Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

Abstract

Animal models are important tools in the development of new drug candidates against the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. In order to increase the translational value of these models, it is important to increase knowledge relating to standard drugs. Using the SCID adoptive transfer colitis model, we have evaluated the effect of currently used IBD drugs and IBD drug candidates, that is, anti-TNF-α, TNFR-Fc, anti-IL-12p40, anti-IL-6, CTLA4-Ig, anti-α4β7 integrin, enrofloxacin/metronidazole, and cyclosporine. We found that anti-TNF-α, antibiotics, anti-IL-12p40, anti-α4β7 integrin, CTLA4-Ig, and anti-IL-6 effectively prevented onset of colitis, whereas TNFR-Fc and cyclosporine did not. In intervention studies, antibiotics, anti-IL-12p40, and CTLA4-Ig induced remission, whereas the other compounds did not. The data suggest that the adoptive transfer model and the inflammatory bowel diseases have some main inflammatory pathways in common. The finding that some well-established IBD therapeutics do not have any effect in the model highlights important differences between the experimental model and the human disease.

Anti-inflammatory Effects of the Chinese Herbal Formula FAHF-2 in Experimental and Human IBD

“…It also lends itself well to testing of medications that are commonly used in the treatment of IBD. 36 Our findings in this model demonstrate FAHF-2 in vivo effectiveness that correlates with our findings in PBMCs and colonic mucosa. We tested FAHF-2’s ability to prevent progression of colitis given that we envision use of this medication in mild disease or for maintenance of remission.…”

“…25,35,36 This model has been found to have multiple similarities to human IBD: chronic, progressive disease with diarrhea and weight loss, heavily inflamed colon, and a Th1/Th17-dominated cytokine profile. It also lends itself well to testing of medications that are commonly used in the treatment of IBD.…”

Protective effects of Fc-fused PD-L1 on two different animal models of colitis

“…Three weeks after T-cell reconstitution, recombinant PD-L1-Fc protein was administered at 1-week intervals at a dose of 20 μg into Rag-1 KO mice for 4 weeks. Since CTLA-4-Ig, when used in intervention mode, was previously known to suppress T-cell transfer colitis in SCID mice,7 another group of mice was treated three times a week with 200 μg CTLA-4-Ig protein over the same time period. At 7 weeks post cell transfer, PD-L1-Fc treatment led to marked amelioration of weight loss, and the degree of protection was similar to CTLA-4-Ig (figure 7A).…”

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

“…Several proinflammatory molecules participating to the model pathophysiology reflect similar mechanisms in humans, especially those specialized in Th1 immune response (IFNγ, TNFα, IL-12p40) (Powrie et al, 1994), thus indicating an orientation to the CD immunologic profile. In order to better characterize the model validity for drug testing, Lindebo Holm et al showed the involvement of other factors contributing to the human pathophysiology, including microbiome imbalances (Lindebo et al, 2012). This model is particularly indicated for those studies investigating mechanisms of cell-mediated immune response involved in autoimmune diseases and in IBD.…”

“…This model is particularly indicated for those studies investigating mechanisms of cell-mediated immune response involved in autoimmune diseases and in IBD. Nevertheless, several discrepancies with the human condition and human response to pharmacological treatment derive from the absence of B-cell and CD8+ T-cell populations in the model's immune system (Lindebo et al, 2012). Moreover, its predictive value is still limited by our knowledge of differences between human and murine immune system (Table 3).…”