From Science Daily website (see original article).
Mar. 1, 2013 — New research in the Journal of Clinical Investigation reveals that tumours in melanoma patients deliberately create conditions that knock out the body's 'premier' immune defence and instead attract a weaker immune response unable to kill off the tumour's cancerous cells.
The study also highlights a potential antibody biomarker that could help predict prognosis and identify which patients are most likely to respond to specific treatments.
The research, led by Dr Sophia Karagiannis and Professor Frank Nestle at King's College London, UK, was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London.
Karagiannis and colleagues have previously shown that, in patients with melanoma, antibodies are produced that can attack tumour cells.
Despite this, the patient's immune system is often ineffective in preventing the cancer from progressing.
The body's B cells (part of the immune system) produce a total of 5 different antibody classes. The most common, IgG, comprises 4 types (or subclasses) of which the researchers have shown that IgG1 subclass antibodies are the most effective at activating immune cells, while antibodies of the IgG4 subclass are thought to be the least efficient.
In this new research, the authors analysed tumour tissue and blood donated by 80 patients from the melanoma clinic of St John's Institute of Dermatology at Guy's and St Thomas', as well as tissue and blood from healthy volunteers.
By analysing the lesions found in melanoma, the authors show that melanoma tumours not only create conditions that attract IgG4, the weakest possible response, but also that IgG4 antibodies interfere with the action of any IgG1 antibodies circulating.
"We were able to mimic the conditions created by melanoma tumours and showed that B cells can be polarised to produce IgG4 antibodies in the presence of cancer cells," says Dr Karagiannis.
In the presence of healthy cells, the body's immune response functions normally, and IgG1 are the main antibodies circulating.
To better understand the functional implications of IgG4 subclass antibodies in cancer, the authors engineered these two antibodies (IgG1, IgG4) against a tumour antigen and demonstrated that unlike IgG1, the IgG4 antibody was ineffective in triggering immune cells to kill cancer cells.
Importantly, IgG4 also blocked the tumour cell killing actions of IgG1, thus preventing this antibody from activating immune cells to destroy tumours.
Additionally, using samples from 33 patients, the authors found that patients with higher IgG4 levels in their blood are more likely to have a less favourable prognosis compared to those whose blood levels of IgG4 are closer to normal levels.
This suggests that IgG4 may help assist in predicting disease progression.
"This work bears important implications for future therapies since not only are IgG4 antibodies ineffective in activating immune cells to kill tumours but they also work by blocking antibodies from killing tumour cells," says Dr Karagiannis.
"The latter means that IgG4 not only prevents the patient's more powerful antibodies from eradicating cancer, but could also explain why treatments may be hindered by those native IgG4 antibodies found in patients, making therapeutic antibodies less effective."
"Now, with the help of our NIHR Biomedical Research Centre, more work needs to be done on developing IgG4 as a potential clinical and prognostic biomarker which can improve patient care by informing clinical decisions and helping to identify patients most likely to respond to treatments," concludes Professor Nestle.
Therefore, these findings are expected to inform the design and help improve the potency and efficacy of future therapies for cancer.
"This study can also inform the rational design of novel strategies to counteract IgG4 actions."
The authors are now broadening the study by examining larger groups of patients.
The team is analysing blood and sera from patients with melanoma and from patients with other cancers to determine whether the presence of IgG4 could inform patient outcomes or predict responses to therapy.
They are also analysing the mechanisms of IgG4 blockade of new and existing therapeutic antibody candidates, and developing new antibody candidates which may be less prone to IgG4 blockade.
Visualizzazione post con etichetta immune system. Mostra tutti i post
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domenica 3 marzo 2013
martedì 12 febbraio 2013
Zinc Helps Against Infection by Tapping Brakes in Immune Response
From Science Daily website (see original article).
Feb. 7, 2013 — New research suggests that zinc helps control infections by gently tapping the brakes on the immune response in a way that prevents out-of-control inflammation that can be damaging and even deadly.
Scientists determined in human cell culture and animal studies that a protein lures zinc into key cells that are first-responders against infection. The zinc then interacts with a process that is vital to the fight against infection and by doing so helps balance the immune response.
