Thanks all for the posts, and thanks kiny for sharing the thoughts and info.
I read through the paper you listed above (Bach H, Rosenfeld G, Bressler B. Treatment of Crohn's disease patients with infliximab is detrimental for the survival of Mycobacterium avium ssp. paratuberculosis within macrophages and shows a remarkable decrease in the immunogenicity of mycobacterial proteins. J Crohns Colitis. 2012 Jun;6(5):628-9.). I am also very impressed by the title. However, the paper did not provide an explanation for the possible mechanism, and it is also beyond my imagination as how infliximab can cause the death of MAP. Apoptosis is the programmed cell death that almost all the cells within our body naturally die ( http://en.wikipedia.org/wiki/Apoptosis). The apoptosis induced by infliximab seems also just through the common routines such as the caspase-dependent pathway as suggested in the studies in your previous post (#159 in this thread). If MAP succumbed along with this natural death of the cells, how can they cause the persistent inflammation seen in CD. According to the paper, the significant decrease in the survival of MAP in the macrophages treated with infliximab only started to show up at 48 hour but not at 24 hour. In my opinion, a more likely explanation would be the treatment with infliximab caused accelerated apoptosis of the macrophages, probably through its binding with the tmTNF-alpha on the cell wall as stated in your post, resulting in the release of MAP from the dead cells into the culture media, rather than the real killing of MAP. This is a very short paper without detailed description of the methods and procedures of the experiment, thus this is just my guess. However, some more meaningful and clinically relevant in vivo studies indeed showed that immunosuppression will result in exacerbated but not alleviated infection of MAP and damage of the tissue, just the same as tuberculosis. Large amounts of Mycobacterium paratuberculosis became showed up in the feces, gut tissue or even liver in mice (Follett DM, Czuprynski CJ. Cyclophosphamide and prednisolone exacerbate the severity of intestinal paratuberculosis in Mycobacterium paratuberculosis monoassociated mice. Microb Pathog. 1990 Dec;9(6):407-15) or chicken (Valente C, et al. Use of an experimental chicks model for paratuberculosis enteritis (Johne's disease). Vet Res. 1997 May-Jun;28(3):239-46) treated with immunosuppressive agents like cyclophosphamide and [wiki2="Prednisolone"]prednisolone[/wiki2]. Still, MAP got eliminated from the body and became undetectable even in the immunodepressed chicks after a few months (Here is the link to the full text), in contrast to the Crohn’s disease in human that lasted forever,
I also felt the notion that the high efficacy of the immune suppression agents like inflixmab and 6-MP is largely due to their bactericidal activity on MAP a fascinating idea, but I just wonder how this miracle occurred. A study (Greenstein RJ, et al. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis. PLoS One. 2007 Jan 24;2(1):e161) showed that although 6-MP have some inhibition on the growth of MAP, its activity is still much lower than some antibiotics like clarithromycin (4 ug/ml 6-MP versus 0.5 ug/ml clarithromycin to cause 80% growth inhibition of the bacteria). For the treatment of IBD, 6-MP is usually used in a dose below 100 mg/day and lasted for several weeks. However, in the study by Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9), even clarithromycin used at 750 mg/day, along with 450 mg/day rifabutin and 50 mg/day clofazimine to treat the patients with Crohn’s disease for up to two years failed to show evidence of sustained benefit. I just cannot image how 6-MP, with much less bactericidal capability and used at a much lower dose and in such a short period can achieve the effective treatment for Crohn’s disease through the claimed killing of MAP.
We live in the age of information explosion. It also generated massive clouds of false information that made it a big challenge to find out those pieces of evidences that bared clues of the truth. Hope these discussions may sharp our vision and clear out thoughts. I think we share the same goal – to find the truth and solve the mystery. Thanks again for sharing the thoughts and info.
