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AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis.

Inflammatory bowel disease (IBD) is frequently associated with the infiltration of a large number of leukocytes into the bowel mucosa. Therefore, the removal of circulating leukocytes may be an attractive approach for the treatment of IBD. Leukocytapheresis with Cellsorba, a column of polyethylenephtarate fibers that captures monocytes, granulocytes, and lymphocytes, has been used to treat IBD, particularly ulcerative colitis, in Japan. The objective of this paper is to provide an overview of current knowledge regarding the mechanisms of action, available clinical data, and possible future perspectives for the use of LCAP with Cellsorba in the management of IBD. Leukocytapheresis appears to remove or inactivate inflammatory cells, to reset immunity by modulating immune system components like cytokines, and to repair the intestinal mucosa by mobilizing mesenchymal progenitors. Although the majority of clinical studies had an open-label design and enrolled only a small number of patients, leukocytapheresis has been demonstrated to exert clinical efficacy with an excellent safety profile. Although leukocytapheresis with Cellsorba appears very promising, its future in the treatment of IBD requires further evaluation.

An array of investigations has revealed that macrophage migration inhibitory factor (MIF) plays an important role in the exacerbation of a wide range of inflammatory diseases. For the past two decades, we have extensively studied MIF's pathophysiological roles in human diseases, and have accumulated evidence elucidating its molecular mechanisms in the pathogenesis of immune disorders and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel diseases (IBD). In a study of IBD, we demonstrated for the first time that anti-MIF antibody suppressed the degree of dextran- sulfate sodium (DSS)-induced colitis, indicating its potential therapeutic use for IBD patients. Following that report, a number of researchers, including us, clarified that MIF was profoundly involved in various gastrointestinal disorders, such as hepatitis and pancreatitis. We recently revealed that a MIF-deficient mouse was resistant to a challenge of DSS, and showed few clinical and pathological signs. Currently, we are developing new therapeutic approaches targeting MIF in inflammatory disorders, particularly IBD. We here overview MIF's pathophysiological function, mainly in IBD, and introduce two therapeutic approaches, anti-MIF antibody treatment and MIF-antisense therapy, via a drug delivery system using 1,3-β glucan.

The complex pathogenesis of inflammatory bowel disease (IBD) and inflammation induced colon cancer involves a wide range of mediators including cytokines. Recent investigations underline the fundamental role of interleukin- 6 (IL-6) signaling in the development and maintenance of IBD and for the progression of this inflammation to colon cancer. The molecular mechanisms of this pathway, the source of the cytokine and the identity of target cells in the intestine are incompletely understood. It is known that the circulating and intestinal levels of IL-6 as well as the soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. Remarkably, mucosal T cells of IBD patients are extremely resistant to apoptosis and a large fraction of these cells express membrane-bound gp130 but not the IL-6R. Increasing evidence suggests that the development and perpetuation of IBD relies on IL-6 synthesized by T-cells and myeloid cells and on increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T-cells, a process called IL-6 trans-signaling. Recent investigations suggested a protective role of IL-6 mediated STAT3 signaling in intestinal epithelial cells. Here we review these pro- and anti-inflammatory properties of IL-6 in IBD and inflammation induced colon cancer and we will summarize the consequences of these new results for the prospects of IL-6 targeted therapeutic strategies for the treatment of chronic inflammatory diseases such as IBD.

It is well established that intestinal microbiota play an important role in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Various methods of altering the composition of intestinal microbiota have been examined. Recent evidence suggests that the administration of select prebiotics, probiotics and synbiotics may improve the clinical outcome of patients with IBD. In addition, IBD patients are well known to carry a higher risk of developing colorectal cancer due to chronic inflammation. Therefore, probiotics and/or prebiotics may be appropriate treatments for prophylactic use due to their physiologic characteristics and lack of obvious toxicity. This review summarizes the current experimental and clinical knowledge about the role of intestinal microbiota in IBD, the prevention of carcinogenesis related to IBD, and its importance as a target for new forms of neutraceutical therapy.

AbstractPrimary sclerosing cholangitis (PSC) is an autoimmune disease of the hepatobiliary system for which effective therapy has not been established. Leukocytapheresis (LCAP) therapy is known to effective in patients with ulcerative colitis (UC). In addition, effects of LCAP therapy were reported on some autoimmune diseases such as Crohn’s disease, rheumatoid arthritis and rapidly progressive glomerulonephritis. Here we report the case of a 29-year-old man with PSC associated with UC who was treated with LCAP therapy. He had a 16-year history of UC and a 12-year history of PSC. Although he was under treatment with prednisolone and ursodeoxycholic acid, exacerbation of UC and PSC-associated cholestasis were seen. Since he showed side effects of prednisolone, he was treated with LCAP. Not only improvement of UC, but also decreased serum alkaline phosphatase, ?-guanosine triphosphate and total bile acids, suggesting improvement of PSC-associated cholestaisis, were seen after treatment with LCAP. Our experience with this case suggests that LCAP therapy could be a new effective therapeutic strategy for patients with PSC associated with UC.Copyright © 2009 S. Karger AG, Basel

