Infl Ammatory Bowel Disease, Past, Present and Future: Lessons From Animal Models

J Gastroenterol 2008; 43:117
DOI 10.1007/s00535-007-2111-3
Review
Inflammatory bowel disease, past, present and future: lessons from
animal models
ATSUSHI MIZOGUCHI1,2 and EMIKO MIZOGUCHI2,3
1
Department of Pathology, Experimental Pathology, Simches 8234, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA,
02114 USA
2
Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
3
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Accumulating data from animal models indicate that

inflammatory bowel disease (IBD) is mediated by a
much more complicated mechanism than previously
predicted. For example, the role of an individual molecule in the pathogenesis of IBD distinctly differs depending on several factors, including the fundamental
mechanism of induction of the disease, the target cell
type, the phase of disease, and the environment. Therefore, it has been difficult in the past to fully explain the
complicated mechanism. Novel concepts have recently
been proposed to further explain the complicated
mechanism of IBD. In this review, we introduce past,
current, and possible future concepts for IBD models
regarding T helper (Th) 1, Th2, and Th17, antigen sampling and presentation, regulatory cell networks, NOD2,
Toll-like receptors, bacteria/epithelia interaction, stem
cells, autophagy, microRNAs, and glycoimmunology,
and we also discuss the relevance of these new concepts,
developed at the bench (in animal models), to the
bedside.
Key words: antigen sampling, autophagy, IBD, Breg,
mucin, NOD2, Th17, TLRs
Introduction
Inflammatory bowel disease (IBD), comprising Crohns
disease (CD) and ulcerative colitis (UC), is a chronic
inflammatory disorder caused by multifactorial conditions in a genetically predisposed host.13 The complicated mechanism underlying IBD is clearly indicated by
the presence of many IBD susceptibility genes.4 Three
Received / Accepted: August 29, 2007

Reprint requests to: A. Mizoguchi
types of genetically engineered mice, T-cell receptor

(TCR-), interleukin (IL)-2-, and IL-10-knockout (KO)
mice were unexpectedly found in 1993, independently
by Mombaerts et al.,5 Sadlack et al.,6 and Kuhn et al.,7
to spontaneously develop chronic colitis. Spontaneous
development of colitis has since been identified in many
kinds of knockout and transgenic mice810 (Fig. 1). The
spontaneous development of colitis in so many different
kinds of genetically engineered mice further emphasizes
the presence of a more complicated mechanism than
previously predicted in the pathogenesis of IBD.
Although the animal models of IBD may not fully
reflect human IBD, these models have provided us great
opportunities to more closely examine the mechanism
of this disease. Indeed, animal models not only have
contributed significantly during the last decade to our
understanding of the complicated mechanism of IBD
but also have provided useful interventions for developing novel therapeutic strategies for this disorder.11 Currently, many animal models of IBD are available,810 and
each model has both merits and disadvantages for studying IBD. For example, acute intestinal injury induced in
mice by continuous administration of dextran sulfate
sodium (DSS) is a useful model for scientifically studying the epithelial barrier and its regeneration and innate
immune responses,12 but it may be an inappropriate
IBD model, for example, for evaluating the potency of
therapeutic agents in IBD patients.
Th17/IL-23
Accumulating data obtained from experimental IBD
models have suggested the involvement of both common
and distinct mechanisms in the pathogenesis of UC
versus CD. One of the major concepts previously used
to explain the different mechanisms is the T helper (Th)
1/Th2 paradigm.811,13 Indeed, Th2 cytokines such as IL-4
and IL-13 contribute significantly to chronic UC-like
A. Mizoguchi and E. Mizoguchi: IBD past, present and future
T H1
Mdr1a
CBI-b
Smad3
PAST
TNF
(ARE)
Common
IL-10
Gi2
IL-2R
IL-2
IL-2R
CD3
TGF
IL-15
IBD
HLAB27
IL-7
gp39
CdCS
IL-4
NCAD
GFAP-HA
Tir8
Tn
A20
TH1
NFATc2 STAT3 GPX1/2

XBP1
LIGHT
Muc2
WASP
Keratin8
STAT4
Runx2
OT
R
E
H
TH2
Fig. 1. Deficiency (knockout mice, red colors) or overexpression (transgenic mice, blue colors) of many different molecules
in mice has been shown to induce the spontaneous development of colitis, which is mediated preferentially by an acquired
(ellipses) or innate (rectangles) immune pathway. The pathogenesis of colitis in some mouse models has significant contributions from the T helper (Th) 1 or Th2 pathway. IBD,
inflammatory bowel disease; IL, interleukin; TGF, transforming growth factor; A20, also known as tumor necrosis factor
(TNF)-induced protein 3; CBl-b, E3 ubiquitin ligase; Gi2, G
protein i2; GFAP-HA, transgenic mice in which enteric glia
are specifically disrupted; GPX, glutathione peroxidase;
HLAB27, HLAB27/human 2 microglobulin transgenic rats;
LIGHT, a TNF superfamily member; Mdr, multiple drug resistance; Muc2, mucin2; NCAD, transgenic mice that overexpress
dominant negative N-cadherin in the intestinal epithelial cells;
NEMO, NF-B essential modulator; NFAT, nuclear factor of
activated T cells; STAT, signal transducer and activator of
transcription; TCR, T-cell receptor; Tir8, also known as
SIGIRR (single Ig interleukin-1-related receptor); TNFARE,
mice lacking TNF AU-rich elements; WASP, Wiskott-Aldrich
syndrome protein; XBP1, X-box binding protein
disease.811 In contrast, the Th1 pathway has been implicated in the pathogenesis of CD.811,13 In addition to the
Th1/Th2 theory, accumulating recent studies have
unveiled the critical involvement of the IL-23/IL-17
pathway in the pathogenesis of CD-like experimental
diseases.1418 IL-12 (p40/p35) has generally been believed
to be a crucial factor involved in the development of
Th1-mediated colitis because of the beneficial effect of
anti-IL-12p40 treatment in CD patients as well as in
Th1-mediated experimental colitis.11 However, recent
studies have demonstrated that IL-23 (a heterodimer of
p40 and p19 subunits) rather than IL-12 (a heterodimer
of p40 and p35 subunits) contributes to the development of Th1-mediated chronic colitis observed in several
murine CD models, including IL-10 KO mice,14 the
CD45RB model,16,17 the cecal bacteria-specific T cellinduced colitis model,18 the Helicobacter hepaticus-
TH2
IL-4
Treg
RA
Tn TGF
IL-12/IFN
NEMO
TCR
TH2
PRESENT
IL-12/IFN
TH1
IL-6
TH17
IL-23
Fig. 2. In the past, the Th1/Th2 paradigm was a major concept

