[Frontiers in Bioscience S4, 1295-1314, June 1, 2012]

Pharmacologic efficacy in inflammatory bowel disease models

Makoto Nagaoka1,2, Zaher A. Radi3

1Clinical Research Development, Pfizer Japan, Tokyo, Japan, 2Drug Safety Research and Development, Pfizer Worldwide Research and Development, Tokyo, Japan, 3Drug Safety Research and Development, Pfizer Worldwide Research and Development, Cambridge, MA, USA


1. Abstract
2. Introduction
3. Chemically- and hapten-induced models
3.1. Dextran sulfate sodium (DSS) model
3.2. Trinitrobenzene-sulfonic acid (TNBS) model
3.3. Oxazolone model
4. Spontaneously developed models
4.1. Senescence accelerated mouse prone 1/yit (SAMP1/Yit) model
5. T-cells models
5.1. CD4+CD45RBhighCD25−-transferred model
6. Transgenic (TG) models
6.1. Interleukin-7 (IL-7) TG model
7. Immunoregulatory knockout (KO) models
7.1. Interleukin-10 (IL-10) KO model
7.2. Interleukin-2 (IL-2) and IL-2 receptor alpha (IL-2Ralpha) KO models
7.3. T-cell receptor alpha (TCRalpha) KO model
7.4. dnKO model
8. Perspective
9. References


The utility of inflammatory bowel disease (IBD) models in evaluating pharmacologic efficacy of novel drug candidates is reviewed. IBD models are generally classified into six groups based on the etiopathogenesis: chemically- and hapten-induced, spontaneously developed, T-cells, transgenic and immunoregulatory knockout models. The chemically- and hapten-induced models are the most widely utilized for evaluating pharmacologic efficacy of novel drug candidates because they are technically simple and rapid to induce gut pathology. In contrast, the T-cells adoptive transfer model is technically more complex to execute with longer study duration, resulting in the rare utility of this model in pharmacologic efficacy studies. Spontaneously developed, transgenic and immunoregulatory knockout IBD models gradually develop spontaneous colitis or ileitis as they age. In this critical review, the pathological and immunological characteristics of various IBD animal models, and the pharmacologic efficacy of current therapeutic agents and drug candidates for IBD in these animal models are compared. Moreover, perspectives on experimental conditions, and applicability to evaluation of prophylactic and therapeutic pharmacologic efficacy of drug candidates in drug discovery and development are discussed.