Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies

Abstract

Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses, and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in clinical trials is to identify the most immunologically-relevant mouse models of IBD and pharmacologic strategies that most closely mimic the clinical situation. This review presents a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies.

Figure 1

Adoptive transfer of CD4⁺CD45RB^high T-cells into RAG-1^−/− recipients induces chronic colitis. Histopathological analysis of RAG-1^−/− injected (ip) with 5×10⁵ CD4⁺CD45RB^low (RB^low) or CD4⁺CD45RB^high (RB^high) T-cells. At 8 weeks following T-cell transfer, animals were euthanized and colonic inflammation was quantified by blinded histopathological analysis using our published scoring criteria(55). Reproduced from Ostanin et. al., Am. J. Physiol, 2009 (55) with permission from the Am. Phys. Soc

Figure 2

Adoptive transfer of CD4⁺CD45RB^high T-cells into RAG-1^−/− recipients induces a mixed Th1/Th17 colitis. Mononuclear cells from MLNs and colonic lamina propria (LP) of colitic mice at 8 weeks post T-cell transfer were activated in vitro, permeabilized and stained with isotype control or IL-17 and IFN-γ mAbs. Representative intracellular staining for the 2 cytokines within CD4⁺ cells is shown. Reproduced from Ostanin et. al., Am. J. Physiol, 2009 (55) with permission from the Am. Phys. Soc.

Figure 3

Histopathology, incidence and severity of jejunal (A.) and ileal (B.) inflammation in RAG-1^−/− reconstituted with CD4⁺CD45RB^high T-cells or CD4⁺CD45RB^low T-cells. Note the villus blunting, bowel wall thickening and inflammatory infiltrate in the mice injected with CD4⁺CD45RB^high T-cells. Reproduced from Ostanin et. al., Am. J. Physiol, 2009 (55) with permission from the Am. Phys. Soc.

Figure 4

Adoptive transfer of CD4⁺CD45RB^high T-cells into RAG-1^−/− recipients induces chronic liver and lung inflammation. A. Histopathology of the liver. Note the periportal and intralobular inflammatory infiltrate composed primarily of mononuclear cells. Reproduced from Ostanin et. al., Am. J. Physiol, 2009 (55) with permission from the Am. Phys. Soc. B. Histopatholgoy of lungs obtained from healthy wild type or RAG-1^−/− mice reconstituted with CD4⁺CD45RB^high T-cells (8 wks post transfer). Virtually all colitic mice presented with chronic bronchitis/pulmonary inflammation with the majority of these animals exhibiting confluent inflammation merged together between small and medium sized bronchi (unpublished data)(72). Varying degrees of perivascular lymphocytic cuffing were also observed in most of the mice however few PMNs were observed and vasculitis was absent.

Figure 5

Time course of drug concentration in blood. A. Time course of drug concentration in blood following intravenous (iv), intraperitoneal (ip), subcutaneous (sc) or oral (po) administration of a small molecule. B. Blood concentration-time curve for iv or ip administration of a monoclonal antibody (mAb; MW=150,000).

Figure 6

Administration of an anti-mouse TNF mAb attenuates chronic colitis. TNF mAb (Centocor) or an isotype control mAb was injected (ip) into RAG^−/− mice beginning 2 wks following transfer of CD4⁺CD45RB^high T-cells. Treatment continued biweekly (100 μg/injection) for 6 wks. At 8 wks, mice were euthanized, colons were removed for blinded histopathological and flow cytometric analyses.