DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, California 94304
![]() |
ABSTRACT |
---|
Interleukin
(IL)-10/
mice
spontaneously develop intestinal inflammation characterized by
discontinuous transmural lesions affecting the small and large
intestine and by dysregulated production of proinflammatory cytokines.
The uncontrolled generation of IFN-
-producing CD4+ T
cells (Th1 type) has been shown to play a causal role in the development of enterocolitis affecting these mutants. This article discusses studies of
IL-10
/
mice that have
investigated the role of enteric organisms in triggering intestinal
disease, the mediators responsible for initiating and maintaining
intestinal disease, the role IL-10 plays in the generation and/or
function of regulatory cells, and the results of IL-10 therapy in
experimental animal models of inflammatory bowel disease (IBD) and
human patients with IBD.
interleukin; counterregulation by IL-10; proinflammatory cytokines; Th1-mediated intestinal disease; IL-10 therapy
![]() |
INTRODUCTION |
---|
BEFORE THE GENERATION OF interleukin
(IL)-10/
mice, it had
already been established that IL-10 was an anti-inflammatory molecule capable of suppressing the in vitro production of numerous cytokines by
macrophages, dendritic cells, T cells, and natural killer
(NK) cells (21). IL-10 was firmly established as an
essential regulator of mucosal responses when it was recognized that
enterocolitis was manifested by
IL-10
/
mice and by
mice with a disruption in the gene encoding an IL-10 receptor component
(CRF2-4
/
) (16,
30).
In addition to IL-10/
mice, other rodents with gene-targeted mutations develop intestinal
disease due to immune imbalances created by either deleting or
overexpressing genes encoding cytokines or other immune components. For
example, intestinal inflammation was present in rodents rendered
deficient in IL-2, IL-2R
, T cell receptor (TCR)-
,
TCR-
, G
i-2, or transforming growth
factor (TGF)-
, as well as in transgenic rodents overexpressing IL-7, tumor necrosis factor (TNF), and human leukocyte antigen (HLA)-B27 (4). Although these genetically engineered mutants share
many abnormalities consistent with tissue inflammation, they also
exhibit distinct pathological changes and cytokine profiles that have been associated with either Crohn's disease (CD) or ulcerative colitis
(UC) in humans. Currently,
IL-10
/
mice and other
genetic mutants are being studied in an effort to answer fundamental
questions about the pathogenic mechanism(s) specific or unique to each
model and to determine how information obtained from these studies may
delineate the multifactoral processes involved in human CD and UC.
![]() |
GENES, GERMS, AND INTESTINAL DISEASE |
---|
Human inflammatory bowel disease (IBD) is generally described as a
condition that occurs in genetically susceptible individuals because of
an aberrant immune response to enteric antigens. Although the
particular antigens responsible for causing human IBD have remained
elusive, enteric flora have proven sufficient to trigger mucosal
inflammation in
IL-10/
mice,
IL-2
/
mice,
TCR-
/
mice, and
HLA-B27 transgenic rats, since none of these mutants develop intestinal
disease under germ-free conditions. In the case of
IL-10
/
mice, their
microbial milieu plays a major role in determining the characteristics
of their disease.
IL-10
/
mutants
derived under conventional conditions developed discontinuous transmural lesions affecting both the upper and lower gastrointestinal tract. Other pathological changes included epithelial hyperplasia, mucin depletion, crypt abscesses, ulcers, and thickening of the bowel
wall (2, 16). In contrast,
IL-10
/
mice derived
under specific pathogen-free (SPF) conditions developed a
mild-to-moderate inflammation restricted almost entirely to the colon.
Furthermore, unlike
IL-10
/
mice raised
under conventional conditions, the SPF mutants developed fewer systemic
complications (i.e., anemia, wasting, splenomegaly, and hepatitis)
until late in the progression of their colitis. Although
IL-10
/
mice are prone
to developing transmural disease throughout the intestinal tract
similar to Crohn's patients, the distribution and severity of their
lesions were dependent on the enteric stimuli encountered by the host.
