As the threat of bioterrorism grows, the military must keep pace by protecting their soldiers against potential biological agents such as Anthrax. Currently, the US military uses an injectable form of vaccine to immunize its soldiers against the threat of anthrax spores. This vaccine requires six does and annual boosters to remain effective (http://www.msnbc.msn.com/id/20323558/). As any individual who has been immunized by the fine staff of the UCHSC mouse colonies can tell you, even a single immunization can be painful and traumatic. Recently, a more effective, inhalation vaccine has been discovered and brought to market by a company called NanoBio Corporation of Ann Arbor, MI.
This new vaccine relies on technology discovered at the University of Michigan in James Baker’s lab that uses a new adjuvant/delivery method to increase the uptake efficiency of antigens by dendritic cells, increasing the vaccine’s overall effectiveness. An adjuvant is a substance that elicits an immune response and activates the innate immune system, resulting in inflammation and enhancing the action of the vaccine (http://en.wikipedia.org/wiki/Immunologic_adjuvant). In this new technology, protective antigen (PA) of B anthracis, is presented to dendritic cells in a “nanoemulsion”. These nanoemulsion particles lyse viruses and retain some of their antigenic determinants. Due to the small size of these particles, endocytosis by antigen presenting cells becomes a more efficient process, resulting in an enhanced adaptive immune response. This in turn leads to better immunological memory cell formation and a more complete protective immunity to Anthrax (Bielinska et al. 2007. “Mucosal Immunization with Novel Nanoemulsion-Based Recombinant Anthrax Protective Antigen Vaccine Protects against Bacillus anthracis Spore Challenge.” Infection and Immunity 75:4020-4029)
In contrast, conventional adjuvants include aluminum potassium sulfate or aluminum hydroxide. These along with biological pathogen associated molecular patterns (PAMPs) elicit a weaker immune response than this nanoemulsion technology. Furthermore, current vaccines carry the risk of toxicity and other side effects, whereas the NanoBio Corporation swears up and down on their website that this is an impossibility with their product (http://www.nanobio.com/Products/Mucosal-Vaccines.html). If their claims are accurate and this product completes clinical trials successfully, it could signal a time when the military no longer pokes and prods its recruits with needles.
20 September 2007
Cytokine Storm and Avian Influenza
Cytokine Storm and Avian Influenza
In class, Dr. Cohen referenced the cytokine storm in association with Multiple Sclerosis on Tuesday [1]. Interestingly enough, cytokine storm is associated with many conditions.
The term “Cytokine Storm” has been used more or less romantically with regard to the hot topics of Emergency Preparedness in a Post 9/11 world. A particular scientist, Dr. Michael Osterholm (http://www.cidrap.umn.edu/),[1, 2] has been one of the loudest voices (many consider him quite controversial – Look at this clip from the Oprah Show - http://www2.oprah.com/tows/pastshows/200601/tows_past_20060124.jhtml) in putting the possible “natural” biological threats like Avian Influenza (H5N1) in the popular media.
Specifically, the threat from bird flu is considered different from the seasonal flu from public health standpoint, in part, because young, healthy individuals might be most at risk. The reason for this – the “Cytokine storm”. It is believed that healthy, young individuals could over respond immunologically. Typically, in the public health community, the oldest and youngest individuals are the target of influenza vaccine programs because they are considered most at risk for death from the seasonal influenza outbreaks. This release of literally hundreds of pro-inflammatory cytokines simultaneous could result in sepsis, or septic shock syndrome, and put younger individuals at most risk. (SSS) (http://www.cytokinestorm.com/). In addition, there is some evidence that inhibition of this response would not protect an individual from the lethality of the infection [3], that the H5N1 infection might have a dual mechanism for causing death.
There is some historical precedent and justification for this - the Spanish Flu of 1918. This world wide Pandemic from the Type A H5N1 Influenza strain resulted in an estimate in upwards of 50 million deaths worldwide. Younger individuals ( e.g. military men, college students, etc.) seemed to be disproportionately affected.
References
1. Link H. The cytokine storm in multiple sclerosis. Mult Scler 1998;4:12-5.
2. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005;352:1839-42.
3. Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 2007;104:12479-81.
In class, Dr. Cohen referenced the cytokine storm in association with Multiple Sclerosis on Tuesday [1]. Interestingly enough, cytokine storm is associated with many conditions.
The term “Cytokine Storm” has been used more or less romantically with regard to the hot topics of Emergency Preparedness in a Post 9/11 world. A particular scientist, Dr. Michael Osterholm (http://www.cidrap.umn.edu/),[1, 2] has been one of the loudest voices (many consider him quite controversial – Look at this clip from the Oprah Show - http://www2.oprah.com/tows/pastshows/200601/tows_past_20060124.jhtml) in putting the possible “natural” biological threats like Avian Influenza (H5N1) in the popular media.
