1 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113 - 8519; and 2 Department of Immunology, Juntendo University School of Medicine, Tokyo 113 - 8421, Japan
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ABSTRACT |
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Interaction of OX40 (CD134) on T cells
with its ligand (OX40L) on antigen-presenting cells has been implicated
in pathogenic T cell activation. This study was performed to explore
the involvement of OX40/OX40L in the development of T cell-mediated
chronic colitis. We evaluated both the preventive and therapeutic
effects of neutralizing anti-OX40L MAb on the development of chronic
colitis in SCID mice induced by adoptive transfer of
CD4+CD45RBhigh T cells as an animal model of
Crohn's disease. We also assessed the combination of anti-OX40L and
anti-TNF- MAbs to improve the therapeutic effect. Administration of
anti-OX40L MAb markedly ameliorated the clinical and histopathological
disease in preventive and therapeutic protocols. In vivo treatment with
anti-OX40L MAb decreased CD4+ T cell infiltration in the
colon and suppressed IFN-
, IL-2, and TNF-
production by lamina
propria CD4+ T cells. The combination with anti-TNF-
MAb
further improved the therapeutic effect by abolishing IFN-
, IL-2,
and TNF-
production by lamina propria CD4+ T cells. Our
present results suggested a pivotal role of OX40/OX40L in the
pathogenesis of T cell-mediated chronic colitis. The OX40L blockade,
especially in combination with the TNF-
blockade, may be a promising
strategy for therapeutic intervention of Crohn's disease.
OX40L; tumor necrosis factor-; Crohn's disease; therapy
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INTRODUCTION |
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CROHN'S DISEASE (CD) is a chronic inflammatory bowel disease characterized by massive infiltration of CD4+ T cells and macrophages in the colon. Although its etiology remains unclear, it has been established that proinflammatory cytokine production by infiltrating T cells and macrophages plays a pivotal role in the pathogenesis of CD (9, 36). Functional activation of T cells requires two distinct signals: one derived from T cell receptor (TCR)-mediated recognition of peptide-major histocompatibility complex on antigen-presenting cells (APC) and another, designated as the costimulatory signal, derived from the interaction of a costimulatory molecule (such as CD28) on T cells and its ligand (such as B7) on APC (4, 6, 16, 30, 39). Although the CD28/B7 interaction constitutes a predominant pathway of T cell costimulation, some intact T cell responses in CD28-deficient mice have suggested the presence of alternative pathways (39).
Some members of the TNF receptor (TNFR) superfamily have been implicated in T cell costimulation, including CD27, 4-1BB (CD137), and OX40 (CD134) (7, 12, 14, 23, 40). OX40 is primarily expressed on T cells on TCR-mediated stimulation (2, 11, 24). Its ligand (OX40L) is a type II membrane protein belonging to the TNF family and is expressed on activated B cells, dendritic cells, and endothelial cells (2, 10, 34, 42). A number of in vitro studies has shown that the OX40/OX40L interaction provides a costimulatory signal resulting in enhanced T cell proliferation and cytokine production (2, 3). It has also been shown that OX40+ T cells preferentially accumulated in inflammatory sites associated with various diseases and disease models, including rheumatoid arthritis (3), inflammatory skin diseases (26), graft vs. host disease (45), experimental autoimmune encephalomyelitis (EAE) (47), and murine inflammatory bowel disease models (13), suggesting pathogenic roles of the OX40/OX40L interaction. Recently, Malmstrom et al. (25) reported that intestinal inflammation in CD4+CD45RBhigh T cell-transferred colitic mice was characterized by a marked increase in the number of OX40L+ dendritic cells in the mesenteric lymph nodes (MLNs). Their finding that anti-OX40L treatment led to retarded T cell proliferation and expression of activation antigens in the MLN suggested that OX40L expression on dendritic cells plays an important role in driving the T cell response in CD4+CD45RBhigh T cell-transferred colitic model.
Accumulating evidences have suggested that TNF- plays a pivotal role
in the development of mucosal inflammation in CD. First, disregulated
expression of TNF gene in mice led to the development of
inflammatory bowel disease reminiscent of human CD (19). Second, in several animal models of CD, administration of neutralizing anti-TNF-
MAb or TNF-
deficiency significantly ameliorated the mucosal inflammation (31). More importantly, dramatic
improvement was achieved in approximately two-thirds of the patients
with CD by a single infusion of anti-TNF-
MAb (Infliximab)
(44, 46). Although these results support the pivotal role
of TNF-
, the refractoriness to Infliximab observed in one-third of
the CD patients suggests an alternative proinflammatory mechanism that
may be mediated by the other members of TNF/TNFR family including the
OX40/OX40L.
