76 results on '"Ilan, Yaron"'
Search Results
2. Platform introducing individually tailored variability in nerve stimulations and dietary regimen to prevent weight regain following weight loss in patients with obesity.
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Khoury, Tawfik and Ilan, Yaron
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REGULATION of body weight ,VAGUS nerve ,WEIGHT gain ,DIETARY supplements ,WEIGHT loss ,NEURAL stimulation - Abstract
Prevention of weight regain following successful weight loss is a major challenge in the treatment of obesity, irrespective of the weight reduction method used. The majority of individuals regain the lost weight over time; thus, achieving long-term sustainability in weight loss remains an unresolved issue. A compensatory adaptation to the weight loss methods occurs in several body organs and partly explains the lack of sustainable effect. Variability is inherent in many biological systems, and patterns of variability constitute a body mechanism that is active at several levels, starting from the genes and cellular pathways through to the whole-organ level. This study aimed to describe a platform that introduces individually tailored variability in vagal nerve stimulation and dietary regimen to ensure prolonged and sustainable weight loss and prevent weight regain. The platform is intended to provide a method that can overcome the body's compensatory adaptation mechanisms while ensuring a prolonged beneficial effect. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Establishing a second-generation artificial intelligence-based system for improving diagnosis, treatment, and monitoring of patients with rare diseases
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Hurvitz, Noa, Azmanov, Henny, Kesler, Asa, and Ilan, Yaron
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Patients with rare diseases are a major challenge for healthcare systems. These patients face three major obstacles: late diagnosis and misdiagnosis, lack of proper response to therapies, and absence of valid monitoring tools. We reviewed the relevant literature on first-generation artificial intelligence (AI) algorithms which were designed to improve the management of chronic diseases. The shortage of big data resources and the inability to provide patients with clinical value limit the use of these AI platforms by patients and physicians. In the present study, we reviewed the relevant literature on the obstacles encountered in the management of patients with rare diseases. Examples of currently available AI platforms are presented. The use of second-generation AI-based systems that are patient-tailored is presented. The system provides a means for early diagnosis and a method for improving the response to therapies based on clinically meaningful outcome parameters. The system may offer a patient-tailored monitoring tool that is based on parameters that are relevant to patients and caregivers and provides a clinically meaningful tool for follow-up. The system can provide an inclusive solution for patients with rare diseases and ensures adherence based on clinical responses. It has the potential advantage of not being dependent on large datasets and is a dynamic system that adapts to ongoing changes in patients’ disease and response to therapy.
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- 2021
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4. The role of chronobiology in drug-resistance epilepsy: The potential use of a variability and chronotherapy-based individualized platform for improving the response to anti-seizure drugs.
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Potruch, Assaf, Khoury, Salim T., and Ilan, Yaron
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Despite progress in the development of anti-seizure drugs, drug-resistant epilepsy (DRE) occurs in a third of patients. DRE is associated with poor quality of life and increased risk of sudden, unexplained death. The autonomic nervous system and chronobiology play a role in DRE. In the present paper, we provide a narrative review the mechanisms that underlie DRE and characterize some of the autonomic- and chronotherapy-associated parameters that contribute to the degree of response to therapy. Variability describes the functions of many biological systems, which are dynamic and continuously change over time. These systems are required for responses to continuing internal and external triggers, in order to maintain homeostasis and normal function. Both intra- and inter-subject variability in biological systems have been described. We present a platform, which comprises a personalized-based machine learning closed loop algorithm built on epilepsy-related signatures, autonomic signals, and chronotherapy, as a means for overcoming DRE, improving the response, and reducing the toxicity of current therapies. [ABSTRACT FROM AUTHOR]
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- 2020
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5. Novel Orally Administered Recombinant Anti-TNF Alpha Fusion Protein for the Treatment of Ulcerative Colitis
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Almon, Einat, Shaaltiel, Yoseph, Sbeit, Wisam, Fich, Alex, Schwartz, Doron, Waterman, Mattitiahu, Szlaifer, Mali, Reuveni, Hadar, Amit-Cohen, Bat-chen, Alon, Sari, Chertkoff, Raul, Paz, Alona, and Ilan, Yaron
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- 2021
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6. Role of the Immune System and the Circadian Rhythm in the Pathogenesis of Chronic Pancreatitis
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Kessler, Asa, Weksler-Zangen, Sarah, and Ilan, Yaron
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Pancreatitis, in both acute and chronic forms, poses a major therapeutic challenge and is associated with great morbidity and several complications. The nature of pancreatic injury in chronic pancreatitis (CP) and the wide range of causative processes that lead to CP have made effective therapy a true unmet need. Multiple physiological, genetic, environmental, and behavioral factors contribute to the development of CP. As a result, several fields of research are aimed at identifying and addressing the factors that contribute to pancreatic injury. In this article, we review the current understanding of the pathogenesis and natural history of CP. We focus on the autonomous nervous system, immune system, and role of a chronobiological therapeutic approach to alleviate symptoms and prevent or reverse pancreatic injury associated with CP. We aim to demonstrate that individualizing chronopharmacological treatments for CP is a promising direction for future treatment using immune, nervous, and circadian systems.