This study revealed for the first time that zinc homes in on this pathway and helps shut it down, effectively ensuring that the immune response does not spiral out of control. The team led by Ohio State University researchers also found that if there is not enough zinc available at the time of infection, the consequences include excessive inflammation.
In this research, zinc's activity was studied in the context of sepsis, a devastating systemic response to infection that is a common cause of death in intensive-care unit patients. But scientists say these findings might also help explain why taking zinc tablets at the start of a common cold appears to help stem the effects of the illness.
"We do believe that to some extent, these findings are going to be applicable to other important areas of disease beyond sepsis," said Daren Knoell, senior author of the study and a professor of pharmacy and internal medicine at Ohio State. "Without zinc on board to begin with, it could increase vulnerability to infection. But our work is focused on what happens once you get an infection -- if you are deficient in zinc you are at a disadvantage because your defense system is amplified, and inappropriately so.
"The benefit to health is explicit: Zinc is beneficial because it stops the action of a protein, ultimately preventing excess inflammation."
While this study and previous work linking zinc deficiency to inflammation might suggest that supplementation could help very sick ICU patients, it's still too early to make that leap.
"I think the question is whom to give zinc to, if anybody at all. We predict that not everybody in the ICU with sepsis needs zinc, but I anticipate that a proportion of them would," Knoell said. "Zinc is a critical element that we get from our diet, but we do not think we can give zinc and fix everything. Usually, if there is zinc deficiency, we would expect to see other nutrient deficiencies, too."
Zinc deficiency affects about 2 billion people worldwide, including an estimated 40 percent of the elderly in the United States -- who are also among the most likely Americans to end up in an ICU.
The research is published in the journal Cell Reports.
Knoell's lab previously showed that zinc-deficient mice developed overwhelming inflammation in response to sepsis compared to mice on a normal diet. Zinc supplementation improved outcomes in the zinc-deficient mice.
Until now, the beneficial effects of zinc in combating infection have not been fully understood at the molecular level. This is because zinc has numerous complex jobs in the body and interacts with thousands of proteins to sustain human life. Of all the zinc contained in our bodies, only about 10 percent of it is readily accessible to help fight off an infection, said Knoell, also an investigator in Ohio State's Davis Heart and Lung Research Institute.
"We believe that our findings help to narrow an important gap that has existed in our understanding of how this relatively simple metal helps us defend ourselves from infection," he said.
In this work, Knoell and colleagues sought to zero in on zinc's role in preventing the inflammation that had led to such poor outcomes in the zinc-deficient mice.
In experiments using human monocytes -- cells involved in the first line of defense against an invading pathogen -- the researchers examined what happens when the immune response is launched.
When a pathogen is recognized, a series of molecules wake up from dormancy to create a process that activates the innate immune response. A major part of this process involves the NF-κB pathway, named for a highly active protein that is known to play an important role in the immune response to infection. Once NF-κB is activated and enters the nucleus, a gene is expressed that produces a zinc transporter called ZIP8. The transporter then rapidly mobilizes to the cell's wall, where it can then shuttle zinc from the bloodstream into the cell.
After cell entry, zinc is then directed to and binds to a different protein in the NF-κB pathway. When this happens, it halts any further activity in that process. The cumulative impact of this feedback loop is that it prevents excessive inflammation, which can be damaging to cells and the body.
"The immune system has to work under very strict balance, and this is a classic example of where more is not always better," Knoell said. "We want a robust inflammatory response, which is part of our natural programming to defend us against a bug. But if that is unchecked, and there is too much inflammation, then it not only attacks the pathogen but can also cause much more collateral damage."
The researchers knew from previously published experiments that if ZIP8 activation was prevented, zinc couldn't come into the cell and the cells died. In the current study, collaborators who specialize in computational modeling of protein interactions helped identify the likely target of zinc once it enters the cell: specific binding sites on a protein called IKKB. When researchers allowed this protein to function unchecked in mice with zinc deficiency, the animals developed excessive inflammation in response to sepsis -- confirmation that IKKB was zinc's target to turn off the inflammatory pathway.