In this study, we used a chronic colitis model, which was induced by
adoptive transfer of CD4+CD45RBhigh T cells to
SCID mice (37), to characterize the ameliorating effects
of anti-OX40L MAb in both preventive and therapeutic settings. In
addition, we also assessed the combination of anti-OX40L and anti-TNF- MAbs to achieve a better therapy. Clinical relevance of
these strategies is discussed.
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MATERIALS AND METHODS |
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Animals. Six- to eight-week-old female BALB/c scid/scid (SCID) mice and female BALB/c mice were purchased from Japan Clea (Tokyo, Japan) and maintained in a specific pathogen-free condition at Tokyo Medical and Dental University. All animal procedures in this study were performed according to the guidelines for animal experiments of Tokyo Medical and Dental University.
Induction of colitis and antibody treatment.
Colitis was induced in SCID mice by adoptive transfer of
CD4+CD45RBhigh T cells, essentially as
described previously (48). CD4+ T cells were
isolated from splenic mononuclear cell from BALB/c mice using the
anti-CD4 (L3T4) MACS magnetic separation system (Miltenyi Biotec,
Auburn, CA) according to the manufacturer's instruction. Enriched
CD4+ T cells were then labeled with phycoerythrin
(PE)-conjugated anti-mouse CD4 MAb (RM4-4, PharMingen, San Diego,
CA) and FITC-conjugated anti-CD45RB MAb (16A, PharMingen) and
sorted into CD45RBhigh (highest staining 30%) and
CD45RBlow (lowest staining 30%) fractions on a FACSVantage
(Becton-Dickinson, Sunnyvale, CA). Each SCID mouse was injected
intraperitoneally with 200 µl of PBS containing 5 × 105 CD4+CD45RBhigh T cells. These
mice were then administered intraperitoneally with 250 µg anti-OX40L
MAb (RM134L, rat IgG2b) (1) in 250 µl PBS three times
per week, starting at the day of T cell transfer, over a period of 8 wk
in the preventive protocol. An equivalent amount of control rat IgG
(Sigma, St. Louis, MO) was administrated in control mice. Because
clinical and histopathological manifestations were evident from
3-5 wk after T cell transfer in our preliminary experiments, we
treated another group of mice by intraperitoneal injection of 250 µg
anti-OX40L MAb or control IgG three times per week, starting from 3 wk
after T cell transfer for 4 wk in the therapeutic protocol. In another
set of experiments, we treated four groups of mice three times per
week, from 3 to 8 wk after T cell transfer, with 1) 500 µg
control IgG, 2) 250 µg anti-OX40L MAb + 250 µg
control IgG, 3) 250 µg anti-TNF- MAb (MP6-XT22) + 250 µg control IgG, or 4) 250 µg anti-OX40L MAb + 250 µg anti-TNF-
MAb. All mice were killed at 7-8 wk after T
cell transfer for histological examination and preparation of lamina
propria (LP) T cells.
Disease monitoring and clinical scoring. Mice were weighed and monitored for appearance and signs of soft stool and diarrhea weekly. Clinical score was assessed at 7-8 wk after T cell transfer as the sum of three parameters as follows: hunching and wasting, 0 or 1; colon thickening, 0-3 (0, no colon thickening; 1, mild thickening; 2, moderate thickening; 3, extensive thickening); and stool consistency, 0-3 (0, normal beaded stool; 1, soft stool; 2, diarrhea; 3, gross bloody stool).
Histological examination. Tissue samples were fixed in 6% phosphate-buffered formalin. Paraffin-embedded sections (5 µm) were stained with hematoxylin and eosin. Three tissue samples from the proximal, middle, and distal parts of the colon were prepared. The sections were analyzed without prior knowledge of the type of treatment. The area most affected was graded by the number and severity of lesions. The mean degree of inflammation in the colon was calculated using a modification of a previously described scoring system (22).
Preparation of lamina propria lymphocytes and splenocytes. For the isolation of LP lymphocytes (LPL) from the colon, the entire length of intestine was opened longitudinally, washed with PBS, and cut into small pieces. The dissected mucosa was incubated two times with Ca2+-Mg2+-free Hanks' balanced salt solution containing 1 mM dithiothreitol (Sigma) for 30 min each to remove mucus. The supernatants containing intraepithelial and epithelial cells were removed. Collected tissues were treated with 2 mg/ml collagenase A (Worthington Biomedical, Freehold, NJ) and 0.01% DNase (Worthington) in RPMI1640 medium for 2 h. The cells were pelleted two times through a 40% isotonic Percoll solution and then further purified by Ficoll-Hypaque density gradient centrifugation (40%/75%). CD4+ LPL were obtained by positive selection using the anti-CD4 (L3T4) MACS magnetic separation system (Miltenyi Biotec). The cells were >95% CD4+ when analyzed by flow cytometry. Splenic mononuclear cells were obtained from the same animals by mechanical dissociation of the spleen followed by Ficoll-Hypaque density gradient centrifugation.