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- 2020
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7. Department of Medicine 2040: Implementing a Constrained Disorder Principle-Based Second-Generation Artificial Intelligence System for Improved Patient Outcomes in the Department of Internal Medicine
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Ilan, Yaron
- Abstract
Internal medicine departments must adapt their structures and methods of operation to accommodate changing healthcare systems. The present paper discusses some challenges departments of medicine face as healthcare providers and consumers continue to change. A co-pilot model is described in this article for augmenting physicians rather than replacing them. The paper presents the co-pilot models to improve diagnoses, treatments, and monitoring. Personalized variability patterns based on the constrained-disorder principle (CDP) are described to assess chronic therapies’ effectiveness in improving patient outcomes. Based on CDP-based enhanced digital twins, this paper presents personalized treatments and follow-ups that improve diagnosis accuracy and therapy outcomes. While maintaining their professional values, departments of internal medicine must respond proactively to the needs of patients and healthcare systems. To meet the needs of patients and healthcare systems, they must strive for medical professionalism and adapt to the dynamic environment.
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- 2023
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8. Immune rebalancing by oral immunotherapy: A novel method for getting the immune system back on track
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Ilan, Yaron
- Abstract
Immune modulating treatments are often associated with immune suppression or an opposing anti‐inflammatory paradigm. As such, there is a risk of exposing patients to infections and malignancies. Contrarily, eliciting only mild immune modulation can be insufficient for alleviating immune‐mediated damage. Oral immunotherapy is a novel approach that uses the inherent ability of the gut immune system to generate signals that specifically suppress inflammation at affected sites, without inducing generalized immune suppression. Oral immunotherapy is being developed as a method to rebalance systemic immunity and restore balance, getting it back on track, rather than pushing the immune response too much or too little in opposing directions. Here, I review recent preclinical and clinical data examining the technique and describe its primary advantages. Review on oral immunotherapy approaches to suppress inflammation without inducing generalized immune suppression.
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- 2019
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9. Reduced liver cell death using an alginate scaffold bandage: A novel approach for liver reconstruction after extended partial hepatectomy.
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Shteyer, Eyal, Ya’acov, Ami Ben, Zolotaryova, Lidia, Sinai, Avital, Lichtenstein, Yoav, Pappo, Orit, Kryukov, Olga, Elkayam, Tsiona, Cohen, Smadar, and Ilan, Yaron
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HEPATECTOMY ,CELL death ,TISSUE scaffolds ,ALGINATES ,LIVER failure ,CELL differentiation - Abstract
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 48h and 6days 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 and alanine aminotransferases 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 48h after hepatectomy. Incorporation of BrdU-positive cells was 30% higher in the alginate-scaffold-treated group, compared with non-treated mice. Serum IL-6 levels were significantly decreased 3h 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. [Copyright &y& Elsevier]
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- 2014
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10. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist, in various rat tissues during the evolution of experimental cholestatic liver disease.
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Avraham, Yosefa, Magen, Iddo, Zolotarev, Olga, Vorobiav, Lia, Nachmias, Avital, Pappo, Orit, Ilan, Yaron, Berry, Elliot M., and Ackerman, Zvi
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CANNABINOIDS ,LABORATORY rats ,HEMODYNAMICS ,BILE ducts ,CREATININE ,POSTOPERATIVE period ,LIVER diseases - Abstract
Abstract: Background/Aim: Changes in tissue levels of 2-arachidonoylglycerol (2-AG), an endocannabinoid, during the evolution of bile duct ligation (BDL) may indicate that endocannabinoids have a role in the hemodynamic changes that occur in this condition. Methods: 2-AG levels, in various organs and vascular beds of BDL rats, 2 and 4 weeks post surgery, were determined. Untouched and sham-operated (SO) rats were used as controls. Results: 2-AG content of a specific organ was not a static finding and depended on the rat''s age, the time from the surgical procedure and the type of procedure. The most pronounced changes were observed in BDL rats 4 weeks post surgery. In these rats, hepatic, pulmonary, cardiac and renal medullary and papillary 2-AG levels were highest observed. No changes in splenic, aortic and renal cortical 2-AG levels were observed. In addition a stepwise increase in 2-AG levels from the cortex to the papilla was detected and was followed by a decrease in creatinine clearance. Conclusions: 2-AG probably has a role in the pathophysiologic changes in the liver, heart, lung and kidney that follows BDL. [Copyright &y& Elsevier]
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- 2008
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11. Immune Therapy for Nonalcoholic Steatohepatitis
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Ilan, Yaron
- 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.
