Background & Aims: TL1A is a tumor necrosis factor–like molecule that mediates a strong costimulation of T-helper (T_H) 1 cells. Expression of TL1A is increased in the mucosa of Crohn's disease patients and murine models of ileitis. The aim of this study was to determine the possible role of TL1A in chronic intestinal inflammation. Methods:We used dextran sodium sulfate (DSS)-induced chronic colitis to investigate the effects of TL1A on the development of colitis. The cytokine profile in the gut-associated lymphoid tissue (GALT) was measured. Neutralizing anti-TL1A antibodies were injected intraperitoneally into DSS-induced chronic colitis and G protein αi2^−/− T-cell transfer colitis models. Severity of colitis was evaluated by body weight, colon length, histology, and cytokine production. Results:DSS-induced chronic colitis was characterized by the infiltration of CD4⁺ T cells. TL1A, death receptor 3, interferon (IFN)-γ, and interleukin (IL)-17 were increased significantly in GALT of DSS-treated mice. TL1A up-regulated both IFN-γ production from T_H1 cells and IL-17 production from T_H17 cells in GALT CD4⁺ T cells. Furthermore, IFN-γ and IL-17 production from CD4⁺ T cells, induced by IL-12 and IL-23 respectively, was enhanced synergistically by combination with TL1A. Anti-TL1A antibody prevented chronic colitis and attenuated established colitis by down-regulation of both T_H1 and T_H17 activation. Conclusions:Our results reveal that TL1A is an important modulator in the development of chronic mucosal inflammation by enhancing T_H1 and T_H17 effector functions. The central role of TL1A represents an attractive, novel therapeutic target for the treatment of Crohn's disease patients.

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopathologic criteria. Recently, the search for a noninvasive marker that could augment or replace part of this diagnostic process has become a focus of IBD research. In this review, antibody markers, including microbial antibodies, autoantibodies and peptide antibodies, will be described, focusing on their common features. At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.

Antisense technologies for the targeted inhibition of gene expression could provide an effective strategy for the suppression of inflammation. However, the effective use of antisense oligonucleotides (ODN) has been limited because of several problems. Therefore, a delivery system for antisense ODNs that enhances antisense stability, while maintaining the specificity of antisense for its target RNA or DNA is needed. We have developed a delivery system for antisense ODN using schizophyllan (SPG), a polysaccharide that belongs to the β-(1-3) glucan family. This system has several advantages enabling the effective suppression of targeted RNA or DNA: the SPG complex is stable in vivo and does not dissolve in the presence of deoxyribonuclease, and the SPG complex is effectively taken up into macrophages by phagocytosis through Dectin-1. Macrophage-migration inhibitory factor (MIF), which is mainly produced by macrophages has been shown to have a pathogenetic role in inflammatory bowel disease (IBD). We developed a technique to create an SPG complex that highly conformed to the antisense MIF. The administration of antisense MIF/SPG complex effectively suppressed MIF production and significantly ameliorated intestinal inflammation. Our result demonstrated a possible new therapeutic approach, i.e., the administration of antisense MIF/SPG complex, for the treatment of IBD.