The first model is the one we saw in the Ruyssers paper we discussed in class. To replicate colitis, a mouse is anesthetized and catheterized. Through the catheter a mixture of TNBS and ethanol will be administered into the lumen of the colon. The ethanol is needed to break the intestinal epithelial barrier while the TNBS is extremely oxidative. The damage from the TNBS will induce a IL-12 driven, Th1 mediated response in the colon [1]. The problem with this model is that the mouse naturally starts to heal this damage so treatments might appear more effective than they might be.
An alternate model looks to induce IBD via excessive effector T cell function. This is done by transferring CD4+/CD45RB T cells minus T-regulatory cells into a mouse that has SCID (severe combined immunodeficiency). If I'm understanding this correctly, as this mouse does not have any T-reg cells to control the newly introduced Th1 cells, the mouse will become inflamed [2].
[1]Boirivant, M et al. (2001). Oral Administration of Recombinant Cholera Toxin Subunit. The Journal of Immunology , 3522-3532.
[2]Ding, X et al.(2005). Inducible nitric oxide synthase-dependent DNA damage in mouse model of inflammatory bowel disease. Cancer Science , 157–163.
-Vinoo
If these are the only models currently available for IBD research, I can see why Ruyssers et al. opted for the model they did. Obviously, a SCID mouse wouldn't develop an immune response to the helminth soluble proteins so it would futile to use these mice to see if this therapy relieves inflammation.
ReplyDeleteHopefully the therapeutic effects of helminths are simply exaggerated by the compounding effects of self-healing in the first mouse model.
Has anyone commented on why the use of other animal models hasn't been effective? Also, the papers that you found date back to 2005, nothing new has been developed to date in regards to the use of a good IBD model?
ReplyDeleteSo to clarify, the models that I've outlined above are two models that kept showing up in the articles I was reading. For example, the Th1 response can be induced via drinking DSS (a sodium salt of sulfuric acid) but this can lead to colorectal cancer ...
ReplyDeleteThere seem to be quite a few knock-out models for IBD. The Jackson Laboratory has 14 different mutant mice that they claim can be used to study CD. They mainly target the NOD2/CARD15 loci which is associated with the proper recognition of bacteria MDP epitopes. Others are towards interleukins or IL receptors. However, these models are quite expensive as a NOD2 altered mouse can cost over $250 for a single mouse.
For all the models see:
http://jaxmice.jax.org/literature/models/ibd.pdf
For NOD2 mice cost see:
http://jaxmice.jax.org/strain/005763.html