"There are certainly other zinc targets in the cell, but we found evidence that zinc is brought in by ZIP8 to turn the pathway off by interacting with this protein at a specific region," Knoell said.
The recommended daily allowance for zinc ranges from 8 to 11 milligrams for most adults. Red meat and poultry provide the majority of zinc in the American diet, according to the National Institutes of Health. Other food sources include beans, nuts, some shellfish, whole grains, fortified cereals and dairy products. The nutrient is also available in supplement form. Knoell said it is possible but relatively uncommon to take in too much zinc to reach toxic levels.
His lab is continuing to study the NF-κB pathway, inflammation and zinc deficiency in other disease processes. And though zinc would be inexpensive and easy to take as a supplement, Knoell said many questions remain about whether zinc should be considered as an intervention for specific disorders.
"There might be therapeutic implications about giving supplemental zinc in a strategic manner to help improve some people with certain conditions. But also, could we learn from this so someday we can be more diagnostic about who it is that needs zinc? And if so, what dose and for how long?" he said.
This work was supported by the National Institutes of Health and the Lifeline of Ohio Tissue Procurement Agency.
Co-authors include Ming-Jie Liu, Shengying Bao, Charlie Pyle, Andrew Rudawsky and Mark Wewers of the Davis Heart and Lung Research Institute; Marina Gálvez-Peralta and Daniel Nebert of the University of Cincinnati Medical Center; Ryan Pavlovicz and Chenglong Li of Ohio State's Biophysics Program (Li is also in the College of Pharmacy); and David Killilea of Children's Hospital Oakland Research Institute.
Feb. 7, 2013 — New research suggests that zinc helps control infections by gently tapping the brakes on the immune response in a way that prevents out-of-control inflammation that can be damaging and even deadly.
Scientists determined in human cell culture and animal studies that a protein lures zinc into key cells that are first-responders against infection. The zinc then interacts with a process that is vital to the fight against infection and by doing so helps balance the immune response.
This study revealed for the first time that zinc homes in on this pathway and helps shut it down, effectively ensuring that the immune response does not spiral out of control. The team led by Ohio State University researchers also found that if there is not enough zinc available at the time of infection, the consequences include excessive inflammation.
In this research, zinc's activity was studied in the context of sepsis, a devastating systemic response to infection that is a common cause of death in intensive-care unit patients. But scientists say these findings might also help explain why taking zinc tablets at the start of a common cold appears to help stem the effects of the illness.
"We do believe that to some extent, these findings are going to be applicable to other important areas of disease beyond sepsis," said Daren Knoell, senior author of the study and a professor of pharmacy and internal medicine at Ohio State. "Without zinc on board to begin with, it could increase vulnerability to infection. But our work is focused on what happens once you get an infection -- if you are deficient in zinc you are at a disadvantage because your defense system is amplified, and inappropriately so.
"The benefit to health is explicit: Zinc is beneficial because it stops the action of a protein, ultimately preventing excess inflammation."
While this study and previous work linking zinc deficiency to inflammation might suggest that supplementation could help very sick ICU patients, it's still too early to make that leap.
"I think the question is whom to give zinc to, if anybody at all. We predict that not everybody in the ICU with sepsis needs zinc, but I anticipate that a proportion of them would," Knoell said. "Zinc is a critical element that we get from our diet, but we do not think we can give zinc and fix everything. Usually, if there is zinc deficiency, we would expect to see other nutrient deficiencies, too."
Zinc deficiency affects about 2 billion people worldwide, including an estimated 40 percent of the elderly in the United States -- who are also among the most likely Americans to end up in an ICU.
The research is published in the journal Cell Reports.
Knoell's lab previously showed that zinc-deficient mice developed overwhelming inflammation in response to sepsis compared to mice on a normal diet. Zinc supplementation improved outcomes in the zinc-deficient mice.
Until now, the beneficial effects of zinc in combating infection have not been fully understood at the molecular level. This is because zinc has numerous complex jobs in the body and interacts with thousands of proteins to sustain human life. Of all the zinc contained in our bodies, only about 10 percent of it is readily accessible to help fight off an infection, said Knoell, also an investigator in Ohio State's Davis Heart and Lung Research Institute.