Background: Intestinal microflora contribute to the pathogenesis of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. Objective: This review summarizes current clinical knowledge about the role of intestinal microflora in inflammatory bowel disease and their importance as targets for new forms of therapy. Methods: Recent knowledge on gut microbial ecology, role of microflora, and pattern recognition receptors is summarized in relation to inflammatory bowel disease. The results of in vitroexperiments, in vivoanimal studies and human clinical trials with the use of agents targeting microflora, including prebiotics, probiotics and synbiotics, are described briefly. Conclusion: Altering the composition of intestinal microflora through prebiotics, probiotics and synbiotics may improve the clinical outcome of patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory state associated with increased risk of intestinal cancers. The aim of this study is to examine serum concentrations of growth-related oncogene (GRO)-α, a cytokine with inflammatory and growth-regulatory properties, in patients with IBD. We measured serum concentrations of GRO-α in 60 patients with ulcerative colitis, 42 patients with Crohn's disease, 16 patients with other colitides, 12 patients with colorectal cancer, and 40 normal subjects using an enzyme-linked immunosorbent assay. We then analyzed how the cytokine was related to clinical and laboratory variables. Serum GRO-α concentrations in patients with active IBD were significantly higher than those in patients with quiescent disease, which in turn were higher than those in normal controls. Concentrations in patients with active ulcerative colitis were higher than in patients with active Crohn's disease. Analysis of paired serum samples showed a decrease in GRO-α after initiation of therapy. Furthermore, serum GRO-α correlated well with laboratory markers of IBD activity. We conclude that GRO-α may have an important role in development of IBD, and might itself be used as a marker of activity. Manipulation of GRO-α function might prove therapeutically useful.

It was reported that angiotensin-converting enzyme (ACE) plays an important role in increasing blood pressure. Recently, it was reported that several food hydrolysates have ACE inhibitory effects in the spontaneous hypertensive rat (SHR) model and mildly hypertensive subjects. Therefore, the anti-hypertensive effects of brewers yeast BY-G were investigated, which contains many kinds of beneficial nutrients (vitamins, minerals, nucleic acids, glutathione, amino acids, etc.). The aim of this study was to evaluate the anti-hypertensive effects of BY-G and i ts component peptides obtained by enzymatic treatment. The peptide fraction KRF814 was obtained by the hydrolysate of BY-G with alkaline protease and then treated with Amberlite XAD-2. The KRF814, which has an inhibitory effect on ACE in vitro, was obtained. BY-G and KRF814 were fed to male SHR and showed significantly anti-hypertensive effects. KRF814 contained alanyl-phenylalanine (AF) and glycyl-phenylalanine (GF), which significantly decreased systolic BP in the SHR model. The active ingredients of KRF814, AF, and GF had about 60 of the potency of the positive control, which was captopril. It i s considered that intake of BY-G or its component peptides as a functional food stuff might be beneficial for improving BP in people with hypertension.

A new protein-rich and fibrous foodstuff, germinated barley foodstuff (GBF), made from brewer's spent grain by physical isolation (milling and sieving) contains glutamine-rich protein and hemicellulose. In addition to improving defecation in healthy volunteers and animals, consumption of GBF prevented inflammation and diarrhea in a colitis model, largely by increasing production of luminal short-chain fatty acids and because of its high water-holding capacity. In this study, we evaluated the safety and efficacy of GBF as a novel nutraceutical therapy in the treatment of patients with ulcerative colitis (UC). Patients showed improvement in their clinical activity and endoscopic score and had an increase in stool butyrate content after GBF administration, without any adverse effects. Further, we examined the mechanism of the effect of GBF. GBF was fermented, and butyrate was produced by Eubacteriumwith the aid of Bifidobacteriumin the gastrointestinal tract. The bacterial butyrate production from GBF improved the intestinal barrier function, resulting in mitigation of colitis. GBF may prove valuable when applied as a new functional foodstuff, especially as a nutraceutical in the treatment of UC.

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6–deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell–dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Abstract: A 17-year-old woman with arterial and venous thrombosis of the leg diagnosed as antiphospholipid syndrome (APS) associated with systemic lupus erythematosus (SLE) is reported. Her serum C-reactive protein (CRP) was elevated and complement concentrations were normal. Symptoms of APS were improved with prednisolone, when the serum CRP concentration decreased, and low serum complement concentration and white blood cell count appeared. These are characteristic features of SLE. It is suggested that APS is a possible complication of SLE and may modify the clinical features of SLE.