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- 2013
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12. The Gut Mucosa as a Site for Induction of Regulatory T-Cells
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Mizrahi, Meir and Ilan, Yaron
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Regulatory T lymphocytes (Tregs) are specialized for immune suppression and are important regulators of the immune response in various settings. Tregs actively suppress enteroantigen-reactive cells and contribute to the maintenance of intestinal immune homeostasis. Distinct Treg subsets coexist in the intestinal mucosa and mesenteric lymph nodes. Disturbances in Treg number and function are associated with immune-mediated disorders. Therefore, Tregs are potential targets for immunotherapies. The gut mucosal immune system is the largest lymphoid organ in the body. This site has continuous antigenic challenges from food antigens, antigens of the abundant normal bacterial flora, and pathogens. Despite this constant antigenic stimulation, controlled inflammatory responses and suppression of inflammation appear to be the rule. The gut immune system differentiates the antigenic signals from the high background noise of food and bacterial antigens. This tight regulation required to maintain homeostasis is achieved through multiple non-immune and immune factors. Oral tolerance is a mechanism in which the gastrointestinal immune system inhibits or promotes its reaction toward an orally administered antigen. Mucosal tolerance is attractive as an approach to the treatment of autoimmune and inflammatory diseases; the benefits of using an oral tolerance approach are: lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. Multiple mechanisms of tolerance are induced by oral antigen administration. Recent data suggest that oral antigen administration of antigens may promote activation of different types of regulatory T lymphocytes, enabling treatment of immune mediated disorders. This review summarizes the recent data on induction of regulatory T-cells by oral antigen administration as a possible mechanism of oral tolerance.
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- 2009
13. β-Glycoglycosphingolipid-Induced Alterations of the STAT Signaling Pathways Are Dependent on CD1d and the Lipid Raft Protein Flotillin-2
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Lalazar, Gadi, Ya'acov, Ami Ben, Livovsky, Dan M., El Haj, Madi, Pappo, Orit, Preston, Sarah, Zolotarov, Lidya, and Ilan, Yaron
- Abstract
β-glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different β- glycosphingolipids, including β-glucosylceramide, on STAT (signal transducers and activators of transcription) signaling pathways and determined whether these effects were mediated by lipid raft microdomains and/or CD1d molecules. The effects of α- and β-structured ligands on the lipid raft protein flotillin-2 were studied in both natural killer T hybridoma cells and leptin-deficient mice. To determine whether CD1d was involved in the effects of the β-glycosphingolipids, an anti-CD1d blocking antibody was used in a cell proliferation assay system. The downstream effects on the protein phosphorylation levels of STAT1, STAT3, and STAT6 were examined in both immune-mediated hepatitis and hepatoma models. The effects of β-glycosphingolipids on the STAT signaling pathways were found to be dependent on CD1d. Lipid rafts were affected by both the dose and ratio of the β-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that β-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.
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- 2009
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14. Immune modulation by antibodies and antibody receptors
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Tayer-Shifman, Oshrat E and Ilan, Yaron
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Mucosal immunoregulation involves the unique cross-talk between epithelial cells and various immune system components. Mucosal secretions contain significant quantities of immunoglobulin (Ig) G. The neonatal Fc receptor for IgG (FcRn) is important in regulating host IgG levels and in transporting IgG and its associated antigens across polarized epithelial barriers. Through its ability to secrete and absorb IgG, FcRn integrates its encounters with luminal antigens with the systemic immune compartments. The FcRn thereby provides essential host defense and immunoregulatory functions at mucosal surfaces. In this review, we examine recent data on the use of FcRn and anti-CD3 for immune modulation. Recent preclinical studies have revealed the significant efficacy of using FcRn or orally administered antibodies as a means of immune modulation. For example, the oral administration of anti-CD3 was recently shown to be effective in the prevention and treatment of several animal models of immune-mediated disorders. In addition, the use of FcRn or orally administered antibodies were recently described in two patents as potential methods for inducing systemic tolerance and for treating immune-mediated disorders. The FcRn patent generally discussed the methods and products for initiating an immune response against an antigen. In particular, this patent described the trans-epithelial delivery of antigens to provoke tolerance and immunity. The anti-CD3 patent emphasized the advantages of an oral route of administration compared to a parenteral one. These advantages included easier chronic use and a reduction in the side effects that are associated with the parenteral use of anti-CD3.