Germ-free and SPF
IL-10/
mice have been
used for microbial reconstitution experiments in an effort to define
the bacterial species capable of triggering enterocolitis. Germ-free
IL-10
/
mice
repopulated with six defined bacterial strains, including Bacteroides vulgatus, developed a very mild form of colitis
compared with transgenic HLA-B27 rats colonized by the same bacteria
(28). Although these studies illustrate that ordinary resident enteric bacteria are sufficient to initiate disease in genetically susceptible animals, the particular bacterial species involved may vary
considerably between different hosts. Helicobacter species are
among the commensal organisms incriminated in the development of
intestinal inflammation in humans and rodents. Helicobacter
hepaticus, in particular, is known to induce chronic mucosal
inflammation in immune-deficient mice and was identified as part of the
complex intestinal flora present in
IL-10
/
mice generated
under conventional conditions. However, H. hepaticus was not
essential for mucosal disease in
IL-10
/
mice, since
this organism was eliminated from SPF mutants that eventually develop
colitis. Nevertheless, infecting SPF mutants with H. hepaticus
significantly exacerbated their colitis (17). Interestingly, these
infected mice still did not show evidence of inflammation in the upper
gastrointestinal tract. So far, the microbial species capable of
triggering pathogenic changes in the small intestine and stomach of
IL-10
/
mice remain undefined.
Other investigations have suggested that the presence of certain types
of bacteria, such as Lactobacillus species, may actually diminish intestinal inflammation. When the enteric flora of neonatal IL-10/
mice were
analyzed, there were decreased levels of Lactobacillus species
combined with increased levels of aerobic adherent and translocated
bacteria (18). Normal colonization by Lactobacillus species was
established in young
IL-10
/
mice through
the rectal delivery of Lactobacillus reuteri or oral lactulose
therapy. Restoring the balance between Lactobacillus species
and other bacterial strains prevented the development of colitis in
mutants housed in SPF conditions.
The large number of genetically engineered mutations that lead to IBD
in rodents, in part, explains why no consistent pattern of
inheritance has been associated with human susceptibility to CD or UC.
Nonparametric linkage studies of affected siblings have suggested a
linkage between genes of the major histocompatibility complex
(MHC) class II and UC. However, it appears that other genetic factors must contribute to disease expression because disease
does not occur in all siblings bearing the same MHC class II allele. To
investigate the impact of inheritable factors on disease expression in
IL-10/
mice, mutants
were generated on three genetic backgrounds with different MHC alleles.
It was determined that enterocolitis developed earlier and was more
severe in IL-10
/
129/SvEv (H-2b) and BALB/c (H-2d) strains
compared with the
IL-10
/
C57BL/6
(H-2b) strain (2). Not surprisingly,
TCR-
/
mice
backcrossed onto several genetic backgrounds also showed differences in
the severity of their colitis (20). By comparison, the C57BL/6
background conferred increased resistance to both IL-10
/
and
TCR-
/
mice.
Strikingly, the BALB/c background resulted in increased disease
severity in IL-10
/
mice but not in
TCR-
/
mice. These
preliminary observations demonstrate that inheritable genetic factors
can profoundly modify disease expression initiated by a single gene
mutation, be it defective IL-10 or TCR-
synthesis. Furthermore, the
modifier genes involved in disease expression will vary depending on
the particular genetic defect predisposing the host to IBD. It is
anticipated that genetically engineered and spontaneous models
(C3H/HeJBir mice) of IBD with relatively defined backgrounds may be
useful in identifying the combination of human genes affecting
susceptibility to CD and UC.
![]() |
COLITIS AND ADENOCARCINOMAS |
---|
During our analysis of
IL-10/
mice, we noted
epithelial extension/invasion into the underlying submucosa, tunica
muscularis, and serosa. The highest incidence occurred in severely
diseased IL-10
/
mice
on BALB/c and 129 SvEv backgrounds (2). Epithelial extension/invasion was most frequently found in the ascending colon and often involved well-differentiated and organized cells. However, in some cases the
glandular structures were irregular, with back-to-back growth and
slight loss of epithelial cell nuclear polarity. These irregular glandular structures were described as adenocarcinomas and were similar
to those found in
G
i-2
/
mice and in mice expressing a dominant-negative N-cadherin (2, 14, 26).