Flow cytometry.
Isolated LPL or splenocytes were preincubated with Fc
receptor-blocking MAb (2.4G2) for 20 min, followed by incubation with FITC-, PE-, or biotin-labeled MAb for 30 min on ice. Biotinylated MAb
was detected with PE-streptavidin. All reagents were obtained from PharMingen. Two-color flow cytometric analysis was performed on
FACScan (Becton-Dickinson) equipped with CellQuest software.
Cytokine ELISA.
LP CD4+ T cells (1 × 105) were cultured
in 200 µl of RPMI1640 medium supplemented with 10% FCS and 2 µg/ml
anti-CD28 MAb (37.51, PharMingen) in 96-well plates (Costar, Cambridge,
MA) precoated with 5 µg/ml anti-CD3 MAb (145-2C11,
PharMingen) for 48 h. Cytokine concentrations in the culture
supernatants were determined by specific ELISA according to the
manufacturer's instructions (R&D, Minneapolis, MN).
Statistical analysis. Significant differences between two groups were determined by Mann-Whitney U-test. P values <0.05 were considered to be statistically significant.
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RESULTS |
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Administration of Anti-OX40L MAb prevents the development of colitis. We induced chronic colitis in BALB/c SCID mice by adoptive transfer of CD4+ CD45RBhigh T cells from normal BALB/c mice. These mice manifested progressive weight loss from 3 wk after T cell transfer and clinical symptoms of colitis such as diarrhea with increased mucus in the stool, anorectal prolapse, and hunched posture by 6-8 wk. The colons from these mice were enlarged and had greatly thickened walls due to severe colonic inflammation (data not shown).
To explore the contribution of OX40/OX40L interaction to the development of chronic colitis, a neutralizing anti-OX40L MAb or control rat IgG was administered to the recipient mice from the day of T cell transfer and then three times per week for 8 wk. As shown in Fig. 1A, the control IgG-treated mice manifested progressive weight loss (wasting disease) from 3 to 5 wk after T cell transfer. These mice had diarrhea with increased mucus in the stool, anorectal prolapse, and hunched posture by 6-8 wk. In contrast, the anti-OX40L MAb-treated mice appeared healthy, with a gradual increase of body weight and without diarrhea during the whole period of observation (Fig. 1A). At 8 wk after T cell transfer, the colon from the control IgG-treated mice but not that from the anti-OX40L MAb-treated mice, was enlarged and had a greatly thickened wall (Fig. 1B). In addition, the splenic enlargement was also present in the control IgG-treated mice compared with the anti-OX40L MAb-treated mice. Totally, the assessment of colitis by clinical scores showed a clear difference between the control IgG-treated mice and anti-OX40L MAb-treated mice (Fig. 1C). Histological examination showed prominent epithelial hyperplasia with glandular elongation with a massive infiltration of mononuclear cells in the lamina propria of the colon from the control IgG-treated mice (Fig. 1D). In contrast, the glandular elongation was mostly abrogated and only few mononuclear cells were observed in the lamina propria of the colon from anti-OX40L MAb-treated mice (Fig. 1D). This difference was also confirmed by histological scoring of multiple colon sections, which was 5.7 ± 1.2 in control rat IgG-treated mice vs. 0.8 ± 0.6 in anti-OX40 MAb-treated mice (P < 0.005; Fig. 1E). A further quantitative evaluation of CD4+ T cell infiltration was made by isolating LPL from the resected bowels. Only a few CD4+ T cells were recovered from the colonic tissue of anti-OX40L MAb-treated mice compared with those from the control rat IgG-treated mice (Fig. 1F). The number of CD4+ cells recovered from the colon of control IgG-treated mice (42.1 ± 18.3 × 105) far exceeded the number of originally injected cells (5 × 105), indicating an extensive T cell proliferation in the inflamed colon, which was mostly abrogated in the anti-OX40L MAb-treated mice (4.7 ± 1.2 × 105). Furthermore, the number of CD4+ splenocytes from control IgG-treated mice was significantly increased as comparable to that from age-matched normal BALB/c mice. In contrast, the number of CD4+ splenocytes from anti-OX40L MAb-treated mice was significantly less than that from control IgG-treated mice (Fig. 1G).
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Therapeutic effect of anti-OX40L MAb.
We next evaluated the therapeutic effect of anti-OX40L MAb treatment on
the ongoing disease. Because the wasting disease started 3 wk after T
cell transfer (Fig. 1A) and the infiltration of lymphocytes and colitis was already detectable at 2 wk (data not shown), we started
the anti-OX40L MAb treatment from 3 wk after T cell transfer. As shown
in Fig. 3A, the anti-OX40L
MAb-treated mice exhibited a significant improvement of weight loss
compared with the control IgG-treated mice. The anti-OX40L MAb-treated
mice did not exhibit clinical manifestations such as diarrhea and
hunched posture, which were substantiated by clinical scoring at 7 wk
(Fig. 3B). Histological examination of the colon from
anti-OX40L MAb-treated mice revealed significant reduction of
granulomatous inflammation, leukocyte infiltration, and epithelial
hyperplasia (Fig. 3C). Histological scores were
significantly decreased in the anti-OX40L MAb-treated mice (2.1 ± 0.6) compared with the control IgG-treated mice (5.4 ± 1.8;
P < 0.05; Fig. 3D). The number of
CD4+ LPL was greatly reduced in the anti-OX40L MAb-treated
mice (7.4 ± 0.2 × 105) compared with that from
the control IgG-treated mice (28.1 ± 6.2 × 105;
P < 0.01; Fig. 3E). Furthermore, the number
of CD4+ splenocytes from anti-OX40L MAb-treated mice was
significantly reduced compared with that from control IgG-treated mice
(Fig. 3F). These results indicated that the therapeutic
administration of anti-OX40L MAb could inhibit the progression of
ongoing colitis by suppressing the expansion and/or infiltration of
pathogenic T cells in the colon.
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Combinational effect of anti-OX40L and anti-TNF- MAbs.
We finally examined the combined effect of anti-OX40L and anti-TNF-
MAbs. At 3 wk after T cell transfer, we started to treat the mice with
control IgG, anti-OX40L MAb alone, anti-TNF-
MAb alone, or
anti-OX40L and anti-TNF-
MAbs until 7 wk. Anti-TNF-
MAb alone, as
well as anti-OX40L MAb alone, markedly improved the weight loss, and
the combination of both MAbs results in further improvement (Fig.
4A). Ameliorating effects of
anti-TNF-
MAb or anti-OX40L MAb alone and the additive effect of
both MAbs were also observed in clinical scores (Fig. 4B).
However, anti-TNF-
MAb alone exerted a rather weak or no significant
effect on histopathological changes (Fig. 4, C and
D) and CD4+ T cell expansion/infiltration in the
colon (Fig. 4E). Nevertheless, the combination of
anti-TNF-
MAb with anti-OX40L MAb resulted in significantly more
improvement of histological score (Fig. 4E) and more
reduction of CD4+ LPL and CD4+ splenocytes
(Fig. 4, E and F) compared with anti-OX40L MAb
alone.
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DISCUSSION |
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In the present study, we demonstrate a possible contribution of OX40/OX40L interaction to the pathogenesis of the murine CD model by showing that administration of neutralizing anti-OX40L MAb effectively prevented the onset and progression of CD4+CD45RBhigh-transferred colitis and significantly abrogated infiltration of CD4+ T cells and local Th1 cytokine production in the inflamed colon. Our present results further substantiated the important role of the OX40-OX40L costimulatory pathway in CD4+ T cell-dependent inflammatory responses and tissue damage in intestinal mucosa. Because the expression of OX40 is predominantly restricted to activated CD4+ T cells, blockade of the OX40/OX40L interaction by anti- OX40L MAb in vivo may be a useful strategy for controlling a variety of T cell-mediated inflammatory diseases. Consistent with our present study, Malmstrom et al. (25) also recently reported that early administration of anti-OX40L MAb (OX89) (starting at the time of disease induction) prevented the development of CD4+CD45RBhigh-transferred colitis. In addition, we also showed that a delayed treatment with anti-OX40L (RM134L) still improved clinical and histological features of ongoing CD4+CD45RBhigh-transferred colitis, suggesting that the blockade of OX40/OX40L interactions would be beneficial for the treatment of human CD.