"We believe that our findings help to narrow an important gap that has existed in our understanding of how this relatively simple metal helps us defend ourselves from infection," he said.
In this work, Knoell and colleagues sought to zero in on zinc's role in preventing the inflammation that had led to such poor outcomes in the zinc-deficient mice.
In experiments using human monocytes -- cells involved in the first line of defense against an invading pathogen -- the researchers examined what happens when the immune response is launched.
When a pathogen is recognized, a series of molecules wake up from dormancy to create a process that activates the innate immune response. A major part of this process involves the NF-κB pathway, named for a highly active protein that is known to play an important role in the immune response to infection. Once NF-κB is activated and enters the nucleus, a gene is expressed that produces a zinc transporter called ZIP8. The transporter then rapidly mobilizes to the cell's wall, where it can then shuttle zinc from the bloodstream into the cell.
After cell entry, zinc is then directed to and binds to a different protein in the NF-κB pathway. When this happens, it halts any further activity in that process. The cumulative impact of this feedback loop is that it prevents excessive inflammation, which can be damaging to cells and the body.
"The immune system has to work under very strict balance, and this is a classic example of where more is not always better," Knoell said. "We want a robust inflammatory response, which is part of our natural programming to defend us against a bug. But if that is unchecked, and there is too much inflammation, then it not only attacks the pathogen but can also cause much more collateral damage."
The researchers knew from previously published experiments that if ZIP8 activation was prevented, zinc couldn't come into the cell and the cells died. In the current study, collaborators who specialize in computational modeling of protein interactions helped identify the likely target of zinc once it enters the cell: specific binding sites on a protein called IKKB. When researchers allowed this protein to function unchecked in mice with zinc deficiency, the animals developed excessive inflammation in response to sepsis -- confirmation that IKKB was zinc's target to turn off the inflammatory pathway.
"There are certainly other zinc targets in the cell, but we found evidence that zinc is brought in by ZIP8 to turn the pathway off by interacting with this protein at a specific region," Knoell said.
The recommended daily allowance for zinc ranges from 8 to 11 milligrams for most adults. Red meat and poultry provide the majority of zinc in the American diet, according to the National Institutes of Health. Other food sources include beans, nuts, some shellfish, whole grains, fortified cereals and dairy products. The nutrient is also available in supplement form. Knoell said it is possible but relatively uncommon to take in too much zinc to reach toxic levels.
His lab is continuing to study the NF-κB pathway, inflammation and zinc deficiency in other disease processes. And though zinc would be inexpensive and easy to take as a supplement, Knoell said many questions remain about whether zinc should be considered as an intervention for specific disorders.
"There might be therapeutic implications about giving supplemental zinc in a strategic manner to help improve some people with certain conditions. But also, could we learn from this so someday we can be more diagnostic about who it is that needs zinc? And if so, what dose and for how long?" he said.
This work was supported by the National Institutes of Health and the Lifeline of Ohio Tissue Procurement Agency.
Co-authors include Ming-Jie Liu, Shengying Bao, Charlie Pyle, Andrew Rudawsky and Mark Wewers of the Davis Heart and Lung Research Institute; Marina Gálvez-Peralta and Daniel Nebert of the University of Cincinnati Medical Center; Ryan Pavlovicz and Chenglong Li of Ohio State's Biophysics Program (Li is also in the College of Pharmacy); and David Killilea of Children's Hospital Oakland Research Institute.
venerdì 8 febbraio 2013
Loneliness, Like Chronic Stress, Taxes the Immune System, Researchers Find
From Science Daily website (see original article).
Jan. 19, 2013 — New research links loneliness to a number of dysfunctional immune responses, suggesting that being lonely has the potential to harm overall health.
Researchers found that people who were more lonely showed signs of elevated latent herpes virus reactivation and produced more inflammation-related proteins in response to acute stress than did people who felt more socially connected.