Because IL-10/
mice
failed to show signs of metastatic disease, we questioned whether the
presence of microinvasive epithelium represented neoplasia or
hyperplasia. Recently,
IL-10
/
mice were
crossed to p53
/
mice,
since p53 tumor suppressor gene mutations are common events in colon
cancer. At 4 mo of age,
p53
/
mice developed
thymic lymphomas, which was the expected phenotype. Age-matched
IL-10
/
mice had
developed colitis and microinvasive colonic epithelium, whereas the
IL-10
/
p53
/
double mutants
had large, high-grade adenocarcinomas of the colon (3). In one case,
there were metastases to lymph nodes and the serosal surface of the
stomach. Colon carcinomas occur in CD and UC patients with a similar
frequency (3-5%). Although risk factors have not been defined,
histological dysplasia in association with chronic intestinal
inflammation has been documented in cases of CD. Comparative studies of
IL-10
/
p53
/
mice generated
on different genetic backgrounds may prove invaluable in identifying
the complexity of genetic factors determining the incidence of
colitis-associated colon cancer.
![]() |
TH1-TYPE CD4+ T CELLS INDUCE ENTEROCOLITIS
IN IL-10![]() ![]() |
---|
Identifying the immune abnormalities, which play a causal role in the
development of enterocolitis in
IL-10/
mice, has been
the major focus of many studies. Analysis of the inflammatory cells
present in the mucosa and submucosa revealed large numbers of
macrophages, B cells, plasma cells, and CD4+
TCR+ T cells (2). Additionally, numerous
cytokines (i.e., IL-1, IL-6, IL-12/p40, and TNF-
) were abnormally
upregulated in these colonic tissues. Circulating colon-reactive IgG
was also detected, suggesting that autoantibodies may contribute to
tissue damage. Despite the plethora of immune cell types and mediators
found to be abnormally upregulated in these mutants, it was concluded that enterocolitis in
IL-10
/
mice is
mediated by the unregulated actions of CD4+ T cells. This
conclusion was based on studies showing that T cell-deficient
IL-10
/
mice failed to
develop disease and CD4+ T cells isolated from the colons
of IL-10
/
readily
transferred colitis to immunodeficient recombination activating gene
(Rag)2
/
recipients
(8). Moreover, the CD4+ T cells present in the
colons and draining mesenteric lymph nodes of
IL-10
/
mice produced
predominately IFN-
, implicating Th1-type cells in the pathogenic
process. Infusing neonatal
IL-10
/
mice with
anti-IFN-
monoclonal antibodies (MAbs) significantly diminished the
onset and severity of intestinal disease, thus confirming a causal role
for this cytokine. Importantly, anti-IL-12 MAb treatment completely
prevented disease in young mutants (6, 7). Presumably, in the absence
of IL-10 suppression, dysregulated IL-12 production is sufficient to
generate large numbers of Th1 cells producing IFN-
.
CD4+ T cells are major effectors, causing intestinal
inflammation in many animal models of IBD. Like
IL-10/
mice, many
were characterized by dominant Th1 cytokine profiles (IFN-
and TNF)
and developed transmural lesions characteristic of CD. These include
IL-2
/
mice,
trinitrobenzene sulfonic acid (TNBS)-induced colitis,
immunization-induced colitis in
IL-2
/
mice, and the
scid and Tg
26-transfer models (4). Recently, another class
of CD4+ T cells producing predominately Th2 cytokines
(IL-4) has been shown to cause intestinal inflammation in
TCR-
/
mice and
oxazolone-induced colitis (5, 19). This latter group developed
superficial ulcerations of the epithelium characteristic of UC.
The distinction between Th1-mediated, CD-like models and Th2-mediated,
UC-like models is an important step in identifying common pathogenic
pathways that may be operational in human IBD. Importantly, most of the
CD-like models, including
IL-10/
mice, share a
dependency on dysregulated IL-12 production as an essential step in
generating pathogenic Th1-mediated responses (4, 7, 11, 22, 29).