The treatment of CD depends largely on chronic use of immunosuppressive
reagents that can result in severe side effects. In the last 5 years, a
number of more specific targets for potential treatment has been
discovered in murine colitis models. This has so far led to the
introdution of an anti-TNF- MAb (Infliximab) to the patients with
CD, which has been effective in two-thirds of CD patients. Infliximab
is a chimeric human/murine MAb of IgG1 isotype with the
specificity for human TNF-
. The treatment with Infliximab has been
reported to induce monocytopenia rapidly after infusion and also to
profoundly downregulate monocytes in CD mucosa. Recently, it has been
shown that Infliximab bound specifically to membrane-bound TNF-
, as
well as TNFR-bound TNF-
, and also that Infliximab induced
apoptosis in peripheral monocytes of patients with chronic
active CD in a dose-dependent manner. Of particular clinical
importance, we showed here that the delayed anti-OX40L treatment does
not only ameliorate established colitis, but also induces a striking
improvement in combination with anti-TNF-
MAb. However, anti-TNF-
MAb alone could not ameliorate established colitis in this study.
Unlike Infliximab, the anti-mouse TNF-
MAb used in the present study
might not be able to induce apoptosis of TNF-
-bearing cells,
such as macrophages and dendritic cells, but just neutrilize the
proinflammatory action of TNF-
. Consistent with this notion,
although the anti-TNF-
treatment alone could not suppress the
intestinal inflammation, it improved wasting, which was caused by
"cachectic" action of TNF-
.
The mode of OX40/OX40L contribution to intestinal inflammation still remains unclear. First, we found that OX40L was not expressed on CD4+ LPL from both normal and colitic mice (data not shown). This suggests that the therapeutic effect of our anti-OX40L (RM134L, rat IgG2b) is not due to the CD4+ T cell depletion by these monoclonal antibodies. In the intestinal environment, dendritic cells sampling intestinal antigens become activated and migrate to the MLN, where they activate T cells to expand. Malmstrom et al. (25) have shown that OX40L was upregulated in local MLN but not inflamed mucosa from colitic mice by immunohistochemical staining, suggesting that the OX40/OX40L interaction may be essential for the process of antigen presentation or effector cell expansion in MLN. Having the evidence that the delayed anti-OX40L treatment did ameliorate the established colitis, we prefer that OX40/OX40L interaction might be involved in the effector T cell expansion in the MLN. However, there are several reports indicating that activated macrophages and dendritic cells existed and might function in inflamed mucosa in this model, which might transiently express OX40L and contribute to activation of pathogenic T cells locally.
The functional role of OX40L vs. CD40, which is a similar member of the TNF family, in the activation of T cells should be mentioned. Previous studies have shown that anti-CD40L prevented the development of 2,4,6-trinitrobenzene sulfonic acid colitis but did not treat colitis (43). In subsequent studies, anti-CD40L was found to ameleriolate several forms of colitis at least partially (8). The failure to treat colitis with anti-CD40L might be attributed to the possibility that after inflammation is initiated, APC can be activated to produce IL-12 by LPS and other factors. Furthermore, previous studies of OX40/OX40L interaction have suggested that the interaction may be necessary not for initial activation of APC, but rather for sustained activation (42). Thus, whereas CD40L induced IL-12 production, both CD40L and OX40 may be necessary for sustained IL-12 production and may be critical to IL-18 production. Together with our present data, anti-CD40L administration at the early phase and anti-OX40L administration at the late stage in the development of colitis might be the best combination therapy. Further study will be necessary to address this point.
Another possible mechanism for anti-OX40L MAb therapy is the prevention of recruitment of OX40+ T cells to sites of inflammation through OX40L expression on endothelial cells. In fact, it has been shown that cells from patients with adult T cell leukemia adhere to endothelial cells through OX40-OX40L interaction (15). In addition, in human inflammatory bowel disease, OX40L+ endothelial cells have been seen (41). Further studies will be required to address this possibility.
So far, accumulating evidence supports the concept that a dominance of
either Th1 or Th2 is associated with distinct manifestations of
autoimmune diseases, and some therapies that induce a shift from Th1 or
Th2 may result in amelioration of diseases (17, 32, 38).