in the pathogenesis of acquired immune-mediated colitis. An
additional Th17/IL-23 pathway has recently been identified.
Interestingly, recent accumulating data have demonstrated the
reciprocal developmental pathways for generation of effector
Th17 and Foxp3+ regulatory T (Treg) cells. Th17 differentiation
is induced by TGF in the presence of proinflammatory cytokines such as IL-6. In contrast, Treg cell differentiation is
induced by TGF in the absence of IL-6 and/or presence of
retinoic acid (RA). IL-23 is required for the survival and maintenance of Th17. IFN, interferon
induced colitis model,16,17 and the CD40-dependent

innate immune-mediated colitis model.15 In addition, a
very recent study has shown that granuloma formation,
a characteristic feature of CD, is mediated by a unique
dendritic cell subset that coexpresses a macrophage
marker (F4/80) and produces a large amount of IL-23.19
Notably, the relevance of the data from these experimental colitis models to human CD is indicated by a
recent study that identifies a negative association
between IL-23 receptor polymorphisms and the development of IBD.20 Another very recent study also shows
that an IL-23R polymorphism (R381Q) is particularly
associated with CD in non-Jewish children.21 In contrast
to Th1-mediated chronic colitis, IL-12 rather than IL23 has been demonstrated to play a pathogenic role in
Th1-mediated acute colitis, induced by administration
of trinitrobenzesulfonic acid (TNBS).22
A current topic in the field of immunology is the discovery of a Th17 T-cell subset characterized by the production of IL-17 (IL-17A) and IL-17F but not interferon
(IFN)- or IL-4.2328 Differentiation of this Th17 subset
is induced through activation of orphan nuclear receptor RORt signaling, depending on the pleiotropic cytokine transforming growth factor (TGF) , which is also
linked to the development of Foxp3+ regulatory T (Treg)
cells.24,26,27 Reciprocal Th17 versus Treg cell differentiation is regulated by proinflammatory cytokines such as
IL-6 (for differentiation to Th17) and retinoic acid (for
differentiation to Treg cells).24,27,29 The expansion and
survival of Th17 T cells are subsequently mediated by
IL-2324,25 (Fig. 2). IL-17 expression is not detectable in
the normal colon of humans, but is readily detectable in
the colon of CD patients, regardless of disease severity.30,31 In contrast, IL-17 expression becomes detectable
only in the moderately to severely affected colon of UC
patients, and the expression levels of colonic IL-17 are
significantly lower in UC than in CD.30,31 The pathogenic
role of IL-17 has been demonstrated in some colitis
models. Neutralization of IL-17A activity results in the
suppression of Th1-mediated chronic colitis in IL-10 KO
mice,14 and the absence of IL-17 receptor in mice induces
resistance to the Th1-mediated acute colitis induced by
TNBS administration.32 In addition, activation of an
IL-17 receptor-mediated signaling pathway via Act1 in
epithelial cells contributes to the development of DSSinduced intestinal injury.33 In contrast, neutralization of
systemic IL-17A activity by administration of anti-IL17A monoclonal antibodies has been shown previously
to exacerbate DSS-induced intestinal injury.34 IL-17A
does not seem to be involved in Th2-mediated chronic
colitis, which develops spontaneously in TCR KO
mice.35 The regulatory role of IL-17 has been documented in a Th2-mediated asthma model.36 Therefore,
the role of IL-17 in the pathogenesis of colitis may differ
distinctly, depending upon, for example, whether the
phase of colitis is chronic or acute, whether Th1 or Th2
has contributed to the disease, and whether IL-17 activity is systemic or local. Interestingly, a recent study has
shown that Treg cells, which are well known to suppress
Th1-mediated colitis in the CD45RB model, are incapable of suppressing IL-17-mediated inflammation.37
Finally, it is important to mention a very recent observation that a T-cell subset producing both IL-17 and IFN-
is present in the inflamed intestine but not in the peripheral blood of CD patients.38
IL-22, which belongs to the IL-10 cytokine family,
specifically targets innate, but not acquired, immune
responses through the activation of STAT3.39 Interestingly, similar to the expression pattern of IL-17, colonic
IL-22 expression is specifically induced by inflammation
in both CD and UC, but the expression level of IL-22 is
significantly higher in CD than in UC.4042 Indeed, recent
studies have demonstrated that, in addition to IL-17,
IL-22 is also expressed preferentially by the Th17 cell
subset.43,44 Functionally, IL-22 has recently been shown
to mediate IL-23-induced inflammation in the skin.44 In
contrast, our recent study demonstrated that IL-22 contributes to the amelioration of ongoing Th2-mediated
chronic colitis, in which IL-23 is not upregulated (unpublished data). Since IL-22 possesses the ability to stimulate production of both regulatory (e.g., IL-10,
antibacterial peptide, and SOCS3) and deleterious (e.g.,
IL-8) molecules,3941,45 the reciprocal regulatory versus
deleterious functions of IL-22 may be determined by
the disease dependence on IL-23.
Antigen sampling and antigen-presenting cells

Presentation of antigens to T cells by professional
antigen-presenting cells (APCs) such as dendritic cells
(DCs) is a critical event for the activation of acquired
immune responses. A well-known lesson from animal
models of IBD is that enteric bacterial antigens are
required for the activation of pathogenic T cells involved
in the induction of colitis.9,11 I2 (a superantigen)46 and
flagellin47 have been identified as bacteria-derived
pathogenic antigens in the activation of deleterious
acquired immune responses. For antigen presentation,
luminal enteric bacterial antigens initially need to gain
access to APCs present in the lamina propria (LP).48 In
the past, the antigen-transport mechanism from the
lumen to the LP was explained only by a pathway mediated by M cells.49 A second pathway by which LP DCs
directly capture the luminal antigens by extending their
dendrites to the intestinal lumen across epithelial cells
was identified 6 years ago by Rescigno et al.50 and elegantly supported by an in vivo imaging system by Niess
and colleagues.51 Very recently, Yoshida et al.52,53 discovered an attractive third pathway by using a novel human/
mouse chimera system. Neonatal Fc receptor (FcRn)
serves as the vehicle that transports LP IgG across the
colonic epithelial layer into the lumen, where the IgG
can bind enteric bacterial antigens. The FcRn then recycles the antigen/IgG complex back across the colonic
epithelial cells into the LP for processing by DCs, which
are capable of presenting the antigens to T cells (Fig. 3).
Similarly, a CD23/IgE-dependent mechanism for transepithelial antigen sampling has recently been documented.54 Since the antigen-transport process represents
the initial event in the activation of pathogenic acquired
immune responses inducing colitis, one can predict that
inhibition of this process may contribute to the inhibition of IBD.
Significant advances in the field of DC biology have
been made during the last decade. The current knowledge regarding mucosal DCs is well summarized in
several excellent reviews.5557 Therefore, in this review,
we briefly describe recent findings regarding the functional role of DCs in colitis. DCs comprise phenotypically heterogeneous populations, and even in a given
subset possess considerable functional plasticity,
depending on their maturation stage and location and
environmental conditions.5558 Many phenotypic and
ex vivo functional studies of intestinal DCs associated
with experimental IBD have been performed, but only
a few studies have investigated whether DCs actually
induce or suppress the development of colitis in vivo.
One study has demonstrated that injection of in vitrogenerated DCs by stimulation with vasoactive intestinal
peptide contributes to the suppression of TNBS-induced
colitis by dampening the Th1 response and generating
Pathway 1
Bacteria
Pathway 3
Pathway 2
Ags
IC
Ags
M cells
FcRn
DCs
T cells
IgG
APC
Fig. 3. There are at least three pathways involved in the transportation of luminal antigens (Ags) to the intestinal lamina propria
(LP). M cells capture luminal Ags and then present them to T cells (Pathway 1). LP dendritic cells (DCs) directly capture the
luminal antigens by extending their dendrites to the intestinal lumen across epithelial cells (Pathway 2). Neonatal Fc receptor
(FcRn) serves as the vehicle that transports LP immunoglobulin G (IgG) across the colonic epithelial layer into the lumen where
the IgG can bind enteric bacterial antigens to form immune complexes (IC). The FcRn then recycles the antigens/IgG IC back
across the colonic epithelial cells into the LP for processing by antigen-presenting cells (APCs) such as DCs, which are capable
of presenting the antigens to T cells (Pathway 3)
IL-10-producing regulatory T cells.59 In addition,

cotransfer of in vitro-generated bone marrow (BM)derived DCs by stimulation with IL-10 may suppress the
colitis that is induced in recipient severe combined
immunodeficient (SCID) mice by transfer of CD4+CD25
T cells.60 In contrast, a unique CD11c+ DC-like subset,
which exhibits phenotypic and functional features of
immature myeloid DCs and is characterized by the
expression of a macrophage marker (F4/80), has recently
been shown to participate in the granuloma formation
associated with CD-like experimental colitis.19 Interestingly, a similar DC subset sharing features with macrophages has also been identified in the lung after infection
with Mycobacterium tuberculosis, which characteristically causes granulomatous inflammation.61 Future
studies employing a more sophisticated, genetic engineering approach capable of deleting specific DC subsets
in mice would allow us to further investigate the functional role of individual DC subsets in the pathogenesis
of IBD.
Regulatory cell network

In the past, the major concept explaining the mechanism by which deleterious acquired immune responses
in autoimmune diseases are generated was an expansion of specific pathogenic T-cell population(s). However, a novel concept was proposed two decades ago by
Sakaguchi et al.62 and Powrie and Mason.63 They proposed that dysregulated immune homeostasis caused by
the absence of a regulatory T-cell population contributes to the development of gastritis and IBD.62,63 This
novel concept has been widely supported during the last

decade by many studies, including a recent report that
CD4+CD25+ Treg cells are present not only in the spleen
but also in the intestinal LP.64 Many excellent reviews
discuss current advances made by studies of Treg
cells6568 and the intestinal immunoregulatory network.69
Therefore, in this review, we discuss other regulatory
cell populations that possess the potential ability to
inhibit the progression, but not the development, of
chronic colitis.
B cells are functionally characterized by their specific
feature of antibody production, but they were not typically considered in the past to be a major source of
cytokines. Harris and colleagues70 revised this concept
in 2000 by elegantly demonstrating that, like Th1/Th2 T
cells, B cells also possess the potential ability to produce
large amounts of several cytokines under certain inflammatory conditions. We also found that a regulatory cytokine, IL-10, is not generally produced by B cells in a
state of health, but a Th2-mediated intestinal inflammatory condition activates the B cells in the mesenteric
lymph nodes (MLNs) to produce IL-10.71 Of note, the
inducible IL-10-producing B cells subsequently contribute to the amelioration of the ongoing Th2-mediated
colitis but do not affect the development (initiation)
of this colitis. In humans and mice, IL-10-producing
regulatory B cells have since been identified in several
kinds of inflammations7282 but not in a state health or
in endotoxin shock induced by lipopolysaccharide
(LPS).83 IL-12p70 was initially identified nearly two
decades ago in an Epstein-Barr virus-transformed Bcell line.84 However, subsequent studies have failed to
detect the production of IL-12 by normal B cells from
PAST
PRESENT
B cells
B cells
2nd APCs
IL-12
Igs
Igs
IL-10
Fig. 4. In the past, immunoglobulin (Ig) production had generally been believed as the major function of B cells. However,
recent accumulating data have unveiled additional novel functions of B cells. B cells possess the abilities to produce several
cytokines such as IL-10 and IL-12 under inflammatory conditions and to serve as a secondary APCs to dampen T-cell
activation
healthy individuals or by LPS-stimulated B cells. Therefore, macrophages and DCs but not B cells have generally been believed to produce IL-12. However, this
concept may need to be revised in light of recent accumulating evidence that production of IL-12 by B cells
becomes easily detectable under certain inflammatory
conditions and when unmethylated CpG dinucleotides
(CpG), which became available for use only recently,
but not LPS, are used for the stimulation.77,85 Indeed,
we recently found that a Th2-mediated intestinal inflammatory condition as well as CpG stimulation induces
the differentiation of IL-12-producing B cells in the
presence of IL-10.35 Importantly, the inducible IL-12producing B cells contributed to the amelioration of
this Th2-mediated colitis. This finding may support
the earlier observations that Toll-like receptor (TLR)
9/CpG signaling contributes to the suppression of
colitis.8688 Interestingly, absence of IL-12-producing B
cells enhances the production of IL-17A by CD4+ T
cells.35 Indeed, IL-12 has previously been demonstrated
to inhibit IL-17 production.89 These data indicate that B
cells possess considerably more functional plasticity
than previously believed (Fig. 4).
The regulatory role of B cells in colitis and ileitis has
been demonstrated by several studies using different
IBD models, including TCR KO mice, Gi2 KO mice,
NFATc KO mice, and the CD45RB model.71,9096 Wei
and colleagues94 have identified a critical cellular
network for B cell-mediated regulation of colitis. MLN
B cells suppress the chronic colitis of Gi2 KO mice by
cooperating with regulatory CD8+ T cells and natural
killer T cells.94 In addition, recent studies in other autoimmune disease models have demonstrated that B cells
indirectly or directly enhance Treg cell function.9799 The
B cells that possess regulatory functions independent of
immunoglobulin production have been termed Breg
cells.95 It is important to mention that B cells, which
serve as a deleterious cell population, have also been

identified in some models of intestinal inflammation. B
cells have been reported to play a pathogenic role in the
ileitis seen in SAMP/YitFc mice,100 and to participate in
the induction of ileal villus atrophy.101 In addition,
genetically engineered ectopic expression of gp39 on B
cells causes the development of colitis and ileitis.102
These findings suggest the coexistence of pathogenic
and regulatory B cell populations in IBD patients.
Future studies are needed to determine whether B cells
can be targeted for the treatment of IBD patients.
NOD2 (CARD15)
One of the significant advances in IBD studies in the
last decade is the discovery of nucleotide-binding oligomerization domain 2 (NOD2)/caspase-recruitment
domain 15 (CARD15) as a CD susceptibility gene by
Hugot et al.103 and Ogura et al.104 Since recent advances
in IBD genetics and NOD2 biology have already been
clearly introduced in excellent reviews,1,3,4,103106 this
review focuses only on findings in murine models regarding the role of NOD2 in the pathogenesis of IBD.
NOD2 induces innate immune responses through
cytosolic recognition of bacterial components such as
muramyl dipeptide (MDP), which is a conserved structure in virtually all types of peptidoglycans (PGN).104 To
explore the role of NOD2 mutation in the pathogenesis
of CD, three independent research groups have generated NOD2 KO mice107,108 or NOD2939ic knockin (KI)
mice, which carry a NOD2 gene mutated at position
2939 (corresponding to 3020 in human NOD2).109 In the
NOD2 KO mice generated by Kobayashi et al.,108 protective innate immune responses mediated by NOD2
recognition of MDP are completely abolished. Although
the NOD2 KO mice do not spontaneously develop
colitis, they are more susceptible, with a significantly
reduced production of an antibacterial peptide (cryptidin) to Listeria monocytogenesis infection but not to
DSS-induced intestinal injury.108 Abnormally low antibacterial peptide production in the ileum (mainly by
Paneth cells) is likely a primary defect in CD.110 Watanabe and colleagues111,112 proposed a role of NOD2 in
the suppression of the TLR2-dependent innate immune
pathway involved in the activation of the Th1 response
in studies using the other NOD2 KO mice generated by
Pauleau and Murray.107 The NOD2 deficiency significantly enhances the production of IFN-, IL-18, and
IL-12p70 by the splenocytes in response to stimulation
with PGN111 and increases the susceptibility of mice to
TLR2-dependent colitis induced by ovalbumin (OVA)specific T cells in the presence of OVA-producing Escherichia coli (ECOVA).112 In contrast, alteration of such
TLR2-mediated immune responses is not observed in
the other NOD2 KO mice108 or in the NOD2939ic KI

mice.109 Therefore, any potential negative role of NOD2
in the TLR2 response may not be a universal phenomenon but may depend on the genetic background of the
mice used.108 The NOD2939ic KI mice also do not develop
colitis spontaneously, but are more susceptible to DSSinduced intestinal injury than wild-type (WT) mice.109
Interestingly, enhancement of NF-B activity and proinflammatory cytokine secretion by macrophages after
stimulation with MDP is observed in the NOD2939ic KI
mice.109 Many research groups have recently identified
and characterized the molecules capable of interacting
with NOD2, which include GRIM-19 (gene associated
with retinoid IFN-induced mortality),113 TAKI (TGFactivated kinase 1),114 Erbin,115 Centaurin 1,116 and
CARD9.117 Since these NOD2-interacting molecules
have been demonstrated to positively or negatively
regulate NOD2-mediated NF-B activation, future
studies using genetically engineered mice targeting
these molecules would further enhance our understanding of the biological function of NOD2 in the pathogenesis of CD.
Since deficiency or mutation of NOD2 in mice cannot
induce the spontaneous development of colitis,108,109
certain combinations of polymorphisms within multiple
IBD susceptible genes may be required to induce full
development of IBD. On the other hand, none of the
identified NOD2 variants are associated with CD in the
Japanese (non-Western) population.118,119 In addition,
the recently reported association of CD with variants in
other major IBD susceptibility genes, autophagy-related
16-like 1 (ATG16L1) and IL23R, is also not found in
the Japanese population.119 Therefore, in addition to
genetic susceptibility, other environmental and host
factors may be required to fully induce development of
IBD.
TLRs
The identification of mammalian TLRs as pattern recognition receptors for specific recognition of bacterial
products by Medzhitov et al.120 and Hoshino et al.121
led to major breakthroughs in many research fields,
including IBD studies. Recent advances in TLR biology
are well summarized in excellent reviews by the pioneers.122124 Therefore, here we focus only on the functional role of TLRs in the pathogenesis of colitis as
revealed by data accumulated during the last 5 years or
so.
TLR2 and TLR4
The role of TLR4 and TLR2 and their common adaptor
protein, myeloid differentiation factor 88 (MyD88), in
maintaining the epithelial barrier against DSS-induced

toxic damage has been well demonstrated by several
groups.125128 In DSS-induced acute intestinal damage,
the impaired epithelial barrier function in TLR2 KO,
TLR4 KO, and MyD88 KO mice leads to increases in
intestinal bleeding, the development of colonic erosion
and ulcers, the translocation of Gram-negative bacteria,
and the mortality rate.125128 Reduction of enteric bacteria flora by administration of a combination of antibiotics also significantly increases the susceptibility of mice
to DSS-induced lethal damage, which is presumably
caused by intestinal bleeding.125 This finding is consistent with the finding that administration of DSS induces
lethal damage, causing severe intestinal bleeding in
germ-free mice.129
As mentioned above, it is clear that the TLR2/TLR4/
MyD88 signaling pathway is required to preserve the
intestinal epithelial barrier against DSS-induced acute
stress.125128 In contrast, the severity of colitis induced by
a continuous DSS challenge varies considerably in
TLR2 KO, TLR4 KO, and MyD88 KO mice. For example,
compared with WT mice, the histological score (colitis
score) of DSS-induced acute intestinal damage in
MyD88 KO mice may be ameliorated,126 exacerbated,127
or unaffected.87,128 In addition, the histological score in
TLR4 KO mice may be ameliorated126,130,131 or exacerbated.87,127 One possible explanation is that different
environmental conditions in different mouse facilities
influence the mucosal immune responses after the disruption of the epithelial barrier. Alternatively, DSSinduced acute injury may not be an appropriate model
for studying colitis (IBD), although this model is very
useful for scientific studies of epithelial homeostasis and
barrier function. Recently, many groups have examined
the recovery phase after a single administration of
DSS.93,132136 Both acquired and innate immune responses
have been implicated in the recovery phase,93,132 and the
epithelial cell regeneration observed during the recovery phase resembles that observed in chronic colitis.135
Therefore, this recovery model may be useful for studying the wound healing process (epithelial regeneration)
and the linkage between innate and acquired immune
responses. Since the balance between damage and
healing is a critical determinant of the progression (after
onset) of IBD, the recovery model may more closely
reflect the mechanism of IBD progression or perpetuation. Utilizing the recovery model, Cario et al.128 recently
demonstrated that TLR2 significantly enhances the
healing process of colitis by regulating ZO-1-associated
epithelial barrier integrity.
The role of TLR2/TLR4/MyD88 in acquired immune
responses involved in the pathogenesis of chronic colitis
has also been investigated recently. The bacterial lipoprotein Pam3Cys-SK4 (TLR1/TLR2 agonist) is able to
transiently suppress the function and Foxp3 expression
of Treg cells. Suppression of CD45RBhigh T cell-induced

colitis (CD45RB model) by Treg cells is significantly
delayed when the cells are pretreated with Pam3CysSK4.137 Administration of the synthetic TLR4 antagonist CRX-526 attenuates the chronic colitis that
spontaneously develops in multidrug resistant gene 1
(Mdr1) KO mice.130 Spontaneous development of colitis
in IL-10 KO mice may be abolished by the absence of
MyD88.138 These data suggest the pathogenic role of
TLR2/TLR4/MyD88 signaling in some types of acquired
immune-mediated chronic colitis. In contrast, development of colitis in IL-2 KO mice is independent of
TLR signaling, as indicated by the development of
colitis in MyD88- and Toll-interleukin 1 receptor
domain-containing adaptor inducing interferon
(TRIF) 1-deficient IL-2 triple KO mice.138 These data,
together with those from the DSS model, indicate that
the contribution of TLR2/TLR4/MyD88 signaling to
the pathogenesis of IBD is determined by many factors,
including the fundamental mechanism of the colitis
(e.g., IL-10 KO versus IL-2 KO mice), the cell type (e.
g., epithelial versus Treg cells), and the phase of colitis
(e.g., acute versus recovery versus chronic). Future
studies are needed to clarify the complicated role of
TLR2/TLR4/MyD88 signaling in the pathogenesis of
IBD.
TLR5
By utilizing a serological expression cloning technique,
Lodes et al.47 identified flagellin (TLR5 ligand), a
common bacterial antigen present on most motile bacteria in the intestine, as the dominant antigen capable
of stimulating Th1 responses in CD patients. In an
experimental mouse system, they confirmed that flagellin-specific CD4+ T cells induced colitis in the recipient
mice.47 The involvement of flagellin in acquired immune
responses is further supported by data showing that
flagellin-specific immunoglobulin production is T celldependent.139 The relevance of flagellin to the pathogenesis of human CD is strongly emphasized by the
following observations. A dominant-negative TLR5
polymorphism (called TLR-stop) is negatively associated with CD in Jewish, but not in non-Jewish, patients.140
Anti-flagellin antibodies are frequently detected in CD
but not in UC patients.141 Interestingly, CD patients carrying at least 1 NOD2 variant exhibit enhanced antiCBir1 flagellin reactivity.142
In addition to the role of flagellin in IBD-associated
acquired immune responses, flagellin can also activate
innate immune responses, as indicated by its ability to
stimulate colonic epithelial cells (CECs) to produce
proinflammatory cytokines.143,144 Interestingly, the flagellin/TLR5 response in CECs is basolaterally polarized in
healthy individuals, and CECs in intact colon therefore
do not respond to flagellin, suggesting that the response

of CECs to flagellin is specifically elicited under inflammatory conditions.144 Consistent with this, rectal administration of flagellin does not induce host responses in
normal mice but aggravates DSS-induced acute colonic
injury.144
TLR9
Unmethylated CpG dinucleotides (CpG), which are
frequently recognized in the genomes of bacteria and
viruses, were initially found in 1995 by Krieg et al.145
to stimulate B cells. A subsequent study by Hemmi and
colleagues146 identified TLR9 as the receptor for CpG.
The role of CpG/TLR9 in the pathogenesis of IBD has
been vigorously investigated by the research groups of
Raz and Falk. Rachmilewiz et al.86,87 initially showed
that intragastric and subcutaneous, but not intrarectal,
administration of CpG oligodeoxynucleotides (ODNs)
suppresses DSS-induced acute intestinal injury, TNBSinduced acute colitis, and chronic colitis in IL-10 KO
mice through downregulation of proinflammatory
cytokine and matrix metalloproteinase expression. The
dependence of this therapeutic effect on TLR9 was
further confirmed in TLR9 KO mice.87 Mechanistically,
innate immune pathway-mediated production of type
I IFN is required for the CpG-mediated suppression
of DSS-induced acute injury.88 Interestingly, a unique
pathway for activation of CECs by CpG was recently
discovered.147 Basolateral TLR9 signals activation of
the NF-B pathway in CECs, whereas apical TLR9
prevents activation of the NF-B pathway by inducing
accumulation of ubiquitinated IB in the cytoplasm.147
There are three types of synthetic CpG ODNs having
distinct structures and immunostimulatory activities.148
The effect of CpG ODNs on proinflammatory cytokine
production in UC patients has been shown to differ
depending on the type of CpG ODNs.149 Class B CpG
ODNs are able to inhibit colonic tumor necrosis factor
(TNF)- and IL-1 production in UC patients. In contrast, class A or C CpG ODNs do not have inhibitory
activity. A possible role of CpG ODNs in the induction
of regulatory properties in nave T cells has also been
proposed. CD4+CD62L+ T cells from CpG ODNpretreated donor mice are unable to induce colitis in
recipient SCID mice and can suppress CD4+ T cellmediated colitis.150 Our recent study showed that CpG
activates a regulatory B-cell population (Breg) in Th2mediated chronic colitis in TCR KO mice.35 These
findings suggest the regulatory role of CpG/TLR9 in
the pathogenesis of colitis.
In contrast, a potential capacity of CpG/TLR9 to
exacerbate colitis has also been demonstrated. Administration of CpG exacerbates DSS-induced acute
injury.151 DSS-induced chronic colitis is attenuated in
TLR9 KO mice.152 In addition, administration of adenoviral CpG oligodeoxynucleotides (AV-ODNs), which

are capable of blocking the CpG effect, contributes to
the amelioration of several types of experimental colitis,
including DSS-induced chronic colitis, the CD45RB
model, and IL-10 KO mice.152 This suppression of colitis
is associated with a decrease in IL-6, IFN-, and T-bet
expression. In addition, our recent study showed that
CpG stimulates a unique DC subset to produce IL-23
and cause granuloma formation.19 Taken together, these
findings suggest that the functions of CpG/TLR9 signaling in the pathogenesis of IBD are extremely complicated. The role of CpG/TLR9 signaling in the
pathogenesis of IBD may be determined by many
factors, such as the type of CpG (class B versus class A
or C), the target cell type (CEC versus unique DCs),
and the route of CpG exposure (systemic and oral
versus rectal exposure or apical versus basolateral exposure in CECs). Future studies are needed to further
dissect the complicated mechanism of CpG/TLR9 signaling in the pathogenesis of IBD.
Other TLRs
Kuwata and colleagues153 recently identified TLRinducible nuclear IB (IBNS) to be a selective inhibitor of TLR-dependent gene expression. Absence of
IBNS enhances the production of IL-6, IL-12p40, and
IL-12p70 but not TNF- by DCs and macrophages in
response to stimulation via TLRs, including TLRs 1, 2,
4, 6, and 7. IBNS KO mice exhibit higher susceptibility
to LPS-induced endotoxin shock and DSS-induced
acute intestinal damage. Therefore, IBNS appears to
be critical for controlling inflammatory responses by
negatively regulating the induction of TLR-dependent
gene expression through modulation of NF-B activity.153 The role of TLR3 in DSS-induced intestinal injury
has recently been investigated in the DSS model.154 Subcutaneous, but not oral, administration of synthetic viral
RNA poly(I:C) protects against DSS-induced acute
intestinal damage in the presence or absence of IL-10.
This protective action of poly(I:C) is abolished in the
absence of TLR3.
Bacteria/epithelial cell interaction and

epithelial function
Humans and other mammals are host to 1012 viable
bacteria per gram of colonic content, comprising 500
1000 microbial species.155 During the last decade, much
accumulating data have clearly shown that commensal
enteric bacteria are critical in determining the development and course of IBD.3,11 In addition to the potentially pathogenic effect of enteric bacteria, the presence
of probiotic bacteria contributing to the suppression of

colitis has also been well documented during the last
decade.156 Most recently, unexpected findings regarding
the function of commensal bacteria have been made.
Bacteroides thetaiotaomicron is able to change its surface
carbohydrates in response to the nutrient glycan environment that it is accessing and also to evade a host
immune response.157 Indeed, a bacterial polysaccharide
derived from Bacteroides fragilis directs the cellular and
physiological maturation of the developing host immune
system.158 Adherent-invasive E. coli (AIEC), which has
been proposed as a potential pathogenic bacteria in CD,
has recently been shown to adhere to CECs through the
interaction of type 1 pili of AIEC and carcinoembryonic
antigen-related cell adhesion molecule 6 (CECAM6) on
the CECs.159 Chitinase 3-like 1, which is a member of
the chi-lectin family capable of binding to chitin, has
also been shown to enhance the binding of AIEC to
CEC.136 In addition to AIEC, Enterococcus faecalis is
capable of inducing the development of colitis in gnotobiotic IL-10 KO mice through activation of MyD88dependent NF-B activation of mucosal immune
cells.160
As the first line of defense against enteric antigens as
well as invasive or noninvasive enteric bacteria, CECs
play a critical role.161 Goblet cell depletion and thin
mucus layers are characteristic features of IBD, particularly UC.162 Because the layer of mucus lining the intestinal tract serves as a lubricant and a physiological
barrier between the luminal contents and mucosal
surface,162,163 it has generally been accepted conceptually, but without direct evidence, that the mucus layer
plays a regulatory role in colitis. Direct evidence
supporting this concept was provided most recently by
An et al.164 The intestinal mucus layer is a dense,
carbohydrate-rich matrix that consists primarily of
O-glycosylated mucins.162,163 Deficiency of 1,3-Nacetylglucosaminyltransferase (C3GnT) in mice impairs
colonic mucus layer formation by eliminating core 3derived O-glycans and significantly increases their susceptibility to DSS-induced acute intestinal injury.164 In
addition, a critical contribution of Muc2 (a secretary
mucin) in the suppression of colitis has been confirmed
by the data that Muc2 KO mice spontaneously develop
colitis.165 A regulatory role of Muc3 (a membrane-bound
mucin) in DSS- and acetic acid-induced acute intestinal
injury has also been demonstrated.166 Most recently, a
study using Muc1 KO mice demonstrated that surface
Muc1 protects epithelial cells from xenobiotic toxins;
increased apoptosis of intestinal epithelial cells was
observed in Muc1 KO mice challenged with Campylobacter jejuni.167 In contrast, genetically engineered overexpression of human Muc1 leads to the exacerbation of
chronic colitis in IL-10 KO mice.168 Therefore, the role
of Muc1 in intestinal inflammation may differ depend-
ing on the type of colitis (e.g., infectious versus chronic