These proteins signal the presence of inflammation, and chronic inflammation is linked to numerous conditions, including coronary heart disease, Type 2 diabetes, arthritis and Alzheimer's disease, as well as the frailty and functional decline that can accompany aging.
Reactivation of a latent herpes virus is known to be associated with stress, suggesting that loneliness functions as a chronic stressor that triggers a poorly controlled immune response.
"It is clear from previous research that poor-quality relationships are linked to a number of health problems, including premature mortality and all sorts of other very serious health conditions.
And people who are lonely clearly feel like they are in poor-quality relationships," said Lisa Jaremka, a postdoctoral fellow at the Institute for Behavioral Medicine Research at Ohio State University and lead author of the research.
"One reason this type of research is important is to understand how loneliness and relationships broadly affect health.
The more we understand about the process, the more potential there is to counter those negative effects -- to perhaps intervene.
If we don't know the physiological processes, what are we going to do to change them?"
The results are based on a series of studies conducted with two populations: a healthy group of overweight middle-aged adults and a group of breast cancer survivors.
The researchers measured loneliness in all studies using the UCLA Loneliness Scale, a questionnaire that assesses perceptions of social isolation and loneliness.
Jaremka will present the research January 19 at the Society for Personality and Social Psychology annual meeting in New Orleans.
The researchers first sought to obtain a snapshot of immune system behavior related to loneliness by gauging levels of antibodies in the blood that are produced when herpes viruses are reactivated.
Participants were 200 breast cancer survivors who were between two months and three years past completion of cancer treatment with an average age of 51 years.
Their blood was analyzed for the presence of antibodies against Epstein-Barr virus and cytomegalovirus.
Both are herpes viruses that infect a majority of Americans.
About half of infections do not produce illness, but once a person is infected, the viruses remain dormant in the body and can be reactivated, resulting in elevated antibody levels, or titers -- again, often producing no symptoms but hinting at regulatory problems in the cellular immune system.
Lonelier participants had higher levels of antibodies against cytomegalovirus than did less lonely participants, and those higher antibody levels were related to more pain, depression and fatigue symptoms.
No difference was seen in Epstein-Barr virus antibody levels, possibly because this reactivation is linked to age and many of these participants were somewhat older, meaning reactivation related to loneliness would be difficult to detect, Jaremka said.
Previous research has suggested that stress can promote reactivation of these viruses, also resulting in elevated antibody titers.
"The same processes involved in stress and reactivation of these viruses is probably also relevant to the loneliness findings," Jaremka said. "Loneliness has been thought of in many ways as a chronic stressor -- a socially painful situation that can last for quite a long time."
In an additional set of studies, the scientists sought to determine how loneliness affected the production of proinflammatory proteins, or cytokines, in response to stress.
These studies were conducted with 144 women from the same group of breast cancer survivors and a group of 134 overweight middle-aged and older adults with no major health problems.
Baseline blood samples were taken from all participants, who were then subjected to stress -- they were asked to deliver an impromptu five-minute speech and perform a mental arithmetic task in front of a video camera and three panelists.
Researchers followed by stimulating the participants' immune systems with lipopolysaccharide, a compound found on bacterial cell walls that is known to trigger an immune response.
In both populations, those who were lonelier produced significantly higher levels of a cytokine called interleukin-6, or IL-6, in response to acute stress than did participants who were more socially connected.
Levels of another cytokine, tumor necrosis factor-alpha, also rose more dramatically in lonelier participants than in less lonely participants, but the findings were significant by statistical standards in only one study group, the healthy adults.
In the study with breast cancer survivors, researchers also tested for levels of the cytokine interleukin 1-beta, which was produced at higher levels in lonelier participants.
When the scientists controlled for a number of factors, including sleep quality, age and general health measures, the results were the same.
"We saw consistency in the sense that more lonely people in both studies had more inflammation than less lonely people," Jaremka said.
"It's also important to remember the flip side, which is that people who feel very socially connected are experiencing more positive outcomes," she said.
Jan. 19, 2013 — New research links loneliness to a number of dysfunctional immune responses, suggesting that being lonely has the potential to harm overall health.
Researchers found that people who were more lonely showed signs of elevated latent herpes virus reactivation and produced more inflammation-related proteins in response to acute stress than did people who felt more socially connected.
These proteins signal the presence of inflammation, and chronic inflammation is linked to numerous conditions, including coronary heart disease, Type 2 diabetes, arthritis and Alzheimer's disease, as well as the frailty and functional decline that can accompany aging.
Reactivation of a latent herpes virus is known to be associated with stress, suggesting that loneliness functions as a chronic stressor that triggers a poorly controlled immune response.
"It is clear from previous research that poor-quality relationships are linked to a number of health problems, including premature mortality and all sorts of other very serious health conditions.
And people who are lonely clearly feel like they are in poor-quality relationships," said Lisa Jaremka, a postdoctoral fellow at the Institute for Behavioral Medicine Research at Ohio State University and lead author of the research.
"One reason this type of research is important is to understand how loneliness and relationships broadly affect health.
The more we understand about the process, the more potential there is to counter those negative effects -- to perhaps intervene.
If we don't know the physiological processes, what are we going to do to change them?"
The results are based on a series of studies conducted with two populations: a healthy group of overweight middle-aged adults and a group of breast cancer survivors.
The researchers measured loneliness in all studies using the UCLA Loneliness Scale, a questionnaire that assesses perceptions of social isolation and loneliness.
Jaremka will present the research January 19 at the Society for Personality and Social Psychology annual meeting in New Orleans.
The researchers first sought to obtain a snapshot of immune system behavior related to loneliness by gauging levels of antibodies in the blood that are produced when herpes viruses are reactivated.
Participants were 200 breast cancer survivors who were between two months and three years past completion of cancer treatment with an average age of 51 years.
Their blood was analyzed for the presence of antibodies against Epstein-Barr virus and cytomegalovirus.
Both are herpes viruses that infect a majority of Americans.
About half of infections do not produce illness, but once a person is infected, the viruses remain dormant in the body and can be reactivated, resulting in elevated antibody levels, or titers -- again, often producing no symptoms but hinting at regulatory problems in the cellular immune system.
Lonelier participants had higher levels of antibodies against cytomegalovirus than did less lonely participants, and those higher antibody levels were related to more pain, depression and fatigue symptoms.
No difference was seen in Epstein-Barr virus antibody levels, possibly because this reactivation is linked to age and many of these participants were somewhat older, meaning reactivation related to loneliness would be difficult to detect, Jaremka said.
Previous research has suggested that stress can promote reactivation of these viruses, also resulting in elevated antibody titers.
"The same processes involved in stress and reactivation of these viruses is probably also relevant to the loneliness findings," Jaremka said. "Loneliness has been thought of in many ways as a chronic stressor -- a socially painful situation that can last for quite a long time."
In an additional set of studies, the scientists sought to determine how loneliness affected the production of proinflammatory proteins, or cytokines, in response to stress.
These studies were conducted with 144 women from the same group of breast cancer survivors and a group of 134 overweight middle-aged and older adults with no major health problems.
Baseline blood samples were taken from all participants, who were then subjected to stress -- they were asked to deliver an impromptu five-minute speech and perform a mental arithmetic task in front of a video camera and three panelists.
Researchers followed by stimulating the participants' immune systems with lipopolysaccharide, a compound found on bacterial cell walls that is known to trigger an immune response.
In both populations, those who were lonelier produced significantly higher levels of a cytokine called interleukin-6, or IL-6, in response to acute stress than did participants who were more socially connected.
Levels of another cytokine, tumor necrosis factor-alpha, also rose more dramatically in lonelier participants than in less lonely participants, but the findings were significant by statistical standards in only one study group, the healthy adults.
In the study with breast cancer survivors, researchers also tested for levels of the cytokine interleukin 1-beta, which was produced at higher levels in lonelier participants.
When the scientists controlled for a number of factors, including sleep quality, age and general health measures, the results were the same.
"We saw consistency in the sense that more lonely people in both studies had more inflammation than less lonely people," Jaremka said.
"It's also important to remember the flip side, which is that people who feel very socially connected are experiencing more positive outcomes," she said.
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