Development Of Chronic Colitis Research Articles

Lymph Node Stromal Cells From Different Draining Areas Distinctly Regulate the Development of Chronic Intestinal Inflammation.

The balance between the responsiveness of the intestinal immune system and the gut environment is fundamental for the maintenance of intestinal homeostasis, which is required for an adequate recognition of entering antigens. The disruption of this homeostasis by exaggerated immune response to harmless antigens can lead to the development of intestinal disorders such as inflammatory bowel disease. Stromal cells are sessile non-hematopoietic cells that build the backbone of the lymph node, an important site for the immune response induction, but also contribute to immune response and tolerance induction. However, the knowledge about the role of stromal cells in the regulation of inflammatory responses is still limited. Therefore, in this study we analyzed the influence of stromal cells on the development of chronic intestinal inflammation. Here, we show that intestinal inflammation alters the immune activation of the mesenteric lymph node-derived stromal cells. Podoplanin+ and CD21/35+ stromal cells showed increased expression of MHC class II molecules, but CD106 expression on CD21/35+ cells was reduced. Stromal cells secreted cytokines and chemokines such as CCL7 and CXCL16 influenced the gut-homing phenotype and proliferation of CD4+ and CD8+ T cells. Furthermore, stromal cells of peripheral lymph nodes transplanted into the mesentery attenuated colitis severity in B6-Il10-/- mice. The reduced colitis severity in these mice was associated with increased expression of IL4 and distinct activation pattern of stromal cells derived from transplanted peripheral lymph nodes. Altogether, our results demonstrate that lymph node stromal cells impact development of chronic colitis via T cell induction. Moreover, lymph node stromal cells from different draining area due to neonatally imprinted processes distinctly regulate the induction of immune responses.

Si-Ni-San ameliorates chronic colitis by modulating type I interferons-mediated inflammation

BackgroundUlcerative colitis (UC) is a chronic relapsing inflammatory disease that markedly elevates the risk of colon cancers and results in disability. The disrupted immune homeostasis has been recognized as a predominant player in the pathogenesis of UC. However, the overall remission rate of current therapies based on immunoregulation is still unsatisfactory. Si-Ni-San (SNS) has been found effective in relieving UC through thousands of years of clinical practice, yet the specific mechanisms of the protective effect of SNS were not fully elucidated. PurposeWe aim to investigate the therapeutic effects of SNS against the development of chronic colitis and the underlying mechanisms. MethodsWe established a DSS-induced chronic experimental colitis mouse model to evaluate the effect of SNS. RNA-sequencing, bioinformatic analysis, and in vitro studies were performed to investigate the underlying mechanisms. ResultsOur data demonstrated that SNS significantly ameliorated chronic experimental colitis via inhibiting the expression of genes associated with inflammatory responses. Interestingly, SNS significantly suppressed DSS-induced type I interferon (IFN) responses instead of directly downregulating the production of pro-inflammatory cytokines, such as Il-6. In vitro study further found that SNS selectively inhibited STING and RIG-I pathway-induced type I IFN responses by modulating TBK1- and IRF3-dependent signaling transduction. SNS also suppressed the expression of IFN-stimulated genes by directly inhibiting STAT1 and STAT2 activation. ConclusionOur study not only provides novel insights into the pathogenic role of type I IFN responses in colitis but also suggested that SNS or bioactive compounds derived from SNS may serve as novel therapeutic strategies for the treatment of UC via interfering type I IFN-mediated inflammation.

The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans.

NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10-/- mice and humans. NLRP3 inflammasome in colonic mucosa, macrophages, and colonic epithelial cells were analysed by western blotting. The NLRP3 inflammasome components were studied by sucrose density gradient fractionation, chemical cross-linking, and co-immunoprecipitation. The role of NLPR3 inflammasome in the pathogenesis of colitis was extensively evaluated in IL-10-/- mice, using a specific NLPR3 inflammasome inhibitor glyburide. NLRP3 inflammasome was upregulated in colonic mucosa of both IL-10-/- mice and Crohn's patients. NLRP3 inflammasome activity in IL-10-/- mice was elevated prior to colitis onset; it progressively increased as disease worsened and peaked as macroscopic disease emerged. NLRP3 inflammasome was found in both intestinal epithelial cells and colonic macrophages, as a large complex with a molecular weight of ≥ 360 kDa in size. In the absence of IL-10, NLRP3 inflammasome was spontaneously active and more robustly responsive when activated by LPS and nigericin. Glyburide markedly suppressed NLRP3 inflammasome expression/activation in IL-10-/- mice, leading to not only alleviation of ongoing colitis but also prevention/delay of disease onset. Glyburide also effectively inhibited the release of proinflammatory cytokines/chemokines by mucosal explants from Crohn's patients. Abnormal activation of NLRP3 inflammasome plays a major pathogenic role in the development of chronic colitis in IL-10-/- mice and humans. Glyburide, an FDA-approved drug, may have great potential in the management of inflammatory bowel diseases.