In the case of collagen-induced arthritis and EAE models, an
IFN--mediated Th1-type response has been shown to be pathogenic, and
an IL-4-mediated Th2 response has been shown to be protective
(27, 28). It has been reported that the blockade of some
costimulatory pathways ameliorated EAE by deviating the pathogenic Th1
response toward the protective Th2 response (18, 21). How
do OX40L molecules function in chronic intestinal inflammation? In this
study, the blockade of OX40/OX40L interaction did not augment the Th2
response, because in vivo treatment with anti-OX40L MAb did not enhance
either IL-4 or IL-10 production. In contrast, anti-OX40L MAb treatment
significantly inhibited the IFN-
production by lamina propria
CD4+ T cells in inflamed mucosa. This suggests that the
ameliorating effect of anti-OX40L MAb on the
CD45RBhigh-transferred colitis model might be, at least in
part, mediated by its inhibitory effect on the development of
pathogenic Th1 cells producing IFN-
. Our present results suggest
that the OX40/OX40L interaction may play a preferential role in the
development of Th1 cells producing IFN-
. Consistent with this
notion, it has been reported that the IFN-
production was most
dramatically affected by the absence of OX40 on T cells or the
absence of OX40L on antigen-presenting cells in OX40- or
OX40L-deficient mice (5, 20, 35). Another possible
mechanism for the ameliorating effect of anti-OX40L MAb on the
CD4+CD45RBhigh-transferred colitis model
may involve its inhibitory effect on the recruitment of
OX40+ T cells to the inflamed mucosa, because the
expression of OX40L on endothelial cells has been implicated in their
interaction with activated T cells expressing OX40 (29,
33). Further studies are needed to elucidate the exact mechanism
for the prevention of colitis by the blockade of OX40/OX40L interaction.
In summary, our present findings suggest that regulation of the
OX40/OX40L pathway may be of key importance in successful treatment of
CD and also that anti-OX40L in combination with anti-TNF- therapy
may be useful for refractory CD.
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ACKNOWLEDGEMENTS |
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We thank Drs. W. Strober and M. Azuma for critically reading the manuscript and H. Fujimoto and H. Nishikawa for technical assistance.
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FOOTNOTES |
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This work was supported, in part, by grants-in-aid from the Japanese Ministry of Education, Culture, and Science and the Japanese Ministry of Health and Welfare.
Address for reprint requests and other correspondence: T. Kanai, Dept. of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan (E-mail: taka.gast{at}tmd.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 10, 2003;10.1152/ajpgi.00450.2002
Received 21 October 2002; accepted in final form 27 December 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Akiba, H,
Oshima H,
Takeda K,
Atsuta M,
Nakano H,
Nakajima A,
Nohara C,
Yagita H,
and
Okumura K.
CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B cells.
J Immunol
162:
7058-7066,
1999
2.
Al-Shamkhani, A,
Birkeland ML,
Puklavee M,
Brown MH,
James W,
and
Barelay AN.
OX40 is differentially expressed on activated rat and mouse T cells and is the sole receptor for OX40 ligand.
Eur J Immunol
26:
1695-1699,
1996[ISI][Medline].
3.
Brugnoni, D,
Bettinardi A,
Malacarne F,
Airo P,
and
Cattaneo R.
CD134/OX40 expression by synovial fluid CD4+ T lymphocytes in chronic synovitis.
Br J Rheumatol
37:
584-585,
1998[ISI][Medline].
4.
Chambers, CA.
The expanding world of co-stimulation: the two-signal model revised.
Trends Biochem Sci
22:
217-223,
2001.
5.
Chen, AI,
McAdam AJ,
Buhlmann JE,
Scott S,
Lupher ML,
Greengield EA,
Baum PR,
Fanslow WC,
Calderhead DM,
Freeman GJ,
and
Sharp AH.
OX40-ligand has a critical costimulatory role in dendritic cell: T cell interactions.
Immunity
11:
689-698,
1999[ISI][Medline].
6.
Coyle, AJ,
and
Gutierrez-Ramos JC.
The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function.
Nat Immun
2:
203-209,
2001[ISI].
7.
De Benedette, MA,
Shahinian A,
Mak TW,
and
Watte TH.
Costimulation of CD28+ T lymphocytes by 4-1BB ligand.
J Immunol
158:
551-559,
1997[Abstract].
8.
De Jong, YP,
Comiskey M,
Kalled SL,
Mizoguchi E,
Flavell RA,
Bhan AK,
and
Terhorst C.
Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration.
Gastroenterology
119:
715-723,
2000[ISI][Medline].
9.
Fiocchi, C.
Inflammatory bowel disease-ethiology and pathogenesis.
Gastroenterology
115:
182-205,
1998[ISI][Medline].
10.
Godfrey, WR,
Fagnoni FF,
Harara MA,
Buck D,
and
Engleman EG.
Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.
J Exp Med
180:
757-762,
1994[Abstract].
11.
Gramaglia, I,
Weinberg AD,
Lemon M,
and
Croft M.
OX40 ligand: a potent costimulatory molecule for sustaining primary CD4 T-cell responses.
J Immunol
161:
6510-6517,
1998
12.
Grewal, IS,
and
Flavell RA.
A central role of CD40 ligand in the regulation of CD4+ T cell response.
Immunol Today
17:
410-414,
1996[ISI][Medline].
13.
Higgins, LM,
McDonald SAC,
Whittle N,
Crockett N,
Shields JG,
and
MacDonald TT.
Regulation of T cell activation in vitro and in vivo by targeting the OX40-OX40 ligand interaction: amelioration of ongoing inflammatory bowel disease with an OX40-IgG fusion protein, but not with with an OX40 ligand-IgG fusion protein.
J Immunol
162:
486-493,
1999
14.
Hurtade, JC,
Kim SH,
Pollok KE,
Lee ZH,
and
Kwon BS.
Potential role of 4-1BB in T cell activation. Comparison with the costimulatory molecule CD28.
J Immunol
155:
3360-3367,
1995[Abstract].
15.
Imura, A,
Hori T,
Imada K,
Ishikawa T,
Tanaka Y,
Maeda M,
Imamura S,
and
Uchiyama T.
The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells.
J Exp Med
183:
2185-2195,
1996[Abstract].
16.
June, CH,
Bluestone JA,
Nadler LM,
and
Thompson CB.
The B7 and CD28 receptor families.
Immunol Today
15:
321-331,
1994[ISI][Medline].
17.
Kawachi, S,
Morise Z,
Iennings SR,
Conner E,
Cockrell A,
Laroux FS,
Chervenak RP,
Wolcott M,
van der Heyde H,
Gray L,
Feng L,
Granger DN,
Specian RA,
and
Grisham MB.
Cytokine and adhesion molecule expression in SCID mice reconstituted with CD4+ T cells.
Inflamm Bowel Dis
6:
171-180,
2000[ISI][Medline].
18.
Khoury, SJ,
Akalin E,
Chandraker A,
Turka LA,
Linsley PS,
Sayegh MH,
and
Hancock WW.
CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spare Th2 cytokines in the central nervous system.
J Immunol
155:
4521-4524,
1995[Abstract].
19.
Kontoyiannis, D,
Pasparakis M,
Pizarro TT,
Cominelli F,
and
Kollias G.
Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathogies.
Immunity
10:
387-398,
1999[ISI][Medline].
20.
Kopf, M,
Ruedl C,
Schmitz N,
Gallimore A,
Lefrang K,
Ecabert B,
Odermatt B,
and
Bachmann MF.
OX40-deficient mice are defective in Th1 cell proliferation but are competent in generating B cell and CTL responses after virus infection.
Immunity
11:
699-708,
1999[ISI][Medline].
21.
Kuchroo, VK,
Prabhu Das M,
Brown JA,
Ranger AM,
Zamvil SS,
Sobel RA,
Weiner HL,
Nabavi N,
and
Glimcher LH.
B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 development pathways: application to autoimmune disease therapy.
Cell
80:
707-718,
1995[ISI][Medline].
22.
Liu, Z,
Geboes K,
Colpaert S,
Overbergh L,
Mathieu C,
Heremans H,
de Boer M,
Boon L,
D'haens G,
Rutgeerts P,
and
Ceuppens IL.
Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions.
J Immunol
164:
6005-6014,
2000
23.
Lynch, DH,
Ramsdell F,
and
Alderson MR.
Fas and FasL in the homeostatic regulation of immune responses.
Immunol Today
16:
569-574,
1995[ISI][Medline].
24.
Mallett, S,
Fossum S,
and
Barelay N.
Characterization of the MRC OX 40 antigen of activated CD4 positive T lymphocytes: a molecule related to nerve growth factor receptor.
EMBO J
9:
1063-1069,
1990[Abstract].
25.
Malmstrom, V,
Shipton D,
Singh B,
Al-Shamkhani A,
Puklavee MJ,
Barclay AN,
and
Powrie F.
CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice.
J Immunol
166:
6972-6981,
2001
26.
Matsumura, Y,
Imura A,
Hori T,
Uchiyama T,
and
Imamura S.
Localization of OX40/gp34 in inflammatory skin diseases: a clue to elucidate the interaction between activated T cells and endothelial cells in infiltration.
Arch Dermatol Res
289:
653-656,
1997[ISI][Medline].
27.
Mauri, C,
Williams RO,
Walmsley M,
and
Feldmann M.
Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis.
Eur J Immunol
26:
1511-1518,
1996[ISI][Medline].
28.
Miossec, P,
and
Van Der Heiden W.
Th1/Th2 cytokine balance in arthritis.
Arthritis Rheum
40:
2105-2115,
1997[ISI][Medline].
29.
Murata, K,
Ishii N,
Takano H,
Miura S,
Ndhlovu LC,
Nose M,
Noda T,
and
Sugamura K.
Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand.
J Exp Med
191:
365-374,
2000
30.
Nakazawa, A,
Watanabe M,
Kanai T,
Yajima T,
Yamazaki M,
Ogata H,
Ishii H,
Azuma M,
and
Hibi T.