Nevertheless, differences have been observed among these CD-like models
with respect to the specific Th1-type mediators that function as
initiators of intestinal disease. For example, IFN-
was identified
as a major mediator initiating colitis in
IL-10
/
neonates,
whereas TNF was not involved in this pathogenic process even though
abnormally high levels of TNF were detected (2, 6). TNBS-induced
colitis and the Tg
26-transfer model of colitis appear to have little
or no dependence on IFN-
; instead, TNF/TNF-related molecules have
been implicated as mediators of disease (4, 15, 23). The scid
transfer model of colitis is partially dependent on both IFN-
and
TNF (25). The particular cytokines that are the dominant mediators of
CD in humans are also likely to vary, and these differences may be
responsible for the heterogeneous forms of CD manifested by these patients.
Because IL-12 plays a central role in the majority of Th1-mediated
models of IBD, it has been identified as a target for therapeutic intervention. Another potential target is nuclear factor (NF)-B, a
transcription factor that regulates the expression of various genes
encoding proinflammatory cytokines. Increased expression of NF-
B was
found in lamina propria macrophages from
IL-10
/
mice and mice
with TNBS-induced colitis (24). The inhibition of NF-
B activity by
the administration of a p65 antisense oligonucleotide significantly
reduced weight loss and histopathology in
IL-10
/
mice. This
treatment also abrogated established TNBS-induced colitis and was
associated with decreased production of IL-1, IL-6, and TNF-
by
lamina propria macrophages. These studies have shown convincingly that
blocking NF-
B signaling is an effective treatment for two models of
colitis (24).
![]() |
WHICH CYTOKINES SUSTAIN THE CHRONIC STAGE OF ENTEROCOLITIS? |
---|
Although IL-12 and IFN- are key mediators responsible for inducing
enterocolitis in young
IL-10
/
mice, their
role in sustaining/perpetuating the chronic phase of disease was
uncertain. We found that treating diseased
IL-10
/
adults with
anti-IFN-
MAb for 8 wk had no effect on their disease progression,
indicating that IFN-
was not required once disease was established
(6, 7). In contrast, anti-IL-12 MAb treatment ameliorated ongoing
disease since both the number and the severity of lesions in adult
IL-10
/
mice were
reduced (7). The beneficial effect of anti-IL-12 treatment was
accompanied by a reduction in the number of CD4+ T cells
present in the intestines and draining lymph nodes, suggesting that
IL-12 is necessary for sustaining the proliferation and/or viability of
chronically activated Th1 cells. It has also been shown that, although
early treatment with IL-10 prevented enterocolitis from developing in
neonatal IL-10
/
mice,
IL-10 treatment of diseased adults diminished but did not cure their
ongoing disease. It is possible that IL-10 may ameliorate ongoing
disease by suppressing IL-12 production because decreased IL-12/p40
mRNA expression was observed in IL-10 treated mice. This possibility
was further supported by the failure of combined anti-IL-12 MAb and
IL-10 treatment to be more effective than using either reagent alone.
The residual inflammation detected in adult
IL-10/
mice following
anti-IL-12 MAb treatment implied that additional factors were
contributing to disease maintenance (7). We have investigated whether
TNF, IL-1, or IL-6 is involved in the chronic phase of disease even
though they were not required for the inductive phase. When
neutralizing antibodies specific for these cytokines were given,
separately or jointly, disease progression was not affected. In
contrast to our findings, TNF plays a significant role in perpetuating the chronic phase of TNBS-induced colitis and dextran sulfate sodium
(DSS)-induced colitis. Administering anti-TNF MAb or
anti-IL-12 MAb was very effective and often completely ablated
established intestinal inflammation in these induced models of colitis
(10, 15). Our current studies are focused on identifying late-acting mediators that work in conjunction with IL-12 to perpetuate disease in
IL-10
/
mice.
Candidate molecules include IL-7, which stimulates the proliferation of
intestinal mucosal lymphocytes and is present in the sera of IBD
patients (31).
![]() |
IL-10 AND REGULATORY T CELLS |
---|
There is considerable evidence that regulatory CD4+ T cells
are required to establish normal intestinal immune responses.