Inhibition of Interleukin 10 receptor signaling induces microbiota-dependent chronic colitis in Apolipoprotein E deficient mice (MUC5P.754)

Abstract Apolipoprotein E (ApoE), a secreted protein, plays major role in cholesterol metabolism. ApoE is also known to exhibit anti-inflammatory properties. However, its role in the intestine, specifically during inflammation is not very clear. First, we verified upregulation of colonic ApoE transcripts in various models of murine acute and chronic colitis models. Age and gender matched ApoEKO mice and their WT littermates (n=5) were given either one or 4 weekly injections of IL-10 receptor (IL-10R) neutralizing mAb intraperitoneally and colitis development was monitored. ApoEKO mice given single injection of IL-10R mAb displayed acute colitis. Four weekly injections IL-10R mAb resulted in the development of chronic colitis as measured by colomegaly, splenomegaly and elevated colonic pro-inflammatory gene expression (TNFα, IFNγ) and histological score when compared to WT littermates. IL-10R neutralization also induced substantial levels of lipocalin 2, a general inflammatory marker in the feces, colon, and circulation in ApoEKO mice. Ablation of gut microbiota by broad-spectrum antibiotics substantially protected ApoEKO mice against IL-10R neutralization induced chronic colitis. In addition, cohousing ApoEKO mice with IL-10KO mice exaggerated spontaneous colitis (rectal prolapse) in IL-10KO mice when compared to WT suggesting ApoEKO harbor colitogenic microbiota. Collectively, our results demonstrate that ApoE plays a critical role in protecting the gut against inflammation.

Tu1947 1,25-Dihydroxyvitamin D3 Regulates the Development of Chronic Colitis by Modulating Both T Helper (Th)1 and TH17 Activation

Tu1947 1,25-Dihydroxyvitamin D3 Regulates the Development of Chronic Colitis by Modulating Both T Helper (Th)1 and TH17 Activation

IL-7rα Expression on CD4 + T Cells, but Not on Other Cells is Essential for the Development of Chronic Colitis

IL-7rα Expression on CD4 + T Cells, but Not on Other Cells is Essential for the Development of Chronic Colitis

Carbohydrate-binding motif in chitinase 3-like 1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells

Host-microbial interactions play a key role during the development of colitis. We have previously shown that chinase 3-like 1 (CHI3L1) is an inducible molecule overexpressed in colonic epithelial cells (CECs) under inflammatory conditions. In this study, we found that chitin-binding motif (CBM) of CHI3L1 is specifically associated with the CHI3L1-mediated activation of the Akt-signaling in CEC by transfecting the CBM-mutant CHI3L1 vectors in SW480 CECs. Downstream, CHI3L1 enhanced the secretion of IL-8 and TNFα in a dose-dependent manner. We previously show that 325 through 339 amino-acids in CBM are crucial for the biological function of CHI3L1. Here we demonstrated that 325th-339th residues of CBM in CHI3L1 is a critical region for the activation of Akt, IL-8 production, and for a specific cellular localization of CHI3L1. In conclusion, CBM region of CHI3L1 is critical in activating Akt signaling in CECs, and the activation may be associated with the development of chronic colitis.

