Animal Models for the Study of Human Disease || Animal Models of Inflammatory Bowel Disease for Drug Discovery

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    i*, Akira AndohyMedical School, Boston, MA, USA

    higa U


    Anti-Integrin-a4 Therapy 506Anti-Integrin-b7 Therapy 507

    Acknowledgments 5182relapsing inflammatory condition that affects over1.5 million Americans.1 The incidence and prevalenceof IBD are increasing with time and in different regionsaround the world, indicating its emergence as a globaldisease. IBD is classified into two major forms, Crohns

    is characterized by transmural inflammation affectingthe entire depth of the intestine throughout the digestivetract (frommouth to anus), while UC is characterized bymore focal inflammation restricted to the mucosa of thecolon. A T-helper cell 1 (Th1)-dominant cytokine profileAnti-Interleukin-12p40 and Anti-Interleukin-23Therapy 507

    References 518


    Inflammatory bowel disease (IBD) is a chronic

    disease (CD) and ulcerative colitis (UC), which aremediated by both common and different mechanismsand have distinct clinical features.36 For example, CDA

    hBiological Therapy and IBD Models 505Anti-TNF-a Therapy 505

    Conclusion 5185-Aminosalicylic Acid 505Cyclosporine/TacrolimusNonsteroidal Anti-Inflammatory Drugs504504Corticosteroids 503nima

    ttp://assical Therapy and IBD Models 5Cl 03Cigarette Smoking 503

    Appendectomy 502

    The Hygiene Hypothesis 501

    iology and Mouse IBD Models 5Et 01assification of Mouse IBD Models 5Cl 01troduction 4In 99O U T*Department of Pathology, HayDepartment of Mucosal Immunology, Srvard499l Models for the Study of Human Disease Keratinocyte Growth Factor Therapy 5Anti-CD20 Therapy 51414Recombinant Interleukin 11 Therapy 514

    Recombinant GM-CSF Therapy 513

    Anti-Interferon-Gamma Therapy 513

    Anti-CD25 Therapy 513

    Anti-CD3 Therapy 511

    Anti-CTLA4 Therapy 511

    Stem Cell Therapy 510

    Recombinant Interleukin-10 Therapy 509

    Anti-CCR9 Therapy 509

    Anti-Interleukin-6R Therapy 509

    Anti-Interleukin-17A Therapy 508I N Eniversity School of Medicine, Shiga, JapanAtsushi MizoguchDisease for Drug DiscoveryC H A


    Animal Models of IT E R

    flammatory BowelCopyright 2013 Elsevier Inc. All rights reserved.

  • is often seen in CD, while UC tends to have contribu-tions from the Th2 response.5

    The mucosal immune system is distinct from itssystemic counterpart by virtue of its enormous anti-genic exposure (commensal flora, food antigens, path-ogens), making IBD pathogenesis more complicated.7

    Indeed, many kinds of knockout (KO) and transgenic(Tg) mouse strains have been shown to develop colitisand/or ileitis spontaneously. So far, at least 69 kindsof animal model are available to study IBD.8 Thesemodels can be classified into four groups dependingon the location of inflammation (Fig. 22.1). The colitismodel develops inflammation only in the colon, theileitis model only in the small intestine, the pan-enterocolitis model in both colon and small intestine,and the systemic model in multiple organsincluding the intestine. Importantly, new therapeuticideas for IBD have been stimulated by preclinicalstudies in the wide variety of animal models ofIBD.9,10

    Over 71 susceptibility loci/genes in CD and over 47 inUC have already been identified in humans.3,11,12 There-fore, one of the current topics in the field of IBD modelsis to identify the biological function of these IBD suscep-tibility genes, and these studies have brought manynovel concepts to further understand IBDpathogenesis.3,1113 Another topic is to identify thecommensal bacterial composition associated with IBD.The importance of this topic has been highlighted bythe fact that development of colitis was abolished inthe majority of murine IBD models when they weremaintained in a germ-free condition.14 The relevanceof this field to human IBD is supported by recent meta-genome analyses of the human intestinal tract, whichhave identified that CD, UC, and healthy individualsall had distinct bacterial composition patterns.15

    Interestingly, Neurath and colleagues have proposed10 mysteries with IBD, some of which are associatedwith the etiological factors.16 Among them, the hygienehypothesis (probiotics), appendectomy, and cigarette