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- 2008
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15. β-Glycosphingolipids-mediated lipid raft alteration is associated with redistribution of NKT cells and increased intrahepatic CD8+T lymphocyte trapping
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Lalazar, Gadi, Ben Ya'acov, Ami, Eliakim-Raz, Noa, Livovsky, Dan M., Pappo, Orit, Preston, Sarah, Zolotarov, Lidya, and Ilan, Yaron
- Abstract
The aim of this study was to determine the effect of β-glycosphingolipids on intra-hepatic natural killer T (NKT) lymphocyte regulatory function and on lymphocyte trapping via alteration of cell membrane lipid rafts. Immune-mediated colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid. Mice were treated with β-lactosylceramide (LC), β-glucosylceramide (GC), β-galactosylceramide, ceramide, or a combination of both GC and LC (IGL), or solvent alone. Lipid rafts were investigated by fluorescence-activated cell sorting analysis of ganglioside-GM1 and fluorescence microscopy of structure. Administration of β-glycosphingolipids resulted in an increased intrahepatic/peripheral NKT ratio, increased intrahepatic CD8+ lymphocyte trapping, decreased serum interferon-γ (IFN-γ) levels and decreased serum IFN-γ/interleukin-10 ratio. Administration of GC, LC, or IGL significantly altered the levels of GM1, a key marker of lipid rafts, on NKT regulatory lymphocytes. The immune modulatory effect of β-glycosphingolipids was associated with increased survival and significant alleviation of colitis as determined by improvement in both the macroscopic and microscopic scores. In conclusion, administration of β-glycosphingolipids increased NKT regulatory lymphocyte redistribution and intrahepatic CD8+T lymphocyte trapping, resulting in alleviation of immune-mediated colitis. The effects of these naturally occurring compounds were associated with modification of the T lymphocyte lipid raft structure, which is a site for immune modulation.
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- 2008
16. β-Glycosphingolipids-mediated lipid raft alteration is associated with redistribution of NKT cells and increased intrahepatic CD8+T lymphocyte trapping
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Lalazar, Gadi, Ben Ya'acov, Ami, Eliakim-Raz, Noa, Livovsky, Dan M., Pappo, Orit, Preston, Sarah, Zolotarov, Lidya, and Ilan, Yaron
- Abstract
The aim of this study was to determine the effect of β-glycosphingolipids on intra-hepatic natural killer T (NKT) lymphocyte regulatory function and on lymphocyte trapping via alteration of cell membrane lipid rafts. Immune-mediated colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid. Mice were treated with β-lactosylceramide (LC), β-glucosylceramide (GC), β-galactosylceramide, ceramide, or a combination of both GC and LC (IGL), or solvent alone. Lipid rafts were investigated by fluorescence-activated cell sorting analysis of ganglioside-GM1 and fluorescence microscopy of structure. Administration of β-glycosphingolipids resulted in an increased intrahepatic/peripheral NKT ratio, increased intrahepatic CD8+ lymphocyte trapping, decreased serum interferon-γ (IFN-γ) levels and decreased serum IFN-γ/interleukin-10 ratio. Administration of GC, LC, or IGL significantly altered the levels of GM1, a key marker of lipid rafts, on NKT regulatory lymphocytes. The immune modulatory effect of β-glycosphingolipids was associated with increased survival and significant alleviation of colitis as determined by improvement in both the macroscopic and microscopic scores. In conclusion, administration of β-glycosphingolipids increased NKT regulatory lymphocyte redistribution and intrahepatic CD8+T lymphocyte trapping, resulting in alleviation of immune-mediated colitis. The effects of these naturally occurring compounds were associated with modification of the T lymphocyte lipid raft structure, which is a site for immune modulation.
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- 2008
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17. Sulfatides for the treatment of autoimmune disorders
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Ya'acov, Ami Ben, Lalazar, Gadi, and Ilan, Yaron
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Natural killer T (NKT) cells are a subset of immune regulatory cells. Several glycolipids and phospholipids derived from mammalian, bacterial, protozoan and plant species have recently been identified as possible natural ligands for NKT cells. One such compound, sulfatide, which is a major glycolipid of myelin, has been shown to modulate NKT cell activity. This patent application claims to ameliorate or prevent symptoms of immune related disorders by application of sulfatides. Although preclinical studies have effectively targeted NKT cells for immunotherapy, little is known regarding the early in vivoresponse of these cells to antigenic stimulation. The data in support of the present patent may suggest that the naturally β-anomeric glycosphingolipids (sulfatides) may be ligands for NKT lymphocytes.
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- 2007
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18. Alleviation of Acute and Chronic Graft-Versus-Host Disease in a Murine Model Is Associated with Glucocerebroside-Enhanced Natural Killer T Lymphocyte Plasticity
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Ilan, Yaron, Ohana, Meir, Pappo, Orit, Margalit, Maya, Lalazar, Gadi, Engelhardt, Dean, Rabbani, Elazar, and Nagler, Arnon
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Natural killer T (NKT) lymphocytes play a role in graft-versus-host disease GVHD (GVHD). Glucocerebroside (GC) is a naturally occurring glycolipid that plays a role in the immune modulation of NKT lymphocytes. This study aims to determine the effect of GC in murine models of semiallogeneic/acute and chronic GVHD.