NHE3 modulates the severity of colitis in IL-10-deficient mice

NHE3, the major intestinal Na(+)/H(+) exchanger, was shown to be downregulated and/or inhibited in patients with inflammatory bowel disease (IBD), a phenomenon believed to contribute to inflammation-associated diarrhea. NHE3(-/-) mice spontaneously develop colitis and demonstrate high susceptibility to dextran sulfate-induced mucosal injury. We investigated the effects of NHE3 deficiency on the development of chronic colitis in an IL-10 knockout (KO) mouse model of Crohn's disease. NHE3(-/-) mice were first backcrossed to 129/SvEv mice for >10 generations, with no apparent changes in their survival or phenotype. These mice were crossed with IL-10(-/-) mice on the same genetic background, and the phenotypes of 10-wk-old wild-type (WT), IL-10(-/-), NHE3(-/-), and IL-10(-/-)/NHE3(-/-) (double-KO) mice were studied. Histological and immunohistochemical examination of the colon established important architectural alterations, including increased neutrophilic and mononuclear cell infiltration in double- compared with single-KO mice. Double-KO mice demonstrated increased colonic expression of neutrophil collagenase matrix metalloproteinase-8 and the chemokines macrophage inflammatory protein-2, CXCL1, CXCL10, and CXCL11. Colonic IFNγ, IL-17, and IL-12/23 p40 protein secretion was significantly increased in double- compared with single-KO mice. IL-10(-/-)/NHE3(-/-) mouse colonic epithelium exhibited increased hallmarks of apoptosis, including a significantly increased number of cleaved caspase-3-positive surface epithelial cells. These results highlight the importance of NHE3 in the maintenance of intestinal barrier integrity and in modulating the inflammatory process in IL-10-deficient mice. Chronic NHE3 inhibition or underexpression observed in IBD may therefore contribute to the pathogenesis of IBD by influencing the extent of the epithelial barrier defect and affect the ultimate degree of inflammation.

IL‐2 is positively involved in the development of colitogenic CD4+ IL‐7Rαhigh memory T cells in chronic colitis

IL-2 and IL-7 share a common gamma-chain receptor and are critical for T-cell homeostasis. We aimed to clarify the reciprocal roles of IL-2 and IL-7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL-2(-/-) CD4(+)CD45RB(high) T cells into RAG-2(-/-) mice and assessed the role of IL-2 in the induction of IL-7R alpha on colitogenic CD4(+) T cells and the development of chronic colitis. RAG-2(-/-) mice transferred with WT but not with IL-2(-/-) CD4(+)CD45RB(high) T cells developed Th1/Th17-mediated colitis. Consistently, re-expression of IL-7R alpha was severely impaired on IL-2(-/-) but not on WT CD4(+) T cells from the transferred mice. To exclude a contribution of the preclinical autoimmunity of IL-2(-/-)mice, WT Ly5.1(+) or IL-2(-/-) Ly5.2(+) CD4(+)CD45RB(high) T cells from GFP mice previously transplanted with the same number of WT and IL-2(-/-) BM cells were transferred into RAG-2(-/-) mice. RAG-2(-/-) mice transferred with IL-2(-/-)-derived CD4(+)CD45RB(high) T cells did not develop colitis, but their splenic CD4(+) T cells changed from effector-memory to central-memory type. These results show that IL-2 is critically involved in the establishment and maintenance of IL-7-dependent colitogenic memory CD4(+)IL-7R alpha(high) T cells.

84 Mitochondrial Stress Induction in the Epithelium Fuels Endoplasmic Reticulum Unfolded Protein Responses via Double-Stranded RNA-Activated Protein Kinase (PKR) Under Conditions of Chronic Intestinal Inflammation

ability of these Tregs to suppress the development of chronic gut inflammation. We found, using blinded histopathological analysis, that adoptive transfer of WT T-cells induced moderate-to-severe colitis in RAG-/recipients at 8 wks post transfer whereas transfer of DKO Tcells induced little or no disease. The inability to induce disease by the DKO T-cells was not due to a delay in the onset of disease as we continued to observe significantly less disease even at 25 wks post transfer. Furthermore, failure to induce disease correlated well with large and significant decreases in the numbers of T-cells within the mesenteric lymph nodes (MLNs) and colonic lamina propria (cLP) suggesting that T-cell activation and/or trafficking may be defective in the DKO T-cells. In order to differentiate between these two possibilities we evaluated T-cell activation and trafficking In Vivo using adoptive transfer of congenic CSFE-labeled WT (CD45.1) and DKO (CD45.2) T-cells (107 cells for each) into RAG-/mice. At 7 days following transfer we observed 12and 4-fold fewer T-cells within the MLNs and cLP, respectively of the DKO→RAG-/mice vs. WT→RAG-/animals. In addition, we observed that both WT and DKO T-cells in the cLP generated similar amounts of IFN-γ and IL-17 and lost equivalent amounts of CFSE fluorescence. These data suggested that CD62L and β7 are not required for T-cell activation and polarization In Vivo. In the second series of studies, we found that DKO Tregs were substantially less effective than WT Tregs at suppressing the development of chronic colitis when co-transferred with WT CD4+CD4RBhigh T-cells. Taken together, our data suggest that both L-selectin and β7 are required for the T-cell-dependent induction and suppression of chronic colitis (NIHPO1 47385).

