More risks for IBD patients

Patients with inflammatory bowel disease are at risk of much more than the common symptoms of diarrhea and abdominal pain. It is shown that IBD patients are at risk of colon cancer which is cancer that affects the colon and primary sclerosing cholangitis, which is a chronic disorder of the liver in which the ducts carrying bile from the liver to the intestine become inflamed, thickened, scarred (sclerotic), and obstructed. They are also at a high risk of thromboembolism, which is the formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. Both of these are very serious life threatening events. Thromboembolism can lead to a list of symptoms which include paresthesias, numbness, weakness, kidney failure, stroke and high blood pressure. Until recently however, it was unknown whether IBD patients were at a high risk of getting thromboembolism (TE). Conflicting data showed a variety of results that linked IBD with TE. From the article Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism? it was confirmed that IBD is in fact a risk factor for TE. The question of why is still being determined. Some believe that it is due to the role of endotoxins which when added to blood samples of IBD patients induced formation of microclots. This clot formation was not induced in healthy patients, suggesting that the effect of endotoxins might be enhanced by an IBD factor. In 60% of TEs in IBD occurred during the presence of complications such as stricture, fistulisation or eruption. There seems to be a specific feature in IBD that was not shown in other inflammatory diseases, such as rheumatoid arthritis and another bowel disease, such as coeliac disease. It is very bizarre how just one disease in all its complications and symptoms can lead to so many other problems and diseases that bring about new complications and symptoms. More information about the article on primary sclerosing cholangitis and IBD can be found at http://www.medscape.com/viewarticle/555670. More information about IBD and colon cancer can be found at http://ibdcrohns.about.com/cs/colorecalcancer/a/ibdcolonrisk.htm.

smoking good?... or smoking bad?

The relationship between smoking and the form of IBD that was manifested in siblings with a genetic predisposition was determined and explained in the article entitled “In siblings with similar genetic susceptibility for inflammatory bowel disease, smokers tend to develop Crohn’s Disease and non-smokers develop ulcerative colitis” by S Bridger, J C W Lee, I Bjarnason, J E Lennard Jones, and A J Macpherson. It was found that CD was more commonly developed in the siblings that smoke, especially in women. Furthermore, it was also determined that the smokers in the study had less of a chance of developing UC. I found this article interesting because it shows an extreme link between “tobacco usage inhibiting UC and enhancing CD pathogenic mechanisms.” It was also stated that “the influences of tobacco on disease pathogenesis are on the immunopathogenic mechanisms at disease onset as opposed to cumulative damage” due to the fact that the manifestation was effectively reversed when the subjects were no longer smoking for a year. Also, it was discussed that there are many diseases that are associated with tobacco smoke, however the mechanisms are not known. It is known that smoking has “multiple effects on many immune and inflammatory functions.” The need for further studies such as the rodent model presented in this article is evident.

More Bad News About Sugars...?

The pathology of IBD links both UC and CD with the degradation of the mucus lining the epithelium of the gut (specifically the large bowel). What I have found interesting is theories suggesting the link between diet and IBD that focuses on the role of carbohydrates. Simple sugars are absorbed into the bloodstream, whereas the more complex sugars require further digestion via intestinal enzymes. When these sugars are not fully digested, the undigested remnants can ferment through bacterial action, serving as an energy source for bacterial replication. Enzymes are soon destroyed, and the mucus-producing cells of the small intestine, the goblet cells, begin to secrete mucus to protect the intestinal wall against microbial toxins and undigested carbohydrates. This mucus-coating prevents sugars and starches needing digestion from reaching the enzyme cells, and fermentation and damage escalate as the cycle continues.

I then linked this information to what we know about the appendix. From prior reading, we now know that the appendix is dependent on the mucus that lines the epithelium of the bowel. We also know that diet may well account for the incidence of appendicitis. So, is it possible that the sugary diet of modern society is damaging the role of the appendix to regulate immune system function, and that this, coupled with the damage to the GI tract by bacteria feeding on these sugars, could be one way of inducing IBD?

Talks about a book on carbohydrates and intestinal health: http://www.sheilashea.com/ibd.html

huOKT3gamma in T1DM

Diabetes Mellitus, or Type 1 Diabetes (T1DM), is an autoimmune disorder in which one’s T cells destroy the insulin-producing pancreatic b cells. (5) Insulin is necessary for the metabolism of glucose and a balance between insulin and glucose must be maintained to avoid either hyperglycemia or hypoglycemia.
b cells account for about 60% of the cells are produced in the islets of the pancreas. The onset of T1DM occurs when one’s b cells have nearly all been destroyed. Once this occurs treatment with exogenous insulin to maintain the proper insulin-glucose balance is required. Food intake must be carefully monitored carefully as is affects this balance.
The monitoring devices, delivery methods and the daily management of T1DM has become more streamlined and convenient, it still requires insulin in the right amounts at the right intervals. The advent of “closed loop” systems would, in essence, act as an artificial pancreas but would still require exogenous insulin. There are two other options that offer promise of dramatically changing treatment. One is islet cell transplantation which restores the pancreas’s ability to produce b cells and thereby endogenous insulin. A second option, and the focus here, is the preservation of islet cell function – the production of b cells which produce insulin. This necessitates interfering in the process that results in b cell destruction as close to onset of frank diabetes as possible.
Anti-rejection therapies used in organ transplantation are a possibility because of their effect on autoimmune responses. One agent with promise has been used in renal and renal-pancreatic transplants: huOKT3g which interferes in the events leading to autoimmune destruction of b cells. (3) huOKT3g is an ati-CD3 antibody; CD 3 is a group of proteins that associates with T-cell receptors to generate an activation signal in T lymphocytes that results in the destruction of b cells. huOKT3g is a humanized, nonmitogenic, Fc receptor non-binding OKT3 antibody. (3) This means that it is an antibody derived from a mouse in which the genetic information for six complimentarity determining regions (CDRs) has been grafted within a human IgG1 monoclonal antibody. (1) This reduces the amount of mouse material to £ 10%. The antibody is nonmitogenic because it contains no substances that signal a cell to divide which would trigger mitosis. (1) In addition, the CH2 region of the IgG1 has been altered by site-directed mutagenesis which changes Fc receptor binding activity which also eliminates T cell activation. Studies have shown that these manipulations of the antibody result in it retaining its immunosuppressive properties, but not its immune activating properties.(1) The most encouraging thing about huOKT3g treatment (by infusion) is that its effect on b cell preservation persists for at least a year post-infusion. Current trials are testing whether reinfusion at 1 year can further extend the preservation of b cells.

References:
Woodle ES, Bluestone JA, Zivin RA, Jolliffe LK, Auger j, Xu D, Thistlethwaite JR, Humanized, Nonmitogenic OKT3 Antibody, huOKT3g (Ala-Ala): Initial clinical Experience, Transplantation Proceedings, 30, 1369-1370, 1998.
Seegan GW, Smith CA, Schumaker VN, Changes in quaternary structure of IgG upon reduction of the interheavy-chain disulfide bond, Proceedings National Academy of Sciences, Vol. 76, No 2. 907-911, February 1979.
Woodle ES, Xu D, Zivin RA, Auger J, Charette J, Olaughlin R, Peace D, Jolliffe LK, Haverty T, Bluestone JA, Thistlethwaited JR, Phase I Trial of Humanized, Fc Receptor Nonbinding OHT3 Antibody, huOKT3[gamma[ in the Treatment of Acute Renal Allograft Rejection, Transplantation, Vol. 68(5), 608-616, 15 September 1999
Chatenoud L, Primo J, Bach, JF, CD3 Antibody-Induced Dominant Self Tolerance in Overtly Diabetic NOD Mice, The Journal of Immunology, 22-1767, 2947-2954, 1997.
Herold KC, Hagopian W, Auger JA, Poumian E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA, Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus, NEJM, 346, No 22, May 30, 2002.

The clinical trial of TGN1412 and an unexpected outcome

Just when one thought in the 21st century that it is certainly safe to participate in the trial of a new and promising drug, something goes terribly wrong! On March 13, 2006, six healthy male volunteers at St. Mark’s Hospital experienced symptoms ranging from headache, nausea, diarrhea, to peripheral vasodilatation, hypotension, tachycardia, to adult respiratory distress syndrome and multiple organ failure, resulting from the administration of what was considered a low dose of a new monoclonal antibody, TGN1412 (1). The use of monoclonal antibodies in the treatment of diseases such as lymphoma is common place in medicine today (2). These antibodies are clones of a single parent B cell, specific to one antigen, and when, in production, they are fused to a substance of interest, they can be used to identify and purify that substance (4). They have thus been used in the treatment of various cancers and, recently, this monoclonal antibody was hoped to be promising in the treatment of leukemia and auto-immune diseases such as rheumatoid arthritis (2).
TGN1412, developed by TeGenero Immuno Therapeutics and tested initially on mice by Parexel, is one such humanized (as opposed to murine or mouse) monoclonal antibody (2). It is unique both because it is a “super-agonist” of the T cell surface receptor CD28 and because normally this trigger would require that the T cell were also attached to a co-stimulator antigen for significant response (3). For TGN1412 this is not the case and given a much greater expected immune system response, it would seem that this antibody would be geared towards patients with a suppressed immune system. Instead, it was found that TGN1412 preferentially activated regulatory T cells and a net suppression of the immune response. This was the thinking in utilizing the drug for patients with conditions like rheumatoid arthritis, where the immune system is hard at work attacking the body’s joints.
Many are calling what occurred in this first human trial with TGN1412 the result of a cytokine storm, characterized by, and evidenced in all six of the volunteers in this clinical trial, the presence of multiple inflammatory mediators in the patient’s serum (1). All six men also suffered early acute lung injury and lymphopenia, (low numbers of lymphocytes) which is not characteristic of cytokine storm (1). All six men survived after extensive treatment, complication, and stay, ranging from 30 to 45 days, in the Intensive Care Unit of the National Health Service hospital in London and an intensive inquiry into the events was immediately underway by the Medicines and Healthcare products Regulatory Agency in the United Kingdom (2). There remain questions related to the after-effects to the six volunteers, including lower than normal numbers of functioning T cells and the development of cancer in one participant (3). TeGenero maintains that all earlier animal testing produced dramatically different results with the clinical trial producing completely unexpected results. The clinical study was approved by the MHRA and according to their reports, protocols were followed, with no deficiencies identified in the manufacture and storage of TGN1412 (3). The conclusion remains that the outcome was the result of an “unpredicted biological action of the drug in humans” and much further monoclonal antibody research has been stunted in the UK (3). While certainly oftentimes the benefits outweigh the negatives of medical research, this example certainly does little to bolster the public’s confidence in placing their safety in our hands.

References:
(1) “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412.” The New England Journal of Medicine, Volume 355:1018-1028, September 7, 2006.
(2) “Catastrophic Immune Response may have caused drug trial horror.” New Scientist, 14:22, March 17, 2006.
(3) “TGN1412.” http://en.wikipedia.org/wiki/TGN1412, 10/2/2007.
(4) “Monoclonal antibodies.” http://en.wikipedia.org/wiki/Monoclonal_antibodies, 10/2/2007.