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- 2007
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19. Glycolipids as Immune Modulatory Tools
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Lalazar, Gadi, Preston, Sarah, Zigmond, Ehud, Ben Yaacov, Ami, and Ilan, Yaron
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NKT cells are a subset of regulatory lymphocytes characterized by co-expression of the NK cell receptor- CD161 and an invariant TCR-α chain (Vα14-Jα28). They are most abundant in the liver, spleen, and bone marrow. NKT lymphocytes have been implicated in the regulation of autoimmune processes in both mice and humans. Activation of NKT lymphocytes leads to rapid amplification of either IFNγ or IL4, endowing these cells with the capability to mediate both pro-inflammatory and anti-inflammatory immune responses. Activation of this subset of cells is associated with significant liver damage in the Concanavalin A immune mediated hepatitis model. Administration of CD1d ligand has a protective role in collagen-induced arthritis in mice. Disease amelioration was associated with a shift in the immune balance from a pathological Th1 type response towards a protective Th2 type response. In humans, patients with SLE, scleroderma, diabetes, multiple sclerosis, and rheumatoid arthritis have lower numbers of peripheral NKT cells. NKT lymphocytes promote tumor rejection in experimental models of tumor immunotherapy. In contrast, NKT lymphocyterelated anti-tumor activity is associated with pro-inflammatory Th1-type immune responses. NKT cells were shown to have a role in suppression of hepatocellular carcinoma (HCC) via immune regulation towards tumor derived antigens, and adoptive transfer of dendritic cells pulsed ex vivo with the same antigens. NKT lymphocytes are activated by interaction of their TCR with glycolipids presented by CD1d, a nonpolymorphic, MHC class I-like molecule expressed by antigen presenting cells, and also by hepatocytes. Several possible ligands for NKT cells have recently been suggested including CD1d bound Glucocerebroside. Glucocerebroside (GC, β- glucosylceramide), a naturally occurring glycolipid, is a metabolic intermediate in the anabolic and catabolic pathways of complex glycosphingolipids. Its synthesis from ceramide is catalyzed by the enzyme glucosylceramide synthase. Inherited deficiency of glucocerebrosidase, a lysosomal hydrolase, results in Gaucher's disease. Patients with Gaucher's disease have altered humoral and cellular immune profiles and increased peripheral blood NKT lymphocytes. CD1d-bound glucocerebroside does not activate NKT cells directly, and may inhibit activation of NKT cells by α-GalCer. On the other hand, glucosylceramide-synthase deficiency was shown to lead to defective ligand presentation by CD1d, with secondary inhibition of NKT cell activation. Recent studies have suggested that a number of glycolipids, including GC, have an immune modulatory effect in several immune mediated disorders. The ability to alter NKT lymphocyte function in various settings and the potential application of natural glycolipids for treatment are discussed.
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- 2006
20. Glucocerebroside Ameliorates the Metabolic Syndrome in OB/OB Mice.
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Margalit, Maya, Shalev, Zvi, Pappo, Orit, Sklair-Levy, Miriam, Alper, Ruslana, Gomori, Moshe, Engelhardt, Dean, Rabbani, Elazar, and Ilan, Yaron
- Abstract
Glucocerebroside (GC) is a naturally occurring glycolipid that may alter natural killer T (NKT) cell function. To determine the effect of GC on the metabolic derangements and immune profile in leptin-deficient mice, Ob/Ob mice were treated by daily injections of GC for 8 weeks and followed for various metabolic and immunological parameters. Marked amelioration of the metabolic alterations characteristic of leptin-deficient mice was observed in GC-treated animals compared with controls. A significant decrease in liver size and hepatic fat content were observed in GC-treated mice. Near-normalization of glucose tolerance and decreased serum triglyceride levels were observed. Fluorescence-activated cell sorting analysis of peripheral and intrahepatic lymphocytes revealed a 1.6-fold increase of the peripheral/intrahepatic NKT lymphocyte ratio. A 33% decrease of serum interferon-gamma level and a 2.6-fold increase of serum interleukin 10 level were noted in GC-treated mice. Immune modulation by GC may have a role in the treatment of nonalcoholic steatohepatitis and other immune-mediated disorders.
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- 2006
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21. Histamine dihydrochloride: actions and efficacy in the treatment of chronic hepatitis C infection
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Lalazar, Gadi and Ilan, Yaron
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The host immune response, in addition to viral factors, is the critical determinant of the pathological consequences of hepatitis C virus infection. Current therapies for genotype 1 are unsuccessful in a substantial number of patients. Histamine dihydrochloride by virtue of its histamine H2agonistic activity, has the potential to prevent damage induced by oxidative stress in tissues and can protect T and natural killer lymphocytes from oxygen radical-induced functional inhibition and apoptosis, thereby, potentiating interferon-α-induced activation of these cells. Coadministration of histamine dihydrochloride and interferon therapy for chronic hepatitis C virus infection was tested in several clinical trials. However, conflicting data and the relatively small numbers of patients enrolled, suggest that this combination should be the focus of further investigation.