    ) 1

    IL-2 KO CD25 KOCD122 KO

    Dominant negative TGFR II Tg

    Ubiquitin-editing enzyme A20 KO

    Autophagy-related gene (Atg) 5- deficient thymus-implanted nu/nu mice

    ) 1


    DSSTNBSCotton-top tamarin

    C3H/HeJBir CD3eTg model

    ( T-cell-specific suppressor of cytokine signaling (SOCS) 1 Tg

    Epithelial-specific core 11,3-galactosyltransferase KO

    IL-7 Tg CD45RB

    Mucin 2 KO IL-10 KO

    CD132 KO

    TCR KO

    Wiskott-Aldrich syndrome protein (WASP) KO

    Phosphatidyl inositol 3 kinase (PI3K) p110 KI

    CD4-specific phosphoinositide-dependent kinase (PDK) 1 KO

    n 1

    G protein Gi2 KO

    Liver-specific soluble CD86 Tg

    CD11c-specific integin 8 KOInducible STAT4 Tg

    Myeloid-specific STAT3 KO

    Inducible STAT3 KO

    24 TCR Tg x CD1d Tg Epithelium polarized sorting factor AP1B KO Epithelial-specific IB kinase NEMO KO

    TLR5 KO

    Keratin 8 KO


    RAG KO with deficiency of nuclear factor of activated T cells (NFAT)c2

    RAG KO with deficiency of T-box transcription factor T-bet


    Systemic Inflammation


    22. ANIMAL MODELS OF INFLAMMATORY BOWEL DISEASE500SAMP/YitEpithelial-specific N-cadherin KI

    TNFR1-deficient, epithelial-specific TGF activation kinas

    Src-homology-2-containing inositol 5 phosphatase (SHIP)1 KO


    CD2-specific TNF



    Runt-related transcription factor RUNX3

    Inducible enteric glia KO

    Epithelial-specific X-box-binding protein (XBP

    Glutathione peroxidase (GPX


    Janus family tyrosine kinase

    RAG KO treated with anti-CD40T cell-specific B-lymphocyte-induced maturation protei

    IL-6 receptor gp130 KI

    Multiple drug resistan

    FIGURE 22.1 The different types of IBD models. These include chspontaneous models (black), congenital models (brown), and geneticallyinto conventional transgenic models (light blue), conventional knockoknockout models (pink), knock-in models (orange), and innate models(colitis, red square), small intestine (ileitis, blue square), or multiple orVI. URINARY TRACT, K1-deficient DKO

    F15 (TL1A) Tg

    ecific IL-15 Tg

    Caspase-8 KO


    TGF KO

    Casitas B-lineage lymphoma protein cb1-b KO

    CD2-specific TNFSF14 (LIGHT) Tg

    B-cell-specific CD40L TgEndothelial-specific integrin V KO

    CD4-specific TGF KO/2 DKO

    JAK) 3 KO (Blimp1) KO

    e (Mdr) 1a KO

    ically induced models (dark green), cell-transfer models (light green),ngineered models. Genetically engineered models are further classifiedmodels (red), conditional transgenic models (dark blue), conditionalrple). These models spontaneously develop inflammation in the colonns including the colon and small intestine (systemic, green square).IDNEY AND BOWEL

  • smoking may have potential for IBD therapy. In addi-

    engineered models are further classified into sixsubgroups.8 Conventional transgenic or conven-

    At least 66 kinds of IBD model had been established

    with high humidity) for microbes in the southern parts,these northsouth gradients may support the hygiene

    ETIOLOGY AND MOUSE IBD MODELS 501tional knockout mice are genetically engineered tocontinuously overexpress or lack the gene of interest inall cell types, respectively. Conditional transgenicmice are genetically engineered using cell-specificpromoters to overexpress the gene of interest in a specificcell type. Conditional knockout mice are geneticallyengineered to lack a gene of interest in a specific celltype or to make the gene deletion inducible at anytime. Knock-in (KI) mice are genetically engineeredto carry a mutation in the gene of interest. Innatemodels are immune-deficient mouse-based systems,such as recombinant activation gene (RAG) KO micethat lack both T and B cells.tion, several conventional and biological drugs havebeen successfully, or unsuccessfully, applied for IBD,or are currently in clinical development.1,17 Therefore,this chapter focuses on these fields (etiological factorsand drugs) that may have immediate therapeutic poten-tial. The authors hope that the datadsummarized in thischapterdwill direct clinicians who are unfamiliar withanimal models of IBD to be familiarized on interpretingdata from IBD models, for the consideration of futureclinical trials of candidate therapies. In addition, thesedata may be helpful for basic researchers to realizesome clinically relevant fields for bridging the gapbetween the bench and the bedside.


    In addition to the location of inflammation (seeabove), IBD models can be classified into five majorgroups depending on the method of disease induction(Fig. 22.1)dchemically induced models such as thedextran sodium sulfate (DSS) model, in which acutecolitis can be induced by administration of DSS indrinking water; cell-transfer models, such as theCD45RB model, in which colitis can be induced inimmunodeficient hosts by adoptive transfer ofCD4CD45RBhigh nave T cells from wild-type (WT)donors; spontaneous models, such as the cotton-toptamarin (a marmoset native to a small geographic regionof Colombia) that develops colitis presumably throughenvironmental stress when maintained at US; congen-ital models, such as SAMP/Yit mice that develop ileitisin a senescence-prone strain derived from 24 genera-tions of siblings from a litter of AKR/J mice; and genet-ically e


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