Specifically, the threat from bird flu is considered different from the seasonal flu from public health standpoint, in part, because young, healthy individuals might be most at risk. The reason for this – the “Cytokine storm”. It is believed that healthy, young individuals could over respond immunologically. Typically, in the public health community, the oldest and youngest individuals are the target of influenza vaccine programs because they are considered most at risk for death from the seasonal influenza outbreaks. This release of literally hundreds of pro-inflammatory cytokines simultaneous could result in sepsis, or septic shock syndrome, and put younger individuals at most risk. (SSS) (http://www.cytokinestorm.com/). In addition, there is some evidence that inhibition of this response would not protect an individual from the lethality of the infection [3], that the H5N1 infection might have a dual mechanism for causing death.
There is some historical precedent and justification for this - the Spanish Flu of 1918. This world wide Pandemic from the Type A H5N1 Influenza strain resulted in an estimate in upwards of 50 million deaths worldwide. Younger individuals ( e.g. military men, college students, etc.) seemed to be disproportionately affected.
References
1. Link H. The cytokine storm in multiple sclerosis. Mult Scler 1998;4:12-5.
2. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005;352:1839-42.
3. Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 2007;104:12479-81.
Inflammation and Infection in Clinical Stroke
A major cause of most coronary artery disease and the majority of ischemic stroke among humans is Atherosclerosis. Atherosclerosis is the process in which fatty acid deposits build up in the inner lining of arteries. Accumulation of fatty acid buildup results in a plaque that can significantly reduce blood flow and possibly even rupture. If they rupture they can cause blood clots to form which may block blood flow or travel to other parts of the body. Several studies suggest that there are several inflammatory mechanisms involved with the development and progression of Atherosclerosis. The cytokines IL-1 beta, IL-6 and TNF-alfa, nitric oxide synthase (NOS), cylcooxygenase-2 (COX-2) intrcelular adhesion molecule-1 (ICAM-1), matrix metalloproteinases, C-reactive protein and leukocytes are all involved with ischemic stroke. Studies suggest IL-6 and TNF alfa can have antiinflammatory, neuroprotective, and proinflammatory effects on ischemic stroke. Nitric oxide synthase produced early may be beneficial to vasodilation whereas if it is produced later may contribute to ischemic injury. Reactive oxygen species are a product of COX-2 reactions and are thought to increase tissue damage during cerebral ischemia. Adhesion molecules such as ICAM-1 are involved with leukocyte infiltration into the brain. Matrix metalloproteinases increase tissue damage and aide in the opening of the blood brain barrier. C-Reactive protein has received a lot of attention since its levels can be measured using a blood test and the protein levels increases during systemic inflammation. It is possible that this test can determine cardiovascular disease risk, and may help predict cardiovascular events such as heart attack and stroke. There are several studies which account for all of these inflammatory factors however little is still known of their actual effects on ischemic stroke. Some studies show the effects to be beneficial and some detrimental. What is known is that there seems to be a strong correlation with inflammation both before and after stroke, it is just unclear as to whether these processes are providing protective effects or further damaging cells and tissue.
Stroke also has a strong correlation with inflammatory conditions and infection. Studies have shown the bacteria Chlamydia pneumoniae may be a risk factor to stroke however it is still unclear. Chronic and recurrent respiratory infections, herpes viruses, periodontal disease and meningitis are just a few of the many conditions that may also cause an increased risk of ischemic stroke. Similar to the inflammatory factors and mechanisms of stroke, the connection of stroke to infections and inflammatory disorders is still unknown. Further scientific research is needed in the both of these areas to increase our knowledge and hopefully eliminate the numerous negative implications of stroke.
Stroke also has a strong correlation with inflammatory conditions and infection. Studies have shown the bacteria Chlamydia pneumoniae may be a risk factor to stroke however it is still unclear. Chronic and recurrent respiratory infections, herpes viruses, periodontal disease and meningitis are just a few of the many conditions that may also cause an increased risk of ischemic stroke. Similar to the inflammatory factors and mechanisms of stroke, the connection of stroke to infections and inflammatory disorders is still unknown. Further scientific research is needed in the both of these areas to increase our knowledge and hopefully eliminate the numerous negative implications of stroke.
tPA and the Time Frame of Administration
In one of the lay articles posted, it mentioned a treatment for strokes called tPA, or tissue plasminogen activator. Out of curiosity, I did some more research to find out more about it.
tPA is a serine protease that converts the proenzyme plasminogen to plasmin, which is an enzyme that breaks down the clotting factor fibrin. When fibrin is inactivated, the clots that normally cause the occlusion of blood flow in the cerebral blood vessels are broken down and the risk is minimized considerably. Like the article stated, the tPA must be administered intravenously within three hours of the initial symptoms of a stroke (in this case, it treats ischemic stroke which constitute about 80% of all strokes) in order to be used to its full potential and possibly prevent the serious long-term effects of ischemic stroke. A major issue surrounding the usage of tPA is that due to this short time period of effectiveness, only a small fraction of ischemic stroke patients are able to put it to use, approximately 3%.