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- 2006
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22. Treatment of Chronic Hepatitis C Virus Infection via Antioxidants
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Melhem, Alla, Stern, Mirela, Shibolet, Oren, Israeli, Eran, Ackerman, Zvi, Pappo, Orit, Hemed, Nilla, Rowe, Mina, Ohana, Hana, Zabrecky, George, Cohen, Robert, and Ilan, Yaron
- Abstract
The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection.
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- 2005
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23. REDUCED INCIDENCE OF HYPERURICEMIA, GOUT, AND RENAL FAILURE FOLLOWING LIVER TRANSPLANTATION IN COMPARISON TO HEART TRANSPLANTATION A LONG-TERM FOLLOW-UP STUDY
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Shibolet, Oren, Elinav, Eran, Ilan, Yaron, Safadi, Rifaat, Ashur, Yaffa, Eid, Ahmed, Zamir, Gideon, Fridlander, Michael, Bdolah-Abram, Tali, Shouval, Daniel, and Admon, Dan
- Abstract
Hyperuricemia and gout are common complications of heart transplantation, reaching a prevalence of 84 and 30, respectively, in heart transplant recipients. In contrast, they are seldom reported following orthotopic liver transplantation (OLT).
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- 2004
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24. Adoptive transfer of ex vivo immune‐programmed NKT lymphocytes alleviates immune‐mediated colitis
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Shibolet, Oren, Kalish, Yossef, Klein, Athalia, Alper, Ruslana, Zolotarov, Lydia, Thalenfeld, Barbara, Engelhardt, Dean, Rabbani, Elazar, and Ilan, Yaron
- Abstract
T lymphocyte‐expressing natural killer (NK) cell markers (NKT cells) play a role in immune regulation. Our aim was to evaluate the in vivo effect of adoptive transfer of immune‐programmed NKT cells. Colitis was induced in C57/B6 mice by 2,4,6‐trinitrobenzenesulfonic acid. NKT, CD4, CD8 lymphocytes, and dendritic cells (DC) were prepared from spleens of naive mice, animals with colitis, and animals with colitis that were orally tolerized. Subsets of splenocytes, NKT, CD4, and CD8 and NKT+CD4, NKT+CD8, and NKT+DC lymphocytes were prepared. Assessment of the T helper cell type 1 (Th1)/Th2 cytokine secretion paradigm in vitro was performed before and following exposure to the antigen. Adoptive transfer of ex vivo immune‐programmed lymphocytes from each group was performed into recipient mice, followed by colitis induction. Ex vivo exposure of NKT cells harvested from mice with colitis‐to‐colitis proteins [colitis‐extracted proteins (CEP)] led to a Th2 cytokine shift. The interleukin (IL)‐4/interferon‐γ (IFN‐γ) ratio increased for NKT harvested from colitis‐harboring mice following exposure to CEP. Adoptive transfer of NKT lymphocytes harvested from colitis‐harboring mice, which were ex vivo‐educated, significantly alleviated experimental colitis in vivo. Intrahepatic NKT lymphocytes increased significantly in mice transplanted with NKT lymphocytes harvested from colitis‐harboring donor mice, which were ex vivo‐exposed to CEP, similar to mice transplanted with NKT lymphocytes harvested from tolerized donors. Exposure of NKT cells to the disease‐target antigen induced a significant increase in the IL‐4/IFN‐γ cytokine ratio. Adoptive transfer of a relatively small number of immune‐programmed NKT cells induced a systemic Th1 to Th2‐immune shift and alleviated immune‐mediated colitis.
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- 2004
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25. Malignancy After Liver Transplantation in Patients With Premalignant Conditions
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Menachem, Yoram, Safadi, Rifaat, Ashur, Yaffa, and Ilan, Yaron
- Abstract
Liver transplant recipients are at increased risk of developing nonhepatic malignant tumors. The aim of the current study was to evaluate the role of premalignant states, not associated with the liver disease prior to transplantation, in the development of posttransplantation malignancy.
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- 2003
26. Late cytomegalovirus disease following liver transplantation
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Shibolet, Oren, Ilan, Yaron, Kalish, Yosef, Safadi, Rifaat, Ashur, Yaffa, Eid, Ahmed, Shouval, Daniel, and Wolf, Dana
- Abstract
The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eighty-one consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5--9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26--60, median: 59 years). There was no association between the development of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir, two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.