Abstract 1351: Lack of matrix metalloproteinase-10 exacerbates inflammation-associated colon tumor development

Abstract Ulcerative colitis is the most common inflammatory bowel disease, and is associated with increased risk of colon cancer. Understanding the mechanisms by which carcinogenesis occurs in the setting of colitis could lead to both prevention strategies and improved therapies. Matrix metalloproteinase-10 (MMP10), a member of the matrix metalloproteinase family of proteolytic enzymes, is expressed at healing edges of colonic ulcers. Although MMPs are usually considered as destructive players in inflammatory disease, we considered the possibility that MMP10 had a beneficial role in ulcerative colitis. We used dextran sulfate sodium (DSS) treatment in MMP10-null and corresponding control wild-type mice to investigate the consequences of MMP10 deletion on colitis development and recovery. Groups of mice were exposed to DSS for 7-day periods and sacrificed at different timepoints following the cessation of the DSS. Strikingly, MMP10-null mice were more severely affected by the treatment as determined by gross observations such as weight loss and colon length. Histological analysis at the various timepoints indicated that wild-type mice showed almost complete recovery from DSS within 14 days after DSS treatment. In contrast, MMP10-null mice still showed clear signs of damage with persistent inflammatory foci and non-healing ulcers. In situ hybridization indicated MMP10 expression predominantly in inflammatory cells, although some fibroblasts were also positive. Colonic epithelium was negative for MMP10. Bone marrow transplant experiments indicated that wild-type bone marrow partially rescued the MMP10-null phenotype. Measurement of cytokines by ELISA in colonic lavage fluid from MMP10-null and wild-type mice showed that IL-1α was significantly increased in the absence of MMP10. Levels of other cytokines such as TNFα, IL6, IL17 and G-CSF were not different. Multiple exposures to DSS results in conversion of an acute colitis to a chronic inflammatory disease. With only 2 DSS exposures, MMP10-null mice manifested a chronic condition which failed to resolve even after 3 months. Similarly-treated wild-type mice, however, appeared normal at this timepoint. Examination of the colonic tissue from the DSS double exposure showed a significant increase in the number of dysplastic foci present in the MMP10-null mice. Thus, expression of MMP10 appears necessary for resolution of colitis, and in its absence, the development of chronic colitis results in tumor development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1351.

S1662 Elimination of Alimentary Antigens Ameliorates the Development of Chronic Colitis in IL-10 Ko Model Mice

S1662 Elimination of Alimentary Antigens Ameliorates the Development of Chronic Colitis in IL-10 Ko Model Mice

T-Cell Induced Colitis Is Associated With Enhanced Myelopoiesis, PMN Infiltration into Secondary Lymphoid Tissue and Modulation of T-Cell Activation (98.6)

Abstract The objective of this study was to determine how the adoptive transfer of naïve T-cells into lymphopenic recipients affects myelopoiesis during the development of chronic colitis. We found that adoptive transfer of CD4+CD45RBhigh T-cells (5x105 cells) into RAG-1−/− recipients induced chronic colitis that was preceded by a dramatic leukocytosis/myelopoiesis in which total circulating leukocytes increased 5–6 fold compared to unmanipulated RAG-1−/− mice with PMNs representing >85% of the total blood leukocytes. In addition, we found that serum levels of the granulopoietic cytokines IL-17 and G-CSF increased by 4- and 9-fold, respectively compared to the healthy CD45RBlow→RAG-1−/− controls. Corresponding to these dramatic increases in systemic PMN production in the CD45RBhigh→ RAG-1−/− mice, were large and significant increases (30–50-fold) in the presence of granulocytes (Gr-1+/Mac-1+) in the spleen, MLNs and colonic lamina propria. Co-culture of irradiated leukocytes (5 x 103 cells) obtained from the MLNs or spleen (>60% PMNs) of colitic mice with CD4+ T-cells (105 cells) enhanced CD/CD28-induced T-cell proliferation by 2–3 fold. We conclude that the T-cell induced myelopoiesis and infiltration of PMNs into the secondary lymphoid tissue of lymphopenic recipients may enhance T-cell activation thereby modulating the onset and/or severity of colonic inflammation (Supported DK64023).