But due to advances in imaging technology, researchers are beginning to find out that there are still some advantages to administering the tPA up to eight hours after the initial symptoms. The reason for this is that the neurons that are damaged by the lack of blood flow may not all be dead in this three hour time period. Newer CT scans and MRI's can now show us which of the affected neural tissue is dead so we can see if it is still beneficial to inject the tPA to salvage some of the tissue. And just as importantly, these scans can also tell us which patients are more susceptible to bleeding when given tPA; a problem that prevents the treatment for some patients even within the initially determined three-hour time period.
These advances in the research of tPA are very beneficial to the well-being of stroke patients, and hopefully researchers will continue to build upon the treatment methods for strokes.
tPA is a serine protease that converts the proenzyme plasminogen to plasmin, which is an enzyme that breaks down the clotting factor fibrin. When fibrin is inactivated, the clots that normally cause the occlusion of blood flow in the cerebral blood vessels are broken down and the risk is minimized considerably. Like the article stated, the tPA must be administered intravenously within three hours of the initial symptoms of a stroke (in this case, it treats ischemic stroke which constitute about 80% of all strokes) in order to be used to its full potential and possibly prevent the serious long-term effects of ischemic stroke. A major issue surrounding the usage of tPA is that due to this short time period of effectiveness, only a small fraction of ischemic stroke patients are able to put it to use, approximately 3%.
But due to advances in imaging technology, researchers are beginning to find out that there are still some advantages to administering the tPA up to eight hours after the initial symptoms. The reason for this is that the neurons that are damaged by the lack of blood flow may not all be dead in this three hour time period. Newer CT scans and MRI's can now show us which of the affected neural tissue is dead so we can see if it is still beneficial to inject the tPA to salvage some of the tissue. And just as importantly, these scans can also tell us which patients are more susceptible to bleeding when given tPA; a problem that prevents the treatment for some patients even within the initially determined three-hour time period.
These advances in the research of tPA are very beneficial to the well-being of stroke patients, and hopefully researchers will continue to build upon the treatment methods for strokes.
19 September 2007
stroke and brain ischemia
Stroke is the third most common cause of death in the United States and the leading cause of serious, long-term disability. Recent work in the area of stroke and brain ischemia have a significant inflammatory response (early responses) accompanying necrotic injury. Although later responses may be beneficial in recovery and repair, future studies are attempting to address the timing of inflammation responses. What this article does is discuss roles of specific cells types (leukocytes, endothelium, microglia, the extracellular matrix) as well as the intracellular inflammatory pathways. As well as discussing the mediators produced by inflammatory cells (cytokines, ROS, etc.) and then linking everything together in the process of inflammation following stroke.
This is an overview of inflammation following stroke beginning with brain ischemia which then triggers inflammatory responses in the presence of necrotic cells. This then generates ROS (reactive oxidative species) and produces inflammatory cytokines with neurons which initiate microglial activation that produces more cytokines causing upregulation of adhension molecules in the cerebral vasculature. At the same time chemokines lead to inflammatory cell chemotaxis to the ischemic brain. The adhesion molecules modulate adhesion of circulating leukocytes to the vascular endothelia and infiltration into the brain parenchyma. When in the brain, the activated leukocytes and microglia produce a diverse amount of inflammatory mediators such as matrix metalloproteinases, inducible nitric oxide synthase (generates nitric oxide), cytokes and more ROS. All which leads to brain edema, hemorrhage and eventually cell death.
When future studies are concluded about later responses playing a important role in recovery and repair, we will be able to reduce the risk of stroke and brain ischemia.
This is an overview of inflammation following stroke beginning with brain ischemia which then triggers inflammatory responses in the presence of necrotic cells. This then generates ROS (reactive oxidative species) and produces inflammatory cytokines with neurons which initiate microglial activation that produces more cytokines causing upregulation of adhension molecules in the cerebral vasculature. At the same time chemokines lead to inflammatory cell chemotaxis to the ischemic brain. The adhesion molecules modulate adhesion of circulating leukocytes to the vascular endothelia and infiltration into the brain parenchyma. When in the brain, the activated leukocytes and microglia produce a diverse amount of inflammatory mediators such as matrix metalloproteinases, inducible nitric oxide synthase (generates nitric oxide), cytokes and more ROS. All which leads to brain edema, hemorrhage and eventually cell death.
When future studies are concluded about later responses playing a important role in recovery and repair, we will be able to reduce the risk of stroke and brain ischemia.
17 September 2007
Dengue virus infection: Don't get it
Dengue virus infection-an interesting immunological explanation why you do not want to get it.
