Yaron Ilan

Hadassah Medical Center, Yerushalayim, Jerusalem, Israel

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Publications (290)1523.22 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine the immune-modulatory and the hepatoprotective effects of oral administration of two soy extracts in immune mediated liver injury and non-alcoholic steatohepatitis (NASH). Two soy extracts, M1 and OS, were orally administered to mice with concanavalin A (ConA) immune-mediated hepatitis, to high-fat diet (HFD) mice and to methionine and choline reduced diet combined with HFD mice. Animals were followed for disease and immune biomarkers. Oral administration of OS and M1 had an additive effect in alleviating ConA hepatitis manifested by a decrease in alanine aminotransferase and aspartate aminotransferase serum levels. Oral administration of the OS and M1 soy derived fractions, ameliorated liver injury in the high fat diet model of NASH, manifested by a decrease in hepatic triglyceride levels, improvement in liver histology, decreased serum cholesterol and triglycerides and improved insulin resistance. In the methionine and choline reduced diet combined with the high fat diet model, we noted a decrease in hepatic triglycerides and improvement in blood glucose levels and liver histology. The effects were associated with reduced serum tumor necrosis factor alpha and alteration of regulatory T cell distribution. Oral administration of the combination of OS and M1 soy derived extracts exerted an adjuvant effect in the gut-immune system, altering the distribution of regulatory T cells, and alleviating immune mediated liver injury, hyperlipidemia and insulin resistance.
    06/2015; 21(24):7443-56. DOI:10.3748/wjg.v21.i24.7443
  • Journal of Cystic Fibrosis 06/2015; 14:S30. DOI:10.1016/S1569-1993(15)30095-3
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    ABSTRACT: To evaluate the safety and efficacy of oral administration of Alequel™, an autologous protein-containing colon extract. A total of 43 patients were enrolled in a randomized, placebo-controlled, double-blind trial. Patients were orally administered with autologous protein-containing colon extract three doses of autologous study drug per week for 15 wk, for a total of 45 doses. Patients were followed for safety parameters. Remission was defined as a Crohn's disease activity index (CDAI) score of less than or equal to 150. All patients were followed for changes in subsets of T cells by fluorescence-activated cell sorting analysis. Analysis was performed on a total number of evaluable patients of 14 in the study drug group and 15 in the placebo group. Treatment was well tolerated by all patients. No major treatment-related adverse events were reported or observed in any of the treated patients during the feeding or follow-up periods. Between weeks 6 and 9 of the study, six of the 14 (43%) evaluable subjects who received the study drug achieved a CDAI of 150 or lower. In contrast, five of the 15 (33%) evaluable subjects in the placebo group achieved remission. Between weeks 9 and 12, the remission rates were 50% and 33% for the drug group and placebo group, respectively. Among the drug-treated subjects who achieved remission, the effect of the drug was judged as stable in eight of the 14 subjects as measured by at least two CDAI scores indicating remission in the 15-wk treatment period. A decreased percentage of peripheral natural killer T regulatory cells (a decrease of 28% vs an increase of 16%) and an increased ratio of CD4(+)/CD8(+) T lymphocytes (an increase of 11% vs a decrease of 9%) were noted in subjects with a significant clinical response. Oral administration of the autologous colonic extract could be a safe and effective for the treatment of patients with moderate to severe Crohn's disease.
    05/2015; 21(18):5685-94. DOI:10.3748/wjg.v21.i18.5685
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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
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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
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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
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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
  • Gastroenterology 05/2014; 146(5):S-587. DOI:10.1016/S0016-5085(14)62127-2
  • Journal of Hepatology 04/2014; 60(1):S240. DOI:10.1016/S0168-8278(14)60673-5
  • Journal of Hepatology 04/2014; 60(1):S164-S165. DOI:10.1016/S0168-8278(14)60460-8
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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
  • Yaron Ilan
    Hepatology International 09/2013; 8(S2):499-504. DOI:10.1007/s12072-013-9501-9
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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
  • 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
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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
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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
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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

Publication Stats

4k Citations
1,523.22 Total Impact Points

Institutions

  • 1988–2015
    • Hadassah Medical Center
      • • Department of Medicine
      • • Liver Unit
      Yerushalayim, Jerusalem, Israel
  • 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
  • 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
  • 1997–1999
    • Albert Einstein College of Medicine
      • • Department of Medicine
      • • Gastroenterology
      New York City, NY, United States