I tried to access the parasitic worm article that Dr. Cohen posted but couldn’t without subscribing so I did a little snooping around to see what I could find out about the Helminthic Therapy. As discussed in class, this is the method of trying to treat IBD by ingesting thousands of these parasitic worms. Apparently, researchers decided to try this out after seeing the positive correlation between the number of people inflicted with IBD and the level of industrialization of the country they live in. The worms that they use are classes of parasitic intestinal nematodes, basically, worms that can live in the digestive tract.
First of all, the mechanisms behind this therapy seem to be that the T regulatory cells that secrete anti-inflammatory cytokines, require exposure to microorganisms that have low pathogenicity (i.e. helminth worms) to reach their full potential. To make the immune system stronger, it needs to be exposed to viruses, bacteria, and pathogens that won’t kill us, kind of like the idea behind vaccines. Whatever doesn’t kill us, just makes us stronger. This would help explain why the more industrialized a nation becomes, the more incidence of IBD are reported. It is kind of funny, the cleaner we get, the weaker we get.
Secondly, the administration of the therapy is as follows: “Patients are normally started with four separate doses taken every one to three weeks. Starting dose is normally 500 ova/dose, for the first 4 doses. Failure to respond to the first four doses will result in an increase in dose to 1000 ova/dose, up to a maximum of 2500 ova/dose every two weeks. A clinical trial on patients with ulcerative colitis indicated that 13 of 30 patients, given 2500 ova/dose bi-weekly for a twelve week period, showed improvement in their disease index activity. Better results were obtained in Crohn’s patients, with a 72% remission rate following eight doses of 2500 ova over a 24 week period. No side effects were reported in either study” (wikipedia).
Say goodbye to the 5 second rule.
http://en.wikipedia.org/wiki/Helminthic_therapy
29 February 2008
27 February 2008
Infl ammatory bowel disease: cause and immunobiology
A large part of this article talked about several primary events seen in patients with inflammatory bowel disease. First, people with IBS tend to have leaky epithelial barriers(increased permeability) preceding the onset of disease. Furthermore, healthy individuals that are first-degree relatives of patients with IBD also show permeability defects. I am curious as to why this does not lead to the disease in these people. Of course, there are other factors but this is a highly genetic disease. Does anybody have insight into this??
Other primary events include:
*disturbed immune mechanisms-different TLR expression, upregulation of NOD2 in epithelial cells, which may compromise the ability to eliminate pathogenic microbes, leading to inflammation.
*disturbed antigen recognition and processing- animals studies show incorrect recognition of commensal bacteria and induction of a proinflammatory response normally caused in response to pathogens. Also, patients show an increase in active dendritic cells that prolong their survival and maintain inflammation, and a decrease in immature dendritic cells. This may contribute to the repeated activation of memory t-cells or failure to delete them.
*atypical antigen presenting cells become potent effector-T-cells
*absense of t-cell apoptosis
*effecor T-cells predominate over regulatory T-cells
***STRESS- increased SNS activity is shown to cause increased colonic paracellular permaeability. I found this to be the most interesting!! The article talks about how the biggest therapeutic challenge is to develop an approach to prevention of the initation of the inflammatory cascade before tissue injury occurs. One thing that we have control over is stress! Maybe if these genetically predisposed people chill out, it will make a difference in there future health status! Although I doubt that this alone will make the difference, it is an important factor in this disease, as well as health in general.
Other primary events include:
*disturbed immune mechanisms-different TLR expression, upregulation of NOD2 in epithelial cells, which may compromise the ability to eliminate pathogenic microbes, leading to inflammation.
*disturbed antigen recognition and processing- animals studies show incorrect recognition of commensal bacteria and induction of a proinflammatory response normally caused in response to pathogens. Also, patients show an increase in active dendritic cells that prolong their survival and maintain inflammation, and a decrease in immature dendritic cells. This may contribute to the repeated activation of memory t-cells or failure to delete them.
