Yaron Ilan

Hadassah Medical Center, Yerushalayim, Jerusalem, Israel

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Publications (294)1661.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The MELD score predicts short-term mortality in patients with cirrhosis; however, some patients with low scores develop complications and die unexpectedly. Consequently, we evaluated the diagnostic accuracy of the methacetin breath test, an assay of liver metabolic function, and the MELD score, to predict the risk of complications of cirrhosis and liver-related death. 165 patients with cirrhosis received oral (13)C-methacetin; (13)CO2 was measured in expired breath (BreathID(®); Exalenz). The cumulative percent dose recovery of (13)CO2 at 20 minutes with a threshold of ⩽0.55% (high-risk) and >0.55% (low-risk) predicted liver-related death and the risk of cirrhotic complications in one year most accurately. MELD thresholds of ⩾15 and ⩾19 were also examined to predict the same endpoints. Dose recovery ⩽0.55% and MELD⩾19 both predicted liver-related death (HR 12.6[95%CI 1.6-98.3]; p=0.016, and HR 5.5[1.6-18.9]; p=0.007, respectively); MELD⩾15 did not. Dose recovery ⩽0.55% (HR 1.9[1.1-3.2]; p=0.03) also predicted the risk of ⩾1 complication(s), and was particularly able to foretell the risk of development/exacerbation of ascites (HR 4.7[1.8-11.9]; p=0.001), which was not achieved by either MELD threshold. Finally, in patients with MELD<19, dose recovery ⩽0.55% predicted the risk of death (p=0.017), development of ⩾1 cirrhotic complication(s) (p=0.062), and development/exacerbation of ascites (p=0.0009). In this pilot study, methacetin breath testing predicted the risk of liver-related death and development/exacerbation of ascites more accurately than MELD ⩾15 or ⩾19. In patients with low MELD (<19 points), MBT may be useful to identify patients in whom the frequency of clinical observation should be intensified. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.07.021 · 11.34 Impact Factor
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    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 · 3.48 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, L-aspartate aminotransferase, and L-alanine aminotransferase. In vitro administration of 2 signifi-cantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum lev-els and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC, and the ability to block the growth of HCC by OAT inhibitors, sup-ports the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of sup-pression of HCC by an OAT inactivator.
    ACS Medicinal Chemistry Letters 05/2015; 6(8):150529114104002. DOI:10.1021/acsmedchemlett.5b00153 · 3.12 Impact Factor
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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; 35(4). DOI:10.1007/s10875-015-0160-6 · 3.18 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; 181(2). DOI:10.1111/cei.12640 · 3.04 Impact Factor
  • Source
    Eran Israeli Md · Ariel Drori Md · Yaron Ilan
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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(8). DOI:10.1111/jvh.12369 · 3.91 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 · 16.72 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-587. DOI:10.1016/S0016-5085(14)62127-2 · 16.72 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S240. DOI:10.1016/S0168-8278(14)60673-5 · 11.34 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S164-S165. DOI:10.1016/S0168-8278(14)60460-8 · 11.34 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; 10(7). DOI:10.1016/j.actbio.2014.02.047 · 6.03 Impact Factor
  • Yaron Ilan
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Currently, there are no treatment options available for a large number of these patients. One of the mechanisms that may contribute to tumor growth is the lack of an effective immune response toward viral antigens or other tumor-associated antigens (TAAs). Immunotherapy has been tested as a potential therapeutic option for these patients. Several methods of immune modulation for augmenting antitumor immunity are being explored and have been shown to be effective in suppressing HCC growth in animal models. Activation of HCC-specific response can be accomplished by targeting hepatitis B or C viral antigens, alpha-fetoprotein, or other TAAs. This review summarizes part of the recent data on the use of adoptive transfer of immunity against viral antigens, oral immune modulation against TAAs, and the use of pulsed innate immune cells and gut adjuvants for the suppression of HCC; it reviews some additional new immunotherapeutic approaches.
    Hepatology International 09/2013; 8(S2):499-504. DOI:10.1007/s12072-013-9501-9 · 1.78 Impact Factor
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    ABSTRACT: Objective: To investigate the effect of β-glucosylceramide (GC), a natural glycolipid, on hepatic fat accumulation and regenerative response after partial hepatectomy (PH). Methods: Male C57Bl/6 mice were assigned to either 70% PH or 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: The 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 were lower 3, 48 and 72 h after PH compared with the control group. Conclusions: Administration of GC delayed hepatic triglyceride accumulation and suppressed early adipogenic gene 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; 14(8). DOI:10.1111/1751-2980.12062 · 1.96 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; 47(4). DOI:10.1097/MCG.0b013e31827873dc · 3.50 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 (HFD) supplementation and immune-mediated hepatitis. Liver damage and immunological status were assessed. Results: Oral administration of DT56a to leptin-deficient (ob/ob) and 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 a hepatoprotective effect associated with an alteration in the distribution of Tregs and NKT cells.
    Journal of Digestive Diseases 10/2012; 14(2). DOI:10.1111/1751-2980.12003 · 1.96 Impact Factor

Publication Stats

4k Citations
1,661.36 Total Impact Points


  • 1991–2015
    • Hadassah Medical Center
      • • Department of Medicine
      • • Liver Unit
      Yerushalayim, Jerusalem, Israel
  • 1999–2014
    • Hebrew University of Jerusalem
      • • Shaare Zedek Medical Center
      • • Department of Gastroenterology
      • • Department of Surgery
      Yerushalayim, Jerusalem District, 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
  • 1997–1999
    • Albert Einstein College of Medicine
      • Department of Medicine
      New York, New York, United States
  • 1998
    • University of Nebraska at Omaha
      Omaha, Nebraska, United States