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- 2002
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27. NK 1.1+T Cell: A Two-Faced Lymphocyte in Immune Modulation of the IL-4/IFN-γ Paradigm
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Trop, Shivti and Ilan, Yaron
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T lymphocytes expressing NK1.1 marker (NK1.1+) have been suggested as being important in peripheral immune modulation. Alteration of the balance between Th1 proinflammatory and Th2 anti-inflammatory cytokine-producing cells can ameliorate immune-mediated disorders. The aim of the study was to determine the role of NK1.1+lymphocytes in the pathogenesis of tolerance and proinflammatory states and to determine their role in altering the Th1/Th2 balance in experimental colitis. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS colitis colonic wall. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Liver-associated lymphocytes and splenocytes were harvested 14 days following tolerance induction. Depletion of NK 1.1+ lymphocytes was performed 36 hr before lymphocyte harvesting. Lymphocytes were cultured for 12 hr with Con A and colitis extracted proteins. To evaluate the role of NK1.1+lymphocytes in keeping a balance between immunogenic and tolerogenic subsets of cells, intracellular staining and flow cytometry assays were performed in tolerized and nontolerized mice. IL-4, IL-12, and IFN-γ levels were measured by ELISA. Administration of mouse-derived colitis-extracted proteins ameliorated experimental colitis. Tolerized mice exhibited significant improvement in all macroscopic and microscopic parameters for colitis. Depletion of NK1.1 following tolerance induction significantly decreased the CD4+IL-4+/CD4+IFN-γ+ratio in tolerized mice. However, depletion of NK1.1 lymphocytes in nontolerized mice increased the CD4+IL-4+/CD4+IFN-γ+ratio, compared with nondepleted nontolerized mice. Induction of tolerance led to an increase in IL4 and a decrease in IFN-γ levels. In the experimental colitis model NK1.1+ lymphocytes play a dual role: In the presence of peripheral tolerance they may be accountable for keeping the high CD4+IL-4+/CD4+IFN-γ+ratio and disease alleviation. However, in nontolerized conditions they may induce a proinflammatory shift.
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- 2002
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28. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers
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Shibolet, Oren, Ilan, Yaron, Gillis, Shmuel, Hubert, Ayala, Shouval, Daniel, and Safadi, Rifaat
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Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.
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- 2002
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29. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers
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Shibolet, Oren, Ilan, Yaron, Gillis, Shmuel, Hubert, Ayala, Shouval, Daniel, and Safadi, Rifaat
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Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.
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- 2002
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30. Prognosis of Symptomatic Versus Asymptomatic Autoimmune Hepatitis
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Kogan, Jacob, Safadi, Rifat, Ashur, Yaffa, Shouval, Daniel, and Ilan, Yaron
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Autoimmune hepatitis (AIH) is a chronic liver disorder of unknown etiology. Disease presentation ranges from asymptomatic to symptomatic onset, fulminant, acute, or chronic.
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- 2002
31. Inducing oral immune regulation of hepatitis B virus envelope proteins suppresses the growth of hepatocellular carcinoma in mice
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Gotsman, Israel, Alper, Ruslana, Klein, Athalia, Rabbani, Elazar, Engelhardt, Dean, and Ilan, Yaron
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Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) expresses hepatitis B surface antigen (HBsAg) on its cell surface, and this may serve as a tumor-associated antigen. It was shown previously that adoptive transfer of immunity against HBsAg facilitates the suppression of experimental human HCC-expressing HBsAg in athymic mice. The authors recently showed that it was possible to augment the anti-HBV immune response through induction of oral immune regulation for HBV-associated antigens. The objective of this study was to evaluate the effect of oral immune regulation for HBV antigens on the growth of HBsAg-expressing HCC. Recipient athymic Balb/c mice were irradiated sublethally and injected with 10
7 human hepatoma cells followed by the adoptive transfer of 2 × 106 splenocytes from donor mice. Four groups of donor Balb/c mice were studied: Two groups were immune modulated through oral administration of HBV antigens (HBsAg, PreS1, and Pre S2) or bovine serum albumin (BSA). Two control groups were immunized for HBsAg and fed HBV antigens or BSA. Recipient mice were followed for tumor volume and serum α-fetoprotein (αFP) levels. The humoral immune response was determined by measuring serum HBs antibodies. HBV specific T-cell immune modulation was assessed in vitro by HBV specific T-cell proliferation and interferon γ (IFNγ) ELISPOT assays as well as cytokine expression by reverse transcriptase-polymerse chain reaction assays. The adoptive transfer of orally immune modulated HBV splenocytes induced complete tumor suppression in recipient mice compared with control mice transplanted with nonimmune modulated cells (BSA), which showed significant tumor growth (serum αFP levels were 3.5 ng/mL and 2320.0 ng/mL, respectively). Control mice transplanted with anti-HBs immunized cells (with or without oral immune modulation) manifested similar tumor suppression (3.5 ng/mL and 0.5 ng/mL, respectively). Immunoregulation for HBV antigens augmented the HBV specific T-cell immune response, as manifested by an increase in HBV specific T-cell proliferation and IFNγ ELISPOT assays in mice orally immune regulated with HBV proteins compared with naïve mice. Tumor suppression was mediated through increased IFNγ production in immune regulated and immunized mice. The induction of oral immune regulation for HBV antigens modulated the antitumor immune response, thus suppressing the growth of HCC in mice. This effect was mediated by the enhancement of anti-HBV specific T-cell immunity. Cancer 2002;94:40614. © 2002 American Cancer Society.- Published
- 2002
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32. Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice
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Gotsman, Israel, Israeli, David, Alper, Ruslana, Rabbani, Elazar, Engelhardt, Dean, and Ilan, Yaron
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Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) was previously shown to facilitate suppression of experimental human hepatocellular carcinoma (HCC) expressing HBsAg in athymic mice. We have shown that oral tolerance induces antigen-specific immune suppression of HBsAg by feeding hepatitis B virus (HBV) antigens. In the present study we evaluated the effect of oral tolerance induction toward HBV or HCC antigens on the growth of experimental HCC-expressing HBsAg in mice. Tolerance induction was induced in mice by 5 oral feedings of 1 μg HBV antigens or HCC-extracted proteins (50 μg protein) before vaccination with recombinant HBsAg. Splenocytes (2 × 106) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 107 human hepatoma Hep3B cells. Adoptive transfer of splenocytes immunized toward HBsAg prevented tumor growth. At 4 weeks after splenocyte transplantation, tumor volume and serum alpha-fetoprotein (AFP) levels in athymic mice transplanted with splenocytes immunized to HBsAg were undetectable as compared with 1,048 ± 738 mm3 and 2,500 ± 1,431 ng/ml in recipients of naïve splenocytes (p < 0.0001). Mice receiving splenocytes tolerized toward Hep3B cells, as manifested by reduced serum HBs antibody levels, reduced HBV-specific stimulation index and reduced HBV-specific-IFNγ spot-forming cells, had early tumor growth evident by elevated AFP serum levels, weight loss and mortality, which were suppressed at 6 weeks. Mice transplanted with splenocytes tolerized toward HBV antigens did not have direct evidence of tumor growth. Induction of oral tolerance toward HCC-extracted proteins enabled transient tumor growth in this model. This effect was mediated through downregulation of the anti-HBV immune response. © 2002 Wiley-Liss, Inc.
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- 2002
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33. Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens – bystander effect
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Shlomai, Amir, Trop, Shivti, Gotsman, Israel, Jurim, Oded, Diment, Judith, Alper, Ruslana, Rabbani, Elazar, Engelhardt, Dean, and Ilan, Yaron
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The imbalance between Th1 pro‐inflammatory and Th2 anti‐inflammatory cytokine‐producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis‐extracted proteins was previously shown to down‐regulate the anti‐colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver‐associated lymphocytes expressing the NK1.1 marker (NK1.1+LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non‐inflammatory colon‐extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1+LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS‐colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon γ (IFNγ) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1+LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non‐tolerized‐mice. The administration of mouse‐derived colitis‐extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNγ serum levels. NK1.1+LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNγ and a decrease in IL10 serum levels, and down‐regulation of NK1.1+LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1+LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance. Copyright © 2001 John Wiley & Sons, Ltd.
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- 2001
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34. Amelioration of Steroid-Resistant Chronic Graft-Versus-Host-Mediated Liver Disease Via Tacrolimus Treatment
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Nagler, Arnon, Menachem, Yoram, and Ilan, Yaron
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Liver disease associated with chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity. Steroids and cyclosporin (CSA), which are the standard therapy, give rather disappointing results, and toxicity is high. Tacrolimus (FK506) is a potent macrolide lactone immunosuppressant that is used in the prevention of solid organ rejection. This study evaluated the therapeutic role of FK506 in the treatment of severe cGVHD-mediated liver disease that did not respond to combined steroids and CSA therapy. Fifteen patients with various hematological disorders who underwent allogeneic stem cell transplantation were enrolled in the study. All patients had severe cholestatic liver disease disturbances and underwent liver biopsy, which was compatible with cGVHD-mediated liver disease. All the patients were negative for markers of chronic liver disease, including viral serology. They received FK506 orally (4–20 mg/day according to serum levels), and were evaluated biweekly by physical examination and liver function tests. Patients were followed for a median of 12 months (range 3–24 months). FK506 treatment ameliorated liver functions in 9 of 15 patients (60%), 5 of whom demonstrated complete normalization of liver enzymes (33%). In 5 patients, no major effect was observed, and 1 patient showed deterioration of his liver functions. Mean GGT levels decreased from 171.5 to 55.6 within 6 months of treatment. Median time to response was 3 months (range 1–11). Side effects were generally transient. Treatment with FK506 was found to be effective in the majority of patients with steroid and CSA-resistant cGVHD-associated liver disease, with manageable side effects. In view of these findings, FK506 may yet evolve into first line therapy for cGVHD induced liver toxicity.
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- 2001
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35. Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model
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Ilan, Yaron, Gotsman, Israel, Pines, Mark, Beinart, Roy, Zeira, Michael, Ohana, Meir, Rabbani, Elazar, Engelhardt, Dean, and Nagler, Arnon
- Abstract
Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5?×?107splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen ?1(I) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFN? was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD.
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- 2000
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36. Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model
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Ilan, Yaron, Gotsman, Israel, Pines, Mark, