Yaron Ilan

Hebrew University of Jerusalem, Yerushalayim, Jerusalem District, Israel

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Publications (288)1518.09 Total impact

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    ABSTRACT: ᅟ: Oral administration of anti-CD3 antibodies induced regulatory T cells (Tregs) alleviating the insulin resistance and liver damage in animal models. To determine the safety and biological effects of oral OKT3 monoclonal antibody (Balashov et al. Neurology 55:192-8, 2000) in patients with NASH. In this Phase-IIa trial, four groups of patients with biopsy-proven NASH (n = 9/group) received placebo (group A) or oral OKT3 (group B: 0.2; C: 1.0; D: 5.0 mg/day) for 30 days. Patients were followed for safety, liver enzymes, glucose, lipid profile, oral glucose tolerance test (OGTT), serum cytokines and Tregs. Oral OKT3 was well tolerated without treatment-related adverse events. OKT3 induced Tregs: with significant increases of CD4(+)LAP(+) (Latency associated peptide) and CD4(+)CD25(+)LAP(+) cells in Group D, and a significant increase in TGF-β in Groups C and D. AST decreased significantly in group D and a trend in Groups B and C. Fasting plasma glucose decreased significantly in all treatment groups compared with placebo. OGTT decreased significantly in Group D. Correlations were observed between the changes in several immune-modulatory effects and clinical biomarkers. While serum anti-CD3 levels where undetectable increases in human anti-mouse antibody levels were observed in Groups C and D. Oral administration of anti-CD3 MAb to patients with NASH was safe and well tolerated. Positive biological effects were noted in several hepatic, metabolic and immunologic parameters. These findings provide the basis for future trials to investigate the effect of oral anti-CD3 MAb immunotherapy in patients with NASH.
    Journal of Clinical Immunology 04/2015; DOI:10.1007/s10875-015-0160-6 · 2.65 Impact Factor
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    ABSTRACT: Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side-effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. To evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled in a 12 week, double-blind controlled trial. Primary end-point was percent of subjects with clinical remission (CDAI <150) or clinical response (100 point CDAI reduction). Twenty-six (56.5%) and 13 (54.2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP vs. 12 weeks for Purinethol. A higher proportion of patients on DR-6MP clinical remission at week 8. A greater improvement in IBDQ score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62+ expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with a significantly lower AEs. There was no evidence of drug-induced leucopenia in the DR-6MP group; The proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side-effects. This article is protected by copyright. All rights reserved. © 2015 British Society for Immunology.
    Clinical & Experimental Immunology 04/2015; DOI:10.1111/cei.12640 · 3.28 Impact Factor
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    ABSTRACT: Background: The long-term learning ability of the gut immune system has never been studied before. Oral administration of the autologous colonic extract, Alequel™, was shown to be a safe and effective treatment for patients with Crohn's disease. 92 patients were enrolled in three randomized, placebo-controlled, double-blind trials. Aims: To evaluate the long-term safety and efficacy of the oral administration of Alequel™. Study: Clinical and laboratory parameters were followed retrospectively to determine the long-term effects of Alequel™. Results: Patients in group A (treated and responded to Alequel™), had a mean flare-free interval of 7.3±3.96 months. Patients in group C (treated and responded to placebo) had a flare-free interval of 3.2±5.4 months. Conclusions: Short-term oral administration of autologous colonic extracts exerts long-term memory and beneficial effects in patients with moderate to severe Crohn's disease.
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    ABSTRACT: Orally administered anti-CD3 antibodies are biologically active in the gut through induction of regulatory T cells, exert an immune-modulatory effect, and alleviate insulin resistance and liver damage in patients with NASH. Aims: To determine the safety of oral anti-CD3 monoclonal antibody (MAb) immunotherapy in chronic HCV patients with associated immune dysfunction. Methods: Four groups (n = 9) of chronic HCV patients who were nonresponders to interferon plus ribavirin therapy received oral placebo (group A) or anti-CD3 MAb at one of three dosage levels for 30 days. Patients were followed for safety parameters and serum levels of liver enzymes, virus, cytokines and regulatory T cells. Results: Oral anti-CD3 immunotherapy was safe and well tolerated; no treatment-related adverse events were noted. The following improvements were noted relative to pretreatment levels: HCV viral load and AST and ALT levels decreased in the low- and high-dose groups following 30 days of therapy. In two of the treated groups, an increase in regulatory T cells (CD4+ CD25+) was noted. The positive effects were somewhat more apparent in subjects with initially elevated liver enzyme levels. Conclusions: Oral anti-CD3 MAb immunotherapy for nonresponder HCV patients was safe and well tolerated. Trends and statistically significant improvements were observed as reductions in viral load and liver enzyme levels, along with an increase in regulatory T-cell levels. These data support a role for the immune system in the pathogenesis of HCV infection and suggest that this immunotherapy is worthy of evaluation in combination with HCV antiviral drugs.
    Journal of Viral Hepatitis 11/2014; 58. DOI:10.1111/jvh.12369 · 3.31 Impact Factor
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    ABSTRACT: Liver steatosis is a common characteristic of obesity and type 2 diabetes, and fatty liver disease is increasingly recognized as a major health burden. Accumulating evidence suggests that β-glycosphingolipids play an important role in insulin sensitivity and thus could affect hepatic steatosis. To determine the effect associated with β-glycosphingolipid-mediated amelioration of liver injury, seven groups of Psammomys obesus on a high-energy diet were studied. Animals were treated with daily injections of β-glucosylceramide, β-lactosylceramide, or a combination of both. β-glycosphingolipids ameliorated the hepatic injury manifested by decreased liver enzymes, liver weight, and hepatic fat, and improved liver histology. Administration of both β-glucosylceramide and β-lactosylceramide also decreased interferon (IFN)-γ serum levels. These effects were associated with improved serum cholesterol and triglyceride levels. These data suggest that β-glycosphingolipids ameliorate liver injury in an animal model of nonalcoholic steatohepatitis.
    Journal of Inflammation Research 10/2014; 7:151-8. DOI:10.2147/JIR.S50508
  • Gastroenterology 05/2014; 146(5):S-901. DOI:10.1016/S0016-5085(14)63276-5 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-587. DOI:10.1016/S0016-5085(14)62127-2 · 13.93 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S240. DOI:10.1016/S0168-8278(14)60673-5 · 10.40 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S164-S165. DOI:10.1016/S0168-8278(14)60460-8 · 10.40 Impact Factor
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    ABSTRACT: Extended partial hepatectomy may be needed in cases of large hepatic mass, and can lead to fulminant hepatic failure. Macroporous alginate scaffold is a biocompatible matrix, which promotes the growth, differentiation and long-term hepatocellular function of primary hepatocytes in vitro. Our aim was to explore the ability of implanted macroporous alginate scaffolds to protect liver remnants from acute hepatic failure after extended partial hepatectomy. An 87% partial hepatectomy (PH) was performed on C57BL/6 mice to compare non-treated mice to mice in which alginate or collagen scaffolds were implanted after PH. Mice were scarified 3, 6, 24 and 48 hours and 6 days following scaffold implantation and the extent of liver injury and repair was examined. Alginate scaffolds significantly increased animal survival to 60% vs. 10% in non-treated and collagen-treated mice (log rank= 0.001). Mice with implanted alginate scaffolds manifested normal and prolonged aspartate aminotransferases (AST) and alanine aminotransferases (ALT) serum levels as compared with the 2-to-20-fold increase in control groups (p<0.0001) accompanied with improved liver histology. Sustained normal serum albumin levels were observed in alginate-scaffold-treated mice 48 hours after hepatectomy. Incorporation of BrdU-positive cells was 30% higher in alginate scaffold-treated group, compared with non-treated mice. Serum IL-6 levels were significantly decreased 3 hours post PH. Biotin-alginate scaffolds were quickly well integrated within the liver tissue. Collectively, implanted alginate scaffolds support liver remnants after extended partial hepatectomy, thus eliminating liver injury and leading to enhanced animal survival after extended partial hepatectomy.
    Acta biomaterialia 03/2014; DOI:10.1016/j.actbio.2014.02.047 · 5.68 Impact Factor
  • Yaron Ilan
    Hepatology International 09/2013; 8(S2):499-504. DOI:10.1007/s12072-013-9501-9 · 2.47 Impact Factor
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    ABSTRACT: OBJECTIVE: To investigate the effect of β-glucosylceramide (GC), a natural glycolipid, on the hepatic fat accumulation and regenerative response after partial hepatectomy (PH). METHODS: Male C57Bl/6 mice were divided to either 70% partial hepatectomy and sham surgery after receiving daily intraperitoneal injection of GC or vehicle for 3 days. Hepatic fat accumulation, cytokines, cell cycle proteins and adipogenic genes expression were assessed at various time points after PH. RESULTS: Administration of GC delayed hepatic triglyceride accumulation during hepatic regeneration. This observation was closely correlated with alterations in the expression of four major adipogenic genes during the course of liver regeneration with reduced expression 3 h after PH and increased expression 48 h post-surgery. GC significantly reduced hepatocellular proliferation 48 h after PH. In GC-treated mice, both tumor necrosis factor-α and interleukin-6 levels decreased 3, 48 and 72 h after PH. CONCLUSION: Administration of GC delayed hepatic triglyceride accumulation and suppressed early adipogenic genes expression during the hepatic regenerative response. These changes are closely associated with early inhibition of liver regeneration and temporal alteration of cytokine secretion.