Ameliorating effect of saporin‐conjugated anti‐CD11b monoclonal antibody in a murine T‐cell‐mediated chronic colitis

Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis. The effects were evaluated of saporin-conjugated anti-CD11b monoclonal antibody (mAb) on the development of chronic colitis in severe combined immunodeficiency (SCID) mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells as an animal model of CD. Significantly increased CD11b-expressing macrophages as well as CD4(+) T cells were found in inflamed colon from colitic mice. Administration of saporin-conjugated anti-CD11b mAb markedly ameliorated the clinical and histopathological disease. In vivo treatment with saporin-conjugated anti-CD11b mAb decreased CD4(+) T-cell infiltration in the colon and suppressed interferon-gamma (IFN-gamma) and TNF-alpha production by lamina propria CD4(+) T cells. Collectively, the present results suggest an initial role of macrophages in the pathogenesis of T-cell-mediated chronic colitis. Furthermore, the macrophage-specific targeting may be a promising strategy for therapeutic intervention in CD.

CXC chemokine receptor 3 expression increases the disease-inducing potential of CD4+ CD25− T cells in adoptive transfer colitis

CD4CD25 T cells induce severe colitis when injected into immunodeficient recipients. The migration of disease-inducing cells to the bowel is controlled by adhesion molecules and chemotactic proteins. Chemokine receptors expressed on the T cells are therefore potential targets for anti-inflammatory therapy in inflammatory bowel disease. In this study, we have investigated the role of the chemokine receptor CXCR3 in the development of chronic colitis in a murine model. Expression of CXCR3 on CD4 T cell from normal and colitic mice was assessed by flow cytometry. Development of colitis was followed after transfer of either normal or CXCR3CD4CD25T cell into immunodeficient host. In addition, the ability of regulatory T cell to function in vivo in the absence of CXCR3 was tested. We find CXCR3 to be expressed on 80% to 90% of CD4 T cells isolated from colitic mice compared with only 4% to 10% of CD4 T cells in normal naïve mice. Injecting CD4CXCR3CD25 T cells into immunodeficient hosts results in an ameliorated form of colitis with a lack of clinical symptoms, suggesting that CXCR3 expression is important for enteroantigen priming of CD4 T cells and/or subsequent migration into the gut wall. In contrast, CXCR3 expression does not affect the function of regulatory T cells because CXCR3 regulatory T cells are just as capable as their wild-type counterpart of controlling disease development. The diminished disease-inducing capability of CXCR3 T cells is not caused by the absence of enteroantigen specificity; we also tested the enteroantigen-specific proliferative ability of CD4CD25 T cells from CXCR3 mice in vitro and found that they respond even more strongly than wild-type cells. The present data indicate that CXCR3 plays an important role in controlling the migration of disease-inducing CD4CD25 T cells into the gut wall. In contrast, lack of CXCR3 expression by regulatory T cells does not compromise their function in this model of colitis.

CD48 Controls T-Cell and Antigen-Presenting Cell Functions in Experimental Colitis