colitis). Alternatively, as appropriately glycosylated
mucins are required to form a tight mucus layer assembly,162,163 it is also possible that overexpressed Muc1,
which may be inappropriately glycosylated, causes
mucus layer formation to be insufficient, thus exacerbating colitis.
During the last decade, accumulating studies have
revealed the role of goblet cells in the pathogenesis of
colitis. Goblet cell-derived intestinal trefoil factor (ITF)
contributes to the suppression of colitis by enhancing
CEC regeneration.169 Interestingly, partial depletion of
goblet cells by genetically engineered expression of the
diphtheria toxin gene under control of the ITF promoter enhances the production of ITF and significantly
increases the resistance of mice to DSS-induced acute
intestinal injury.170 As mentioned above, some Muc
proteins, which are produced preferentially by goblet
cells, participate in the suppression of colitis.165,166 In
contrast, resistin-like molecule (RELM), which is
specifically expressed by intestinal goblet cells, is a
pathogenic factor in DSS-induced acute intestinal injury
through the activation of TNF- production by macrophages171 or through activation of IL-13 production.172
Interestingly, IL-13 KO mice are protected against DSSinduced acute intestinal injury.172 In contrast to DSS
injury, RELM plays a regulatory role in Th1-mediated
acute colitis induced by TNBS.172 These data suggest
that the pathophysiological role of goblet cells in intestinal inflammation is more complicated than previously
predicted.
In addition to the barrier function of CECs, novel
biological functions of CECs have been identified during
the last decade. The biological functions of CECs under
intestinal inflammatory conditions vary significantly
depending upon several factors, such as the phase of
colitis (acute versus recovery versus chronic) and the
fundamental mechanism of colitis development (Th1
versus Th2 contributions).135,173 Detoxification pathways
in CECs are significantly downregulated in chronic but
not in acute colitis. Anti-inflammatory molecules such
as antibacterial peptides are commonly upregulated in
CECs in acute and chronic colitis. Production of a Ctype lectin, RegIII, by CECs is markedly increased
under chronic and acute intestinal inflammatory conditions but not in the recovery phase of colitis.135 Interestingly, RegIII has recently been shown to serve as an
antimicrobial protein and to be induced by microbial
epithelial contact through MyD88-mediated signaling.110,174
Moreover,
enhanced
expression
of
antigen-presenting molecules on CECs is specifically
observed in chronic, but not in acute, colitis.135 Indeed,
the ability of CECs to serve as APCs has been well
documented in IBD patients.161 CECs can induce unique
CD8+ regulatory T cells through interaction with CEC-
derived carcinoembryonic antigen 5.161 Interestingly,

CECs also activate a CD-associated pathogenic
CD4+ T-cell population through the interaction of MICA
on CECs and NKG2D on the CD4+ T cells.175 In addition, CECs have recently been demonstrated to be
capable of controlling the T cell-independent immunoglobulin class switching of intestinal B cells to IgA, positively by producing APRIL176, or negatively by producing
secretory leukocyte protease inhibitor.177 Furthermore,
CECs have been shown to condition intestinal DCs
through the constitutive release of thymic stromal
lymphopoietin.178
The activation of CECs is controlled by several signaling molecules. STAT3 activation in acquired immune
cells has been well documented to contribute to the
development or exacerbation of colitis.179 In contrast,
STAT3 activation of CECs contributes to the suppression of colitis, as indicated by the spontaneous development of colitis in conditional KO mice, in which STAT3
is specifically deleted in the CECs.180 Similar observations have been made regarding NF-B signaling. NFB signaling has been well implicated in the pathogenesis
of acquired immune-mediated colitis181 and DSSinduced intestinal injury.182 In contrast, a very recent
study has elegantly demonstrated that specific deletion
of NEMO (NF-B essential modulator) in the CECs
induces the spontaneous development of colitis.183 These
data clearly indicate that activation of the major signaling pathways in acquired versus innate (CEC) immune
responses results in distinctly different outcomes in the
pathogenesis of colitis. Therefore, as suggested by
Plevy,184 given the double-edged functioning of such
major signaling cascades in colitis, careful attention
should be directed toward the cell population that is
being targeted when contemplating the inhibition or
activation of these signaling cascades in human IBD.
Future topics
Basic science has been continuously progressive both
technically and conceptually. In the following section,
we introduce attractive novel avenues of investigation
in IBD research and discuss classical, but clinically relevant, subjects that might contribute to the immediate
translation from bench to bedside of concepts for
improving the lives of patients with IBD.
Stem cells
A major current topic in science and medicine is stem
cell biology. Further advances in this field are guaranteed to contribute significantly to breakthroughs in the
development of novel therapeutic strategies for several
diseases. Importantly, the relevance of stem cell biology
10
to the treatment of IBD was initially introduced in 2002

by Okamoto and colleagues,185 who showed that bone
marrow-derived stem cells possess the potential ability
to differentiate into CECs in humans. In addition, the
intestine has been identified as a location of the differentiation of lin c-kit immune precursors to T cells (in
mice) and natural killer cells (in humans).186,187 Of note,
recent studies have emphasized the therapeutic potency
of stem cell-based treatment of IBD. Administration of
CD34 stem cells, which are capable of differentiating
into endothelial cells, contributes to the suppression of
DSS-induced intestinal injury.188 BM cells that are
capable of differentiating into myofibroblasts, endothelial cells, pericytes, and vascular smooth muscle cells,
particularly under intestinal inflammatory conditions,
can contribute to the amelioration of TNBS-induced
colitis.189
Autophagy
Autophagy is a unique process of membrane trafficking in which the membrane compartment (autophagosomes) engulfs both organelles and cytosolic
macromolecules and delivers them to the lysosome for
degradation.190 Notably, ATG16L1 was identified most
recently as a new susceptibility gene in CD.191,192 Since
the appearance of bacteria in the cytoplasm in APCs
triggers specialized autophagy (xenophagy),190 this
cytoplasmic process fits well with the cytoplasmic recognition of bacterial antigens through NOD2. In addition, the TRIF-dependent, MyD88-independent TLR4
signaling pathway has recently been identified to regulate autophagy (xenophagy).193 This finding strongly
indicates the significant relevance of this field to IBD.
Alternatively, the major function of autophagy is the
regulation of self-responses.190 Autophagy contributes
to apoptotic cell clearance by a mechanism that involves
the generation of energy-dependent engulfment
signals.194 Importantly, macroautophagy constitutively
and efficiently delivers cytosolic protein (e.g., selfantigens and pathogens in host cells) for MHC class II
presentation to activate the acquired immune system.195,196
The role of autophagy in self-responses revives past
findings in IBD models. An involvement of impaired
clearance of apoptotic cells in the exacerbation of
chronic colitis was proposed in 1997.90 A study conducted in 1999 demonstrated the ability of self-antigen
(hsp60)-specific CD8+ T cells to induce ileitis.197 In addition, self-antigens have previously been shown to contribute to the conditioning of the clonality of the
pathogenic CD4+ T-cell population capable of inducing
colitis.198 Interestingly, the self-reactive CD4+ T-cell population induces the mild, but not the severe, form of
colitis. This previous observation may be consistent
with recent data that commensal bacteria are required
for exacerbation but not development of ileitis in

SAMP1/YitFc mice.199 Therefore, autophagy may be
an important process in IBD pathogenesis, inducing
not only innate immune responses against exogenous
antigens but also acquired immune responses against
self-antigens.
MicroRNA
MicroRNAs (miRNAs) have recently been implicated
in an increasingly wide variety of biological processes,
including innate and acquired immune responses.200,201
Currently, 474 human miRNA sequences have been
identified, but the total number of miRNA genes according to computer-assisted estimates might be closer to a
thousand.200 In bovines, expression of some miRNAs
(e.g., bya-miR-145) is restricted to the small intestine,202
suggesting a functional role of miRNA in intestinal
homeostasis or intestinal immune responses. Therefore,
miRNA research may represent a new avenue of exploration to further enhance our understanding of the
pathogenesis of IBD. However, no study on miRNAs in
IBD has yet been carried out.
Glycoimmunology
The majority of immune responses are mediated by
protein/protein interactions such as cytokine/receptor
interactions. However, in some cases, there are unusual
results that cannot easily be explained by protein/protein
interactions. Such results have frequently been described
by the terminologically useful phrase conformational
changes of receptors. Importantly, the majority of
immune receptors are N- or O-glycosylated, and the
assembly of receptors is significantly affected by the
glycosylation state, which is controlled by many kinds
of glycosylation-associated enzymes.203,204 The expression pattern of these glycosylation-associated enzymes
is altered by several factors, such as inflammation, suggesting the modification of carbohydrate (sugar) assembly in the cells under inflammatory conditions. Therefore,
carbohydrate assembly actively participates in the regulation of the acquired and innate immune responses that
control autoimmune diseases.205207 The importance of
protein/carbohydrate interactions has been highlighted
by studies on cell homing through selectin pathways.208
In addition, the involvement of protein/carbohydrate
interactions in pathogen recognition through C-type
lectins such as DC-SIGN has recently been well documented.209,210 Protein/carbohydrate interactions also
contribute to activation or dampening of T-cell responses.
A protein (a lectin called galectin-1) induces the apoptosis of T cells211 and also dampens Th1 differentiation.212
Indeed, a regulatory role of galectin-1 in TNBS colitis
has been demonstrated.213 In contrast to galectin-1,
11
which preferentially binds to a lactosamine unit of

mature core 2-branched O-glycan,203,204 galectin-4,
which is capable of interacting with immature core 1
O-glycan,214 has been demonstrated to contribute to the
exacerbation of Th2-mediated chronic colitis (TCR
KO mice) by stimulating intestinal, but not systemic,
CD4+ T cells to produce IL-6 only under inflammatory
conditions.93 These findings emphasize the significant
involvement of protein/carbohydrate interactions in the
pathogenesis of IBD.215 However, the mechanism underlying this phenomenon has not been vigorously investigated in IBD.
are capable of specifically targeting more restricted cell

population(s) may be more appropriate for reducing
the risk of development of unwanted adverse effects.
Other topics
References
A large body of epidemiological studies has clearly

demonstrated that prior appendectomy and cigarette
smoking are protective against the development of UC.2
The suppressive role of appendectomy (resection of the
cecal patch in mice) in the development of experimental
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concentration on established chronic colitis in IL-10 KO
mice has been recently demonstrated.217 Since such
studies (appendectomy and cigarette smoking) have significant clinical relevance, a full understanding of the
suppressive mechanism is needed to provide a basis for
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IBD patients. Another attractive field that might be
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Conclusion
Finding accumulated in the past and more recently
clearly show that IBD is mediated by a much more
complicated mechanism than previously or even currently predicted. Future studies in animal models of
IBD will contribute to the full dissection of the complicated mechanism of IBD and provide important bases
for developing novel therapeutic strategies to save the
lives of patients with IBD. Since the roles of several
molecules in the pathogenesis of IBD distinctly differ
depending on the type of cell, therapeutic strategies that
Acknowledgments. This study was supported by NIH grants

DK64351 (AM) and DK64289, DK74454, and DK43351 (EM).
We also thank the Eli and Edythe L. Broad Medical Foundation for support.
We thank Ms. Sarah Murphy for her secretarial
assistance in preparing this manuscript. We also thank Drs.
Kiyotaka Nagahama, Mayumi Kawada, Yasuyo Shimomura,
Ken Sugimoto, Atsuko Arihiro, Katsunori Shirane, and
Atsuhiro Ogawa for their excellent contributions.
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Infl Ammatory Bowel Disease, Past, Present and Future: Lessons From Animal Models

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J Gastroenterol 2008; 43:117

Accumulating data from animal models indicate that

Received / Accepted: August 29, 2007

types of genetically engineered mice, T-cell receptor

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

NFATc2 STAT3 GPX1/2

Fig. 2. In the past, the Th1/Th2 paradigm was a major concept

induced colitis model,16,17 and the CD40-dependent

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

Antigen sampling and antigen-presenting cells

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

IL-10-producing regulatory T cells.59 In addition,

Regulatory cell network

novel concept has been widely supported during the last

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

serve as a deleterious cell population, have also been

the other NOD2 KO mice108 or in the NOD2939ic KI

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

maintaining the epithelial barrier against DSS-induced

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

of Treg cells. Suppression of CD45RBhigh T cell-induced

do not respond to flagellin, suggesting that the response

TLR9 KO mice.152 In addition, administration of adenoviral CpG oligodeoxynucleotides (AV-ODNs), which

Bacteria/epithelial cell interaction and

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

of probiotic bacteria contributing to the suppression of

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

ing on the type of colitis (e.g., infectious versus chronic

derived carcinoembryonic antigen 5.161 Interestingly,

to the treatment of IBD was initially introduced in 2002

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

for exacerbation but not development of ileitis in

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

which preferentially binds to a lactosamine unit of

are capable of specifically targeting more restricted cell

A large body of epidemiological studies has clearly

Acknowledgments. This study was supported by NIH grants

1. Sands BE. Inflammatory bowel disease: past, present and future.

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

cells requires combined activation with CD40 ligand and CpG

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

118. Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

196. Schimid D, Munz C. Innate and adaptive immunity through

A. Mizoguchi and E. Mizoguchi: IBD past, present and future

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