*atypical antigen presenting cells become potent effector-T-cells
*absense of t-cell apoptosis
*effecor T-cells predominate over regulatory T-cells
***STRESS- increased SNS activity is shown to cause increased colonic paracellular permaeability. I found this to be the most interesting!! The article talks about how the biggest therapeutic challenge is to develop an approach to prevention of the initation of the inflammatory cascade before tissue injury occurs. One thing that we have control over is stress! Maybe if these genetically predisposed people chill out, it will make a difference in there future health status! Although I doubt that this alone will make the difference, it is an important factor in this disease, as well as health in general.
Symptoms of Crohn's disease
While reading the articles, I realized that I wasn't really aware of what the symptoms for Crohn's disease were, so I'm posting this link to the mayo clinic website that describes them briefly in case anyone else was unsure.
http://www.mayoclinic.com/health/crohns-disease/DS00104
http://www.mayoclinic.com/health/crohns-disease/DS00104
Worms as treatment for IBD
Here's an interesting paper related to a novel treatment of IBD.
"In a stunt reminiscent of the TV reality show Fear Factor, dozens of unpaid volunteers have recently been gulping Gatorade laced with 2500 live eggs from parasitic worms"
http://www.sciencemag.org/cgi/reprint/305/5681/170?maxtoshow=&HITS=10&hits
=10&RESULTFORMAT=&fulltext=worms+immune&searchid=
1&FIRSTINDEX=0&resourcetype=HWCIT.pdf
"In a stunt reminiscent of the TV reality show Fear Factor, dozens of unpaid volunteers have recently been gulping Gatorade laced with 2500 live eggs from parasitic worms"
http://www.sciencemag.org/cgi/reprint/305/5681/170?maxtoshow=&HITS=10&hits
=10&RESULTFORMAT=&fulltext=worms+immune&searchid=
1&FIRSTINDEX=0&resourcetype=HWCIT.pdf
Dendritic Cells in IBD Pathogenesis
After reading "Translational Research in Inflammatory Bowel Disease" the role of dendritic cells in pathogenesis of IBD interested me. A little info : All dendritic cells are derived from bone marrow progenitor cells and once differentiated, are termed "immature" dentritic cells. These immature cells constantly "sample" their environement for viruses, bacteria, and other pathogens via high endocytotic ability. Toll-like receptors are prevalent on the immature cell surface and bind to highly conserved chemical signatures on pathogens as a part of innate immunity (i.e. passed on genetically). Once the toll like receptor binds to its particular ligand, the immature dendritic cell becomes activated into a mature dendritic cell and phagocytosizes the pathogen. They upregulate cell surface receptors that act to activate T-cells such as CD80, CD86, and CD40. Dendritic cells release powerful cytokines as well as high levels of TNF alpha and the anti-inflammatory cytokine IL-10, both of which begin and escale the inflammatory response, which is the main factor in IBD.
Dendritic cells then move to lymphatic tissue in the spleen or lymph nodes via blood and it is here that ingested pathogen is broken down and some of its protein sequences are expressed on the surface. The antigen is presented to and activates helper T cells, killer T cells, and B-cells, which in turn create antibodies to continue the immune response. This is a likely starting point in the pathogenesis of IBD, as the main problem is an abnormal initial immune response to normal gut flora. Toll like receptors, which are genetically encoded, may play a large role in IBD as they are the first point at which a normal pathogen is seen by the immunity as foreign and as cause for an inflammatory response.
The article speaks about a possible "IBD chip" in the near future, where an individual can be genetically screened and possible mutant toll like receptor genes, or other IBD related genes can be pin pointed and perhaps small molecules or anitbodies can be used to antagonize the abnormal immune response. This is very interesting and t seems to me that this would be the best point to begin in fighting IBD, at its root.
Dendritic cells then move to lymphatic tissue in the spleen or lymph nodes via blood and it is here that ingested pathogen is broken down and some of its protein sequences are expressed on the surface. The antigen is presented to and activates helper T cells, killer T cells, and B-cells, which in turn create antibodies to continue the immune response. This is a likely starting point in the pathogenesis of IBD, as the main problem is an abnormal initial immune response to normal gut flora. Toll like receptors, which are genetically encoded, may play a large role in IBD as they are the first point at which a normal pathogen is seen by the immunity as foreign and as cause for an inflammatory response.
The article speaks about a possible "IBD chip" in the near future, where an individual can be genetically screened and possible mutant toll like receptor genes, or other IBD related genes can be pin pointed and perhaps small molecules or anitbodies can be used to antagonize the abnormal immune response. This is very interesting and t seems to me that this would be the best point to begin in fighting IBD, at its root.
26 February 2008
Why Blocking T Helper cells works
The article entitled "Translational Research in IBD" mentions antagonizing Th1 cytokines without really explaining why this is an effective treatment option for IBD...so I looked into it.
First, upon seeing an antigen piece presented to it, helper T cells will differentiate into either Th1 or Th2 cells (just type 1 or type 2 helper T cells). Both these T cells will then produce cytokines and stimulate other functions. In Crohn's Disease (CD), Th1 is of particular interest because of the particular cytokines it produces, namely interferon-gamma. It also encourages macrophages to produce IL-12, which is an pro-inflammatory cytokine, which is obviously bad when you are trying to get rid of an inflammatory disease.
The reason Th1 has been targeted to antagonize instead of Th2 is because Th2 may actually produce IL-10, which the article mentions as an anti-inflammatory cytokine. This may be a limitation to the strategy of blocking T cell activation, which the article mentions as an area of research. Because it is not currently clear how the body decides which helper cell type to produce, this treatment might be very hard to perfect.
On a side note, and for those of you curious to learn more, Digestive Disease Week 2008 is coming up! It goes from May 17-22 in San Diego. Here's a website to it: http://www.ddw.org/wmspage.cfm?parm1=679
First, upon seeing an antigen piece presented to it, helper T cells will differentiate into either Th1 or Th2 cells (just type 1 or type 2 helper T cells). Both these T cells will then produce cytokines and stimulate other functions. In Crohn's Disease (CD), Th1 is of particular interest because of the particular cytokines it produces, namely interferon-gamma. It also encourages macrophages to produce IL-12, which is an pro-inflammatory cytokine, which is obviously bad when you are trying to get rid of an inflammatory disease.
The reason Th1 has been targeted to antagonize instead of Th2 is because Th2 may actually produce IL-10, which the article mentions as an anti-inflammatory cytokine. This may be a limitation to the strategy of blocking T cell activation, which the article mentions as an area of research. Because it is not currently clear how the body decides which helper cell type to produce, this treatment might be very hard to perfect.
On a side note, and for those of you curious to learn more, Digestive Disease Week 2008 is coming up! It goes from May 17-22 in San Diego. Here's a website to it: http://www.ddw.org/wmspage.cfm?parm1=679
Probiotics in Yogurt
The Newsweek article posted talks about all of the wonders and benefits of probiotics and reminded me of a news story I had heard. I guess Dannon (yogurt company) is one of those companies that has been using probiotics and marketing the effects of them, especially in digestion. Anyways, there's been a recent lawsuit placed against them, claiming that Dannon has mislead consumers and claiming that the benefits of the probiotics are just claims with no scientific support. I don't know what's worse: Dannon making claims and charging the consumer extra money for it or people being sue-happy. Here's some info on the suit.
http://www.webmd.com/digestive-disorders/news/20080125/yogurt-maker-sued-over-health-claims
http://www.importantlawsuits.com/lawsuits/dannon-activia-lawsuit/
http://www.webmd.com/digestive-disorders/news/20080125/yogurt-maker-sued-over-health-claims
http://www.importantlawsuits.com/lawsuits/dannon-activia-lawsuit/
"Translational Research in IBD" (Abreu et al)
As mentioned by Lian, Inflammatory Bowel Disease (IBD) is an overactive and uncontrolled immune response in the digestive tract. The article assigned this week, “Translational Research in Inflammatory Bowel Disease” (Abreu et. al) contains a good amount of information regarding the disease. The researchers identify that IBD is caused by a dysregulated mucosal immune response to a luminal antigen. Furthermore, people with IBD have an imbalance of T-helper effector cells and T regulatory cells being activated. The effector cells are identified as being responsible for producing the proinflammatory cytokines whereas the latter are responsible for producing the anti-inflammatory cytokines. The imbalance of these immune cells (more effector cells) results in inflammation and this leads to the protective layer of the gut being less effective, leaving the gut exposed and vulnerable.