Functional expression of costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa.
Gastroenterology
117:
536-543,
1999[ISI][Medline].
31.
Neurath, MF,
Fuss I,
Pasparakis M,
Alexopoulou L,
Haralambouos S,
Meyer zum Buschenfelde 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].
32.
Nicholson, LB,
and
Kuchroo VK.
Manipulation of the Th1/Th2 balance in autoimmune disease.
Curr Opin Immunol
8:
837-842,
1996[ISI][Medline].
33.
Nohara, C,
Akiba H,
Nakajima A,
Inoue A,
Koh CS,
Ohshima H,
Yagita H,
Mizuno Y,
and
Okumura K.
Amelioration of experimental autoimmune encephalomyelitis with anti-OX40 ligand monoclonal antibody: a critical role for OX40 ligand in migration, but not development, of pathologic T cells.
J Immunol
166:
2108-2115,
2001
34.
Ohshima, Y,
Tanaka Y,
Tozawa H,
Takahashi Y,
Maliszewski,
and
Delespesse G.
Expression and function of OX40 ligand on human dendritic cells.
J Immunol
159:
3838-3848,
1997[Abstract].
35.
Pipping, SD,
Pana-Rossi C,
Long J,
Godfrey WR,
Fowell DJ,
Reiner SL,
Birkeland ML,
Locksley RM,
Barclay AN,
and
Killen N.
Robust B cell immunity but impaired T cell proliferation in the absence of CD134 (OX40).
J Immunol
163:
6520-6529,
1999
36.
Podolsky, DK.
Inflammatory bowel disease.
N Engl J Med
325:
928-937,
1995.
37.
Powrie, F.
T cells in inflammatory bowel disease: protective and pathogenic role.
Immunity
3:
171-174,
1995[ISI][Medline].
38.
Racke, MK,
Bonomo A,
Scott DE,
Cannella B,
Levine A,
Raine CS,
Shevach EM,
and
Rocken M.
Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.
J Exp Med
180:
1961-1966,
1994[Abstract].
39.
Shahinian, A,
Pfeffer K,
Lee KP,
Kundig TM,
Kishihara K,
Wakeham A,
Kawai K,
Ohashi PS,
Thompson CB,
and
Mak TW.
Differential T cell costimulatory requirements in CD28-deficient mice.
Science
261:
609-612,
1993[ISI][Medline].
40.
Smith, CA,
Farrah T,
and
Goodwin RG.
The TNF receptor superfamily of cellular and viral proteins: activation, costimulation and cell death.
Cell
76:
959-962,
1994[ISI][Medline].
41.
Souza, HS,
Elia CCS,
Spencer J,
and
MacDonald TT.
Expression of lymphocyte-endothelial receptor-ligand pairs, a4b7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease.
Gut
45:
856-863,
1999
42.
Stuber, E,
and
Strober W.
The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response.
J Exp Med
183:
979-989,
1996[Abstract].
43.
Stuber, F,
Strober W,
and
Neurath M.
Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.
J Exp Med
183:
693-698,
1996[Abstract].
44.
Targan, SR,
Hanauer SB,
van Deventer SJH,
Mayer L,
Present DH,
Braakman T,
Dewoody KL,
Schaible TF,
and
Rutgeerts PJ.
A short term study of chimeric monoclonal antibody (cA2) to tumor necrosis factor a for Crohn's disease.
N Engl J Med
337:
1029-1035,
1997
45.
Tittle, TV,
Weinberg AD,
Steinkeler CN,
and
Maziarz RT.
Expression of the T-cell activation antigen, OX-40, identifies alloreactive T cells in acute graft-versus-host disease.
Blood
89:
4652-4658,
1997
46.
Van Dullemen, HM,
van Deventer SJH,
Hommes DW,
Bijl HA,
Jasen J,
Tytgat GNJ,
and
Woody J.
Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2).
Gastroenterology
109:
129-135,
1995[ISI][Medline].
47.
Weinberg, AD,
Lemon M,
Jones AJ,
Vainiene M,
Celnik B,
Buenafe AC,
Culbertson N,
Bakke A,
Vandenbark AA,
and
Offner H.
OX40 antibody enhances for autoantigen specific V8.2+ T cells within the spinal cord of Lewis rats with autoimmune encephalomyelitis.
J Neurosci Res
43:
42-49,
1996[ISI][Medline].
48.
Yamamoto, M,
Yoshizaki K,
Kishimoto T,
and
Ito H.
IL-6 is required for the development of Th1 cell-mediated murine colitis.
J Immunol
164:
4878-4882,
2000