A 17-year-old woman with arterial and venous thrombosis of the leg diagnosed as antiphospholipid syndrome (APS) associated with systemic lupus erythematosus (SLE) is reported. Her serum C-reactive protein (CRP) was elevated and complement concentrations were normal. Symptoms of APS were improved with prednisolone, when the serum CRP concentration decreased, and low serum complement concentration and white blood cell count appeared. These are characteristic features of SLE. It is suggested that APS is a possible complication of SLE and may modify the clinical features of SLE.

The clinical significance of circulatingvascular endothelial growth factor (VEGF) in patientswith various liver diseases was investigated. Twenty-onepatients with acute hepatitis (AH), 40 with chronic hepatitis (CH), 34 with cirrhosis (LC), 16 withfulminant hepatitis (FH), 10 with primary biliarycirrhosis (PBC), 12 with autoimmune hepatitis (AIH), and120 healthy individuals were included. Serum VEGF levels were measured by a chemiluminescenceenzyme-linked immunosorbent assay. The mean values ofserum VEGF levels in the patients with AH, CH, LC, FH,AIH, PBC, and control were 172.7, 58.0, 44.1, 37.3, 49.7, 74.9, and 65.0 pg/ml, respectively. Thepatients with AH had a level of serum VEGF significantlyhigher than that of the control group (P < 0.001).The serum VEGF levels in survivors of FH weresignificantly increased, but not in the nonsurvivors in therecovery phase compared with the levels on admission (P< 0.05). In the LC patients, serum VEGF levels weresignificantly lower than those of the control group (P < 0.05). These findings suggest thatserum VEGF level may be associated with hepatocyteregeneration grade.

The significance of interleukin-6 (IL-6) in patients with inflammatory bowel disease (IBD) was studied by measuring the IL-6 level in serum and colonic tissue by means of an enzyme-linked immunosorbent assay (ELISA), and by examining its localization using an immunohistochemical method. The serum IL-6 level reflected the degree of disease activity, and the extent of affected area, and was also correlated with the serum C-reactive protein (CRP) level. In the colonic mucosa of active IBD, the tissue IL-6 level was markedly elevated, and immunoreactive products of anti-IL-6 antibody were present in infiltrative mononuclear cells in the lamina propria. This indicates that IL-6 production in these cells is enhanced at the site of affected intestine. These results, together with its biological activity and the type of cell producing it, suggest that IL-6 is an available marker to assess disease conditions of IBD and that it might be also involved in the pathophysiology of IBD.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder associated with uncontrolled inflammation within the gastrointestinal tract, which has been shown to predispose patients to the development of colorectal cancer later in life. The pathogenesis of IBD is complex, but the current model favors a dysregulated cytokine network that is triggered by intestinal microbiota in a genetically-susceptible host. Interestingly, a germ free rodent model was reported not to cause cytokine dysregulation and intestinal inflammation. Therefore, microbiota and cytokines are both considered as theoretical targets for therapeutic approaches in IBD. This special issue of Current Pharmaceutical Design focuses on the role of microbiota and cytokines in IBD. Furthermore, therapeutic approaches targeting these two factors are also discussed including functional food and the pharmacological and non-pharmacological treatment modalities. First of all, Possemiers S, et al. provided a brief overview on the importance of the indigenous microbial community and its enormous metabolic potential, microbe-microbe interactions, mechanisms of host-bacterium cross-talk and discussed the onset of obesity, a specific disease state in which intestinal microbiota play a role [1]. Andoh A, et al. provided a review focusing on new insights into the role of commensal microbiota in gut health and disease, and presented recent advances in molecular approaches to the imbalance of intestinal microbiota in IBD [2]. Kanauchi O, et al. introduced the therapeutic impact of manipulating microbiota in IBD [3]. This review shows that the administration of selected prebiotics, probiotics and synbiotics may improve the clinical outcome of patients with IBD as a target for new forms of functional food. In addition, they describe the possibility of preventive treatment of IBD-associated colon cancer by using special prebiotics because of their physiologic characteristics and lack of obvious toxicity.

The aortitis syndrome is a chronic inflammatory process that affects the aorta and its primary branches. Patients with aortitis syndrome exhibit various ocular changes. We present a patient in whom cataract was the initial objective finding. The serum concentration of vascular endothelial growth factor, a cytokine that affects neovascularization, and vasopermeability, was elevated before the initiation of prednisolone treatment. Cataract should be considered as a possible characteristic initial finding in patients with aortitis syndrome. Vascular endothelial growth factor may be involved in the progression of aortitis syndrome. Masaru Harada, Second Department of Medicine, Kurume University School of Medicine, Asahi-Machi 67, Kurume 830, Japan