The article notes that there are many causes and risk factors associated with IBD. A major risk factor includes genetic predisposition and therefore, people who have had occurrences of IBD in their family are more susceptible to the disease. The NOD2/CARD15 and OCTN1/2 genes and mutations of them are the primary genes associated with risk for IBD. The CARD15 gene is responsible for recognizing antigens and will release proinflammatory cytokines as a response. A mutation in this gene will lead to greater inflammatory responses. The OCTN genes function in carnatine transport across the membrane of epithelial cells in the GI. Mutations of OCTN lead to a greater amount of harmful antigens being transported across the membrane, which then warrants a greater immune response, which means more inflammation.
They also mention Toll-like Receptors (TLR) and Dendritic cells. The TLRs are expressed on cells in the GI and function in recognizing and binding antigenic ligands and after doing so, warrant an immune response. So basically, the TLRs contributes to a greater and more sensitive immune response. The Dendritic cells, they note, sample the contents in the lumen of the GI and upon sensing antigens/bacteria, will then signal T cells to either inhibit or activate an immune response.
It goes on by mentioning treatments, therapies, and ideas on how to treat IBD. They mention restoring the balance of all the cytokines and T cells involved in the immune response. This would help keep the inflammation in check. Another treatment is through the use of antibiotics/probiotics. The idea here is to repopulate the GI with the good or beneficial bacteria while ridding it of the bad bacteria.
They end off by mentioning the “IBD chip”. This chip would provide a personal and specific solution for the person with IBD. The chip would identify all of the genes and proteins expressed in that person’s mucosa and provide sort of a map on where and what to attack.
Abreu M, Sparrow M. Translational Research in Inflammatory Bowel Disease.
The article notes that there are many causes and risk factors associated with IBD. A major risk factor includes genetic predisposition and therefore, people who have had occurrences of IBD in their family are more susceptible to the disease. The NOD2/CARD15 and OCTN1/2 genes and mutations of them are the primary genes associated with risk for IBD. The CARD15 gene is responsible for recognizing antigens and will release proinflammatory cytokines as a response. A mutation in this gene will lead to greater inflammatory responses. The OCTN genes function in carnatine transport across the membrane of epithelial cells in the GI. Mutations of OCTN lead to a greater amount of harmful antigens being transported across the membrane, which then warrants a greater immune response, which means more inflammation.
They also mention Toll-like Receptors (TLR) and Dendritic cells. The TLRs are expressed on cells in the GI and function in recognizing and binding antigenic ligands and after doing so, warrant an immune response. So basically, the TLRs contributes to a greater and more sensitive immune response. The Dendritic cells, they note, sample the contents in the lumen of the GI and upon sensing antigens/bacteria, will then signal T cells to either inhibit or activate an immune response.
It goes on by mentioning treatments, therapies, and ideas on how to treat IBD. They mention restoring the balance of all the cytokines and T cells involved in the immune response. This would help keep the inflammation in check. Another treatment is through the use of antibiotics/probiotics. The idea here is to repopulate the GI with the good or beneficial bacteria while ridding it of the bad bacteria.
They end off by mentioning the “IBD chip”. This chip would provide a personal and specific solution for the person with IBD. The chip would identify all of the genes and proteins expressed in that person’s mucosa and provide sort of a map on where and what to attack.
Abreu M, Sparrow M. Translational Research in Inflammatory Bowel Disease.
Subscribe to:
Posts (Atom)