    Journal of Digestive Diseases 04/2013; DOI:10.1111/1751-2980.12062 · 1.92 Impact Factor
  • Yaron Ilan
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    ABSTRACT: Metabolic syndrome, obesity, and nonalcoholic steatohepatitis are associated with a state of chronic inflammation. The immune system and the inflammatory cascade can be involved in the development of any of the above common conditions. This association raises the question of whether immune therapy can be used for the treatment of nonalcoholic steatohepatitis. Although immune therapy is not yet feasible for clinical use, here, we review some of the recent data on the potential role of the various arms of the immune system in the development of nonalcoholic steatohepatitis and several potential therapeutic targets.
    Journal of clinical gastroenterology 02/2013; DOI:10.1097/MCG.0b013e31827873dc · 3.19 Impact Factor
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    ABSTRACT: Nonalcoholic steatohepatitis (NASH) is considered to be part of the nonalcoholic fatty liver disorders and its incidence is increasing. Imm124-E (Immuron Ltd, Melbourne, Australia), containing hyperimmune bovine colostrum, has been shown to exert an immunomodulatory effect and to alleviate target organ damage in animal models of NASH. The aim of our study was to determine the safety and efficacy of oral administration of Imm124-E to patients with insulin resistance and NASH. In an open-label trial, ten patients with biopsy-proven NASH and insulin resistance were orally treated with Imm124-E for 30 days. Oral administration of Imm124-E was safe, and no side effects were noted. Alleviation of insulin resistance was reflected by significantly improved hemoglobin A(1c) (HbA(1c)) values in all ten treated patients. For between five and eight responders, the following effects were noted: a decrease in fasting glucose levels; improved oral glucose tolerance test (OGGT) and homeostatic model assessment insulin resistance (HOMA) scores; and alleviation in lipid profile. These effects were accompanied by increased serum levels of glucagon-like peptide 1 (GLP-1), adiponectin and T regulatory cells. Hyperimmune colostrum alleviates NASH.
    Journal of Inflammation Research 12/2012; 5:141-50. DOI:10.2147/JIR.S35227
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    ABSTRACT: OBJECTIVE: To determine the metabolic and immunological effects of the oral administration of DT56a, an enzymatic isolate of soybeans. METHODS: DT56a was orally administered to mice in three animal models: leptin deficiency, high-fat diet supplementation and immune-mediated hepatitis. Liver damage and immunological status were assessed. RESULTS: Oral administration of DT56a to ob/ob and high-fat diet (HFD) mice led to a significant reduction in serum triglyceride (TG) and total cholesterol (TC) levels. DT56a-treated mice in both models exhibited a significant reduction in hepatic levels of TG and marked alleviation of glycemic control as indicated by significant decreases in fasting blood glucose levels and glucose tolerance tests. The levels of liver enzymes were reduced; these metabolic effects were associated with altered distributions of regulatory T (Tregs) and natural killer T (NKT) cells. DT56a suppressed the immune-mediated liver damage induced by concanavalin A indicated by decreased liver enzymes and serum interferon-γ levels and by improved histology and decreased hepatic apoptosis. Oral administration of DT56a also alleviated immune-mediated hepatitis and affected Tregs and NKT cells. CONCLUSIONS: Oral administration of DT56a promotes hepatoprotective effect associated with an alteration in the distribution of regulatory T and NKT cells.
    Journal of Digestive Diseases 10/2012; 14(2). DOI:10.1111/1751-2980.12003 · 1.92 Impact Factor
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    Yaron Ilan
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    ABSTRACT: Gut flora and bacterial translocation (BT) play important roles in the pathogenesis of chronic liver disease, including cirrhosis and its complications. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen predispose patients to bacterial infections, major complications and also play a role in the pathogenesis of chronic liver disorders. Levels of bacterial lipopolysaccharide, a component of gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver disease. Impaired gut epithelial integrity due to alterations in tight junction proteins may be the pathological mechanism underlying bacterial translocation. Preclinical and clinical studies over the last decade have suggested a role for BT in the pathogenesis of nonalcoholic steatohepatitis (NASH). Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of NASH and its complications. A better understanding of the cell-specific recognition and intracellular signaling events involved in sensing gut-derived microbes will help in the development of means to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases. These may suggest new targets for potential therapeutic interventions for the treatment of NASH. Here, we review some of the mechanisms connecting BT and NASH and potential therapeutic developments.