The cell-surface receptor CD48 is a lipid-anchored protein expressed on all antigen-presenting cells and T cells. CD2 and 2B4 are known ligands for CD48, which themselves are expressed on the surface of hematopoietic cells. Here we examine the effect of CD48 in the development of chronic experimental colitis and how CD48 affects adaptive and innate immune functions. The role of CD48 in experimental colitis was first assessed by transferring CD4(+)CD45RB(hi) cells isolated from either wild-type or CD48(-/-) mice into either Rag-2(-/-) or CD48(-/-) x Rag-2(-/-) mice. Development of chronic colitis in these adoptively transferred mice was assessed by disease activity index, histology, and production of interferon-gamma in mesenteric lymph nodes. Relevant functions of CD48(-/-)CD4(+) T cells and CD48(-/-) macrophages were examined using in vitro assays. In a second set of experiments, the efficacy of anti-CD48 in prevention or treatment of chronic colitis was determined. CD48(-/-)CD4(+) cells induced colitis when transferred into Rag-2(-/-) mice, but not when introduced into CD48(-/-) x Rag-2(-/-) recipients. However, both recipient mouse strains developed colitis upon adoptive transfer of wild-type CD4(+) cells. Consistent with a CD4(+) T-cell defect was the observation that in vitro proliferation of CD48(-/-)CD4(+) T cells was impaired upon stimulation with CD48(-/-) macrophages. In vitro evidence for a modest macrophage functional defect was apparent because CD48(-/-) macrophages produced less tumor necrosis factor alpha and interleukin 12 than wild-type cells upon stimulation with lipopolysaccharide. Peritoneal macrophages also showed a defect in clearance of gram-negative bacteria in vitro. Treatment of the CD4(+)CD45RB(hi)-->Rag-2(-/-) mice or the wild-type BM-->tg26 mice with anti-CD48 (HM48-1) ameliorated development of colitis, even after its induction. Both CD48-dependent activation of macrophages and CD48-controlled activation of T cells contribute to maintaining the inflammatory response. Consequently, T cell-induced experimental colitis is ameliorated only when CD48 is absent from both T cells and antigen-presenting cells. Because anti-CD48 interferes with these processes, anti-human CD48 antibody treatment may represent a novel therapy for inflammatory bowel disease patients.

Preferential Migration of CD62L+ Cells into the Appendix in Mice with Experimental Chronic Colitis

Background: Clinical and experimental studies suggest that appendectomy can protect against development of ulcerative colitis and Crohn’s disease. However, how T cells in the appendix affect the development of colitis has not been clarified. Aim: To investigate the in vivo migration and activation of colitis-inducing CD62L⁺ cells during development of chronic colitis. Methods: CD62L⁺CD4⁺ cells were fluorescently labeled and transferred to severe combined immunodeficient (SCID) mice to induce colitis. In vivo migration of T cells into the mucosa of the appendix and colon was quantified by in vivo microscopy after 7 weeks. In a second experiment, unlabeled CD62L⁺CD4⁺ cells were transferred, reisolated after 7 weeks, and adhesion molecule (integrin α₄β₇) and costimulatory molecule (CD154) expression was analyzed. Results: Six to eight weeks after CD62L⁺CD4⁺ cell transfer, SCID mice developed chronic colitis. In vivo microscopic analysis demonstrated a preferential migration of fluorescence-labeled CD62L⁺CD4⁺cells into the mucosa of the appendix versus the colon. Re-isolation of lamina propria cells from mice with colitis confirmed that CD62L⁺CD4⁺ cell migration was significantly enhanced in the appendix, compared to the colon (3.5-fold). Furthermore, a higher proportion of CD62L⁺CD4⁺ cells re-isolated from the appendix expressed integrin α₄β₇ and CD154 than from the colon. Conclusion: This study demonstrates the preferential migration of CD62L⁺CD4⁺cells into the appendix as compared to the colon. This migration pattern correlated with upregulation of integrin α₄β₇and CD154 (CD40 ligand) on T cells. Our results suggest an important role of the appendix in the pathogenesis of colitis.

Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis.

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(+)CD45RB(high) T cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-alpha 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-gamma, IL-2, and TNF-alpha production by lamina propria CD4(+) T cells. The combination with anti-TNF-alpha MAb further improved the therapeutic effect by abolishing IFN-gamma, IL-2, and TNF-alpha 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-alpha blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.

Correction: Development of chronic colitis is dependent on the cytokine MIF

In the November 2001 issue of Nature Immunology the name of an author was printed incorrectly. The name of ninth author listed should read Mazen Alsahli.

Role of the innate immune system in the development of chronic colitis.

Based on Pasteur's work on the microbial nature of fermentation, it was widely believed that the presence of bacteria in the intestine was essential for the life of the host. It has also been known for decades that gut commensal microbes effect the activation and development of the systemic immune system through gut-associated lymphoid tissues (GALT). Recent extensive studies have shown that recognition of microbes is mediated by a set of germline-encoded receptors, Toll-like receptors (TLRs), in mammals. This article reviews the role of the innate immunity system in the development of GALT and the pathogenesis of inflammatory bowel diseases (IBD).