize.

"We were very excited when we realized E. coli has the same genetic setup as Acetobacter aceti," said Kappock, whose findings were published in the journal PLOS ONE.

Kappock and doctoral students Elwood A. Mullins and Kelly L. Sullivan found that Acetobacter aceti and E. coli each contain an enzyme with a previously unknown function, called YfdE in E. coli.

DNA sequencing had identified related genes in each bacterium, but provided little insight about its function.

"When we look at a bacterial genome by DNA sequencing, we can't tell what many of the proteins in the organism do," Kappock said. "I compare it to knowing that a vehicle has an internal combustion engine. You don't know if it's in an Indy car or a diesel truck. DNA sequencing tells us we have an internal combustion engine in this organism, but we don't know what it's for or what it can do."

Many other bacteria have the same genes but don't seem to be capable of using them.

"A few bacteria in the gastrointestinal tract eat oxalate, and we think we know how those work," Kappock said. "But we don't know why so many others are killed by oxalate, even though they have genes that would seem to be able to protect them. Oxalate is a very hard nut to crack. It's a very stable molecule that is difficult to decompose. The enzymes that process it are pretty specialized and don't seem to connect to normal bacterial metabolic pathways in an obvious way."

The researchers determined which chemicals are processed by the YfdE enzyme, following a hunch that it would use oxalate. Their results connected oxalate degradation to the core of bacterial metabolism.

Assigning a function to YfdE may help identify beneficial bacteria that could serve as probiotic agents in the human gastrointestinal tract to reduce the risk of kidney stone formation. Kidney stones, which affect more than 5 percent of the U.S. population, can cause painful blockages of the urinary tract.

"If we understand what bacteria need to degrade oxalate, then we might have a better idea how to identify strains that can do that, and thereby suppress the uptake of dietary oxalate" he said. "There are probably bacteria out there that have engineered themselves to do this for us."

Genome-sequencing information will increase the speed of the search, Kappock said.

"Because we've figured out what the gene product does, we will be able to find it in any organism and can zero in on those that might be beneficial," he said.

The researchers used X-ray crystallography to pinpoint the most important regions of the YfdE enzyme.

Kappock said the information has other applications, as well. Scientists and engineers who are interested in mapping and reprogramming microbial metabolism now know what one more gene product does.

"Our one piece of the puzzle will help others understand other metabolic networks," he said.

Agricultural Research at Purdue, the National Science Foundation and the U.S. Department of Energy funded the research.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Abstract:

Acetyl-CoA:Oxalate CoA-transferase 1 Function and X-ray Crystal Structure of Escherichia coli YfdE

Elwood A. Mullins 1, 2; Kelly L. Sullivan 1; T. Joseph Kappock 1;

1 Dept. of Biochemistry, Purdue University, West Lafayette, Indiana, USA

2 Dept. of Chemistry, Washington University, St. Louis, Missouri, USA

Many food plants accumulate oxalate, which humans absorb but do not metabolize, leading to the formation of urinary stones. The commensal bacterium Oxalobacter formigenes consumes oxalate by converting it to oxalyl-CoA, which is decarboxylated by oxalyl-CoA decarboxylase (OXC). OXC and the class III CoA-transferase formyl-CoA:oxalate CoA-transferase (FCOCT) are widespread among bacteria, including many that have no apparent ability to degrade or to resist external oxalate. The EvgA acid response regulator activates transcription of the Escherichia coli yfdXWUVE operon encoding YfdW (FCOCT), YfdU (OXC), and YfdE, a class III CoA-transferase that is ~30% identical to YfdW. YfdW and YfdU are necessary and sufficient for oxalate-induced protection against a subsequent acid challenge; neither of the other genes has a known function. We report the purification, in vitro characterization, 2.1- A crystal structure, and functional assignment of YfdE. YfdE and UctC, an orthologue from the obligate aerobe Acetobacter aceti, perform the reversible conversion of acetyl-CoA and oxalate to oxalyl-CoA and acetate. The annotation of YfdE as acetyl-CoA:oxalate CoA-transferase (ACOCT) expands the scope of metabolic pathways linked to oxalate catabolism and the oxalate-induced acid tolerance response. FCOCT and ACOCT active sites contain distinctive, conserved active site loops (the glycine-rich loop and the GNxH loop, respectively) that appear to encode substrate specificity.

Purdue University

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