Regulatory CD4+ T cells, expressing low levels of CD45RB
molecules, were first functionally characterized in the scid
transfer model of colitis. In cotransfer experiments, CD4+
CD45RBlow T cells were able to prevent the
induction of colitis caused in scid mice implanted with
CD4+ CD45RBhigh naive T cells. Initially it was
shown that the ability of the CD45RBlow T subset to
suppress colitis was ablated by anti-TGF- mAb treatment (25). It was
reported recently that anti-IL-10 receptor mAb treatment also ablated
the protection provided by CD45RBlow T cells (1). Thus both
TGF-
and IL-10 appear necessary for proper T cell regulation of
mucosal responses in this model. A critical role for IL-10 is also
evident from studies of transgenic mice. When normally pathogenic
CD4+ CD45RBhigh T cells were isolated from mice
expressing an IL-10 transgene under the control of the IL-2 promoter,
they not only failed to cause colitis on transfer into scid
mice, they inhibited the pathogenic activity of cotransferred
CD4+ CD45RBhigh T cells. Importantly, IL-10 has
recently been identified as a growth factor required for the in vitro
generation of a murine regulatory T cell line (Tr1) (12). Tr1 cells
derived from IL-10-supplemented cultures share many properties in
common with naturally occurring CD4+ CD45RBlow
regulatory T cells. Both populations produce IL-10 and TGF-
and are
capable of preventing colitis by CD45RBhigh T cells on
cotransfer into scid mice (12, 25).
In the scid transfer model mentioned above, the anti-IL-10
receptor MAb treatment, which ablated the protective effects of the
CD45RBlow T cells, was started at the time of T cell
reconstitution (CD45RBhigh plus CD45RBlow T
cells) (1). Therefore, it was unclear whether IL-10 production by
regulatory cells was required for their own expansion to prevent disease in the transplanted host, required as the mediator of their
suppressive actions, or both. To address this question, a series of
experiments were conducted with
IL-10/
mice. It was
found that inhibition of colitis development in young
IL-10
/
mice was
dependent on the continuous administration of IL-10 because intestinal
inflammation began to develop once treatment ceased. Moreover,
CD4+ CD45RBlow T cells, isolated from
disease-free mutants after continuous treatment with IL-10, showed no
signs of regulatory activities because they still failed to prevent
colitis in Rag2
/
mice
when cotransferred with CD4+ CD45RBhigh T
cells. In fact, the CD4+ CD45RBlow T cells from
IL-10-treated mice caused colitis in
Rag2
/
when transferred in the absence of
CD4+ CD45RBhigh T cells (6). Although these
studies do not preclude a role for IL-10 in the generation of
regulatory T cells, it is apparent that CD4+
CD45RBlow T cells from IL-10-treated
IL-10
/
mice are still
functionally impaired due to their inability to directly produce IL-10.
![]() |
PROSPECTS FOR IL-10 THERAPY OF IBD |
---|
The overproduction of immune-inflammatory cells and their mediators has
consistently been implicated in the pathogenesis of human IBD.
Moreover, patients often experience intermittent remission and
reactivation of their disease, suggesting a fluctuating balance between
pro- and anti-inflammatory cell types and mediators. Expectations that
exogenously administered IL-10 may be an effective therapeutic treatment for IBD patients are based largely on the outcome of murine
studies. Theoretically, IL-10 treatment could dampen the activities of
proinflammatory cells and at the same time augment the
development/activities of regulatory T cells to counterbalance the
large number of chronically activated effectors present in established
mucosal lesions. In the case of experimental models of IBD, it has
already been shown that continuous IL-10 administration prevented
intestinal disease in neonatal
IL-10/
mice, in
scid and
Rag2
/
transfer models
of colitis, in granulomatous enterocolitis induced in rats by bacterial
cell wall polymers, and in DSS-induced and TNBS-induced colitis (2, 6,
10, 13, 15). IL-10 was also administered after the establishment of
disease in some of these models and was shown to have beneficial effects.
Will IL-10 infusions prove effective in suppressing human IBD? In short-term studies, IL-10 administered rectally to a small number of UC patients resulted in improved histological scores and diminished cytokine production by lamina propria and circulating mononuclear cells (9, 27). As encouraging as these results appear, the benefits of long-term treatment with IL-10 are not yet known. Multiple cytokines are dysregulated in IBD patients, and those involved in perpetuating the chronic phase of disease may differ between individuals, as in the case of experimental animal models. Therefore, the most successful therapeutic strategies will probably include combinations of drug, cytokine-based (i.e., IL-10) and antibody-based (i.e., anti-TNF) treatments.