Dengue fever is a mosquito-borne (Aedes aegypti) tropical disease that is caused by any of the four serotypes of the Dengue virus (DV). (A “serotype” is a specific microorganism as characterized by serologic typing-aka, testing for recognizable antigens on the surface of the microorganism.)
There are an estimated 50-100 million cases of Dengue fever (DF) per annum worldwide, 500000 of which result in the severe form of the disease, Dengue hemorrhagic fever (DHF) marked by abnormal vascular permeability.
Humans, mosquitos and some primates can be infected through the bite of infected A. aegypti that breed in domestic and peridomestic water containers.
DV causes an acute infection that is effectively controlled after 3 to 7 days. Individuals that have recovered from DV infection are immune to re-challenge with the same type but not with other serotypes of DV. Sequential infection with a second serotype usually results in the severe form of disease, DHF. In short, this virus can and will cause a very painful death in most people who get infected again, but this time with a different serotype.
If you think about this, the question that arises is the following:
What makes the secondary infection with the virus much worse than the first?
Interestingly, this phenomenon has little to do with the direct activation of immune cells through antigen expressed by the infecting virus.
Studies have lead to the hypothesis that infection with a second dengue virus serotype results in antibody-mediated immune enhancement. Antibodies generated against the first infecting serotype (#1) will bind the second (#2). Unfortunately, these antibodies are not able to neutralize serotype #2 and they will facilitate FC-receptor mediated and complement-mediated virus-uptake and replication in phagocytic cells (ADE-antibody-dependent enhancement). This means that the same antibody that works well to decrease the number of the first infecting virus does the exact opposite to the second infecting virus. By helping it to enter phagocytic cells it helps more viral particles to grow and more viral offspring will infect new cells. In the end, the virus will take over and the patient’s immune system will not be able to fight it anymore.
This increased severity of a secondary infection has been observed in different virus infections in vitro (aka, in a test tube) and one can imagine that it could potentially be a problem when new vaccines are created. For example, imagine giving a vaccine against serotype 1 of the HIV virus and the person is getting infected with serotype 2. This means that the person’s immune system has already created antibodies against serotype 1 (this is the whole idea behind vaccinations) that –unfortunately- can help to enhance viral entry of serotype 2 into the host cell. As a result, the infectivity of serotype 2 increases.
Selected references
Dengue fever is a mosquito-borne (Aedes aegypti) tropical disease that is caused by any of the four serotypes of the Dengue virus (DV). (A “serotype” is a specific microorganism as characterized by serologic typing-aka, testing for recognizable antigens on the surface of the microorganism.)
There are an estimated 50-100 million cases of Dengue fever (DF) per annum worldwide, 500000 of which result in the severe form of the disease, Dengue hemorrhagic fever (DHF) marked by abnormal vascular permeability.
Humans, mosquitos and some primates can be infected through the bite of infected A. aegypti that breed in domestic and peridomestic water containers.
DV causes an acute infection that is effectively controlled after 3 to 7 days. Individuals that have recovered from DV infection are immune to re-challenge with the same type but not with other serotypes of DV. Sequential infection with a second serotype usually results in the severe form of disease, DHF. In short, this virus can and will cause a very painful death in most people who get infected again, but this time with a different serotype.
If you think about this, the question that arises is the following:
What makes the secondary infection with the virus much worse than the first?
Interestingly, this phenomenon has little to do with the direct activation of immune cells through antigen expressed by the infecting virus.
Studies have lead to the hypothesis that infection with a second dengue virus serotype results in antibody-mediated immune enhancement. Antibodies generated against the first infecting serotype (#1) will bind the second (#2). Unfortunately, these antibodies are not able to neutralize serotype #2 and they will facilitate FC-receptor mediated and complement-mediated virus-uptake and replication in phagocytic cells (ADE-antibody-dependent enhancement). This means that the same antibody that works well to decrease the number of the first infecting virus does the exact opposite to the second infecting virus. By helping it to enter phagocytic cells it helps more viral particles to grow and more viral offspring will infect new cells. In the end, the virus will take over and the patient’s immune system will not be able to fight it anymore.
This increased severity of a secondary infection has been observed in different virus infections in vitro (aka, in a test tube) and one can imagine that it could potentially be a problem when new vaccines are created. For example, imagine giving a vaccine against serotype 1 of the HIV virus and the person is getting infected with serotype 2. This means that the person’s immune system has already created antibodies against serotype 1 (this is the whole idea behind vaccinations) that –unfortunately- can help to enhance viral entry of serotype 2 into the host cell. As a result, the infectivity of serotype 2 increases.
Selected references
- Tirado SM, Yoon KJ. 2003. Antibody-dependent enhancement of virus infection and disease. Viral Immunol 13(6): 387
- Takada A, Kawaoka Y. 2003. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol 16(1): 69
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