    World Journal of Gastroenterology 06/2012; 18(21):2609-18. DOI:10.3748/wjg.v18.i21.2609 · 2.43 Impact Factor
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    ABSTRACT: The prevalence of obesity is growing to epidemic proportions, and there is clearly a need for minimally invasive therapies with few adverse effects that allow for sustained weight loss. Behavior and lifestyle therapy are safe treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. Gastric electrical stimulation (GES) has received increasing attention as a potential tool for treating obesity and gastrointestinal dysmotility disorders. GES is a promising, minimally invasive, safe, and effective method for treating obesity. External gastric pacing is aimed at alteration of the motility of the gastrointestinal tract in a way that will alter absorption due to alteration of transit time. In addition, data from animal models and preliminary data from human trials suggest a role for the gut-brain axis in the mechanism of GES. This may involve alteration of secretion of hormones associated with hunger or satiety. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatment's outcome. Here, we review the current status, potential mechanisms of action, and possible future applications of gastric stimulation for obesity.
    World Journal of Gastroenterology 05/2012; 18(19):2309-19. DOI:10.3748/wjg.v18.i19.2309 · 2.43 Impact Factor
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    ABSTRACT: Insulin resistance and metabolic syndrome are chronic inflammatory conditions that lead to hepatic injury and non-alcoholic steatohepatitis (NASH). Bovine colostrum has therapeutic effects in a variety of chronic infections. However its effectiveness in NASH was never studied. Natural killer T (NKT) cells have been shown to be associated with some of the pathological and metabolic abnormalities accompanying NASH in leptin-deficient (ob/ob) mice. In the present study, we used hyperimmune bovine colostrum to treat hepatic injury and insulin resistance and we also assessed the effects on NKT cells. We used ob/ob mice that were fed for 6 weeks with either 0·1 mg bovine colostrum prepared from non-immunized cows, 0·1 mg hyperimmune colostrum raised against a bacterial lipopolysaccharide (LPS) extract or 0·001, 0·1 or 1 mg of immunoglobulin (Ig)G purified from hyperimmune colostrum (IgG-LPS). NKT cells were phenotyped by flow cytometry, and hepatic injury and insulin resistance were assessed by measuring fasting glucose levels, glucose tolerance tests and liver enzymes. Fat accumulation was measured in the liver and plasma. Oral administration of hyperimmune colostrums decreased alanine aminotransferase (ALT) serum levels and serum triglycerides compared to controls. Glucose intolerance was also improved by the hyperimmune colostrum preparations. These results were accompanied by a decrease in serum tumour necrosis factor (TNF)-α levels following oral treatment with 0·1 or 1 mg of IgG-LPS. The beneficial effects of hyperimmune colostrums were associated with an increase in the number of splenic NKT cells. These data suggest that oral administration of hyperimmune colostrum preparations can alleviate chronic inflammation, liver injury and insulin resistance associated with NASH.
    Clinical & Experimental Immunology 02/2012; 167(2):252-60. DOI:10.1111/j.1365-2249.2011.04511.x · 3.28 Impact Factor
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    ABSTRACT: There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. Treatment-naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5μg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0μg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5μg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800-1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs. B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5μg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment.
    Journal of Hepatology 09/2011; 55(3):554-63. DOI:10.1016/j.jhep.2010.12.024 · 10.40 Impact Factor
  • International Immunology 07/2011; 23(7):465. DOI:10.1093/intimm/dxr054 · 3.18 Impact Factor

Publication Stats

4k Citations
1,518.09 Total Impact Points

Institutions

  • 1999–2014
    • Hebrew University of Jerusalem
      • • Department of Gastroenterology
      • • Shaare Zedek Medical Center
      • • Department of Surgery
      Yerushalayim, Jerusalem District, Israel
    • Keio University
      Edo, Tōkyō, Japan
  • 1988–2012
    • Hadassah Medical Center
      • • Liver Unit
      • • Department of Medicine
      Yerushalayim, Jerusalem, Israel
  • 2010
    • Harvard University
      Cambridge, Massachusetts, United States
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2000–2004
    • Enzo Biochem
      New York, New York, United States
  • 1996–1999
    • Albert Einstein College of Medicine
      • • Department of Medicine
      • • Gastroenterology
      New York City, NY, United States