![]() |
ACKNOWLEDGEMENTS |
---|
The DNAX Research Institute is supported by the Schering-Plough Corporation.
![]() |
FOOTNOTES |
---|
* Twelfth in a series of invited articles on Lessons From Genetically Engineered Animal Models.
Address for reprint requests and other correspondence: D. M. Rennick, DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, CA 94304.
![]() |
REFERENCES |
---|
1.
Asseman, C,
Mauze S,
Leach MW,
Coffman RL,
and
Powrie F.
An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.
J Exp Med
190:
995-1003,
1999
2.
Berg, DJ,
Davidson NJ,
Kühn R,
Müller W,
Menon S,
Holland G,
Thompson-Snipes L,
Leach MW,
and
Rennick D.
Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4+ TH1-like responses.
J Clin Invest
98:
1010-1020,
1996
3.
Berg, DJ,
Lauricella D,
Lynch R,
Lynch N,
and
Rennick D.
Locally-advanced and metastatic colon cancer in p53-deficient IL-10-/- mice (Abstract). Washington DC: Exper Biol 99 Annu Meeting, 1999.
4.
Blumberg, RS,
Saubermann LJ,
and
Strober W.
Animal models of mucosa inflammation and their relation to human inflammatory bowel disease.
Curr Opin Immunol
11:
648-656,
1999[ISI][Medline].
5.
Boirivant, M,
Fuss IJ,
Chu A,
and
Strober W.
Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4.
J Exp Med
188:
1929-1939,
1998
6.
Davidson, NJ,
Fort MM,
Müller W,
Leach MW,
and
Rennick DM.
Insufficient counter regulation of a Th1 response.
Int Rev Immunol
19:
91-121,
2000[Medline].
7.
Davidson, NJ,
Hudak SA,
Lesley RE,
Menon S,
Leach MW,
and
Rennick DM.
IL-12, but not IFN-, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice.
J Immunol
161:
3143-3149,
1998
8.
Davidson, NJ,
Leach MW,
Fort MM,
Thompson-Snipes L,
Müller W,
Berg DJ,
and
Rennick DM.
T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice.
J Exp Med
184:
241-251,
1996[Abstract].
9.
Deventer, SJ van,
Elson CO,
and
Fedorak RN.
Multiple doses of intravenous interleukin-10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group.
Gastroenterology
113:
383-389,
1997[ISI][Medline].
10.
Duchmann, R,
Schmitt E,
Knolle P,
Meyer zum Büschenfelde KH,
and
Neurath M.
Tolerance towards residential flora in mice is abrogated in experimental colitis and restored by treatment with interleukin 10 or antibodies to interleukin 12.
Eur J Immunol
26:
934-938,
1996[ISI][Medline].
11.
Ehrhardt, RO,
Lídvíksson BR,
Gray B,
Neurath M,
and
Strober W.
Induction and prevention of colonic inflammation in IL-2-deficient mice.
J Immunol
158:
566-573,
1997[Abstract].
12.
Groux, H,
O'Garra A,
Bigler M,
Rouleau M,
Antonenko S,
de Vries JE,
and
Roncarolo MG.
A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis.
Nature
389:
737-742,
1997[ISI][Medline].
13.
Herfarth, HH,
Mohnaty SP,
Rath HC,
Tonkonogy S,
and
Sartor RB.
Interleukin 10 suppresses experimental chronic, granulomatous inflammation induced by bacterial cell wall polymers.
Gut
39:
836-845,
1996[Abstract].
14.
Hermiston, ML,
and
Gordon JI.
Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin.
Science
270:
1203-1207,
1995[Abstract].
15.
Kojouharoff, G,
Hans W,
Obermeier F,
Männel DN,
Andus T,
Schölmerich J,
Gross V,
and
Falk W.
Neutralization of tumor necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sodium sulfate-induced colitis in mice.
Clin Exp Immunol
107:
353-358,
1997[ISI][Medline].
16.
Kühn, R,
Löhler J,
Rennick D,
Rajewsky K,
and
Müller W.
Interleukin-10-deficient mice develop chronic enterocolitis.
Cell
75:
263-274,
1993[ISI][Medline].
17.
Kullberg, MC,
Ward MJ,
Gorelick PL,
Caspar P,
Hieny S,
Cheever A,
Jankove D,
and
Sher A.
Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin (IL-10)-deficient mice through an IL-12- and gamma-interferon-dependent mechanism.
Infect Immun
66:
5157-5166,
1998
18.
Madsen, KL,
Doyle JS,
Jewell LD,
Tavernini MM,
and
Fedorak RN.
Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice.
Gastroenterology
116:
1107-1114,
1999[ISI][Medline].
19.
Mizoguchi, A,
Mizoguchi E,
and
Bhan AK.
The critical role of interleukin 4 but not interferon gamma in the pathogenesis of colitis in T-cell receptor mutant mice.
Gastroenterology
116:
320-326,
1999[ISI][Medline].
20.
Mombaerts, P,
Mizoguchi E,
Grusby MJ,
Glimcher LH,
Bhan AK,
and
Tonegawa S.
Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice.
Cell
75:
275-282,
1993[ISI].
21.
Moore, KW,
O'Garra A,
de Waal Malefyt R,
Vieira P,
and
Mosmann TR.
Interleukin-10.
Annu Rev Immunol
11:
165-190,
1993[ISI][Medline].
22.
Neurath, MF,
Fuss I,
Kelsall BL,
Stüber E,
and
Strober W.
Antibodies to interleukin 12 abrogate established experimental colitis in mice.
J Exp Med
182:
1281-1290,
1995[Abstract].
23.
Neurath, MF,
Fuss I,
Pasparakis M,
Alexopoulou L,
Haralambous S,
Meyer zum Büschenfelde KH,
Strober W,
and
Kollias G.
Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice.
Eur J Immunol
27:
1743-1750,
1997[ISI][Medline].
24.
Neurath, MF,
Pettersson S,
Meyer-zum Büschenfelde KH,
and
Strober W.
Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NFkappa B abrogates established experimental colitis in mice.
Nat Med
2:
998-1004,
1996[ISI][Medline].
25.
Powrie, F,
Leach MW,
Mauze S,
Menon S,
Barcomb Caddle L,
and
Coffman RL.
Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.
Immunity
1:
553-562,
1994[ISI][Medline].
26.
Rudolph, U,
Finegold MJ,
Rich SS,
Harriman GR,
Srinivasan Y,
Braget P,
Boulya G,
Bradley A,
and
Birnbaumer L.
Ulcerative colitis and adenocarcinoma of the colon in Gi2-deficient mice.
Nat Genet
10:
693-699,
1995.
27.
Schreiber, SHT,
Thiele HG,
and
Raedler A.
Experimental immunomodulatory therapy of inflammatory bowel disease.
Neth J Med
53:
S24-S31,
1998[ISI][Medline].
28.
Sellon, RK,
Tonkonogy S,
Schultz M,
Duieleman LA,
Grenther W,
Balish E,
Rennick DM,
and
Sartor RB.
Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice.
Infect Immun
66:
5222-5231,
1998.
29.
Simpson, SJ,
Shah S,
Comiskey M,
de Jong YP,
Wang B,
Mizoguchi E,
Bhan AK,
and
Terhorst C.
T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin12/signal transducer and activator of transcription (stat)-4 pathway, but is not conditional on interferon- expression by T cells.
J Exp Med
1998:
1225-1234,
1998.
30.
Spencer, SD,
DiMarco F,
Hooley J,
Pitts-Meek S,
Bauer M,
Ryan AM,
Sordat B,
Gibbs VC,
and
Aguet M.
The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor.
J Exp Med
187:
571-578,
1998
31.
Watanabe, M,
Ueno Y,
Yajime T,
Iwao Y,
Tsuchiya M,
Ishikawa H,
Aiso S,
Hibi T,
and
Ishii H.
Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes.
J Clin Invest
95:
2945-2953,
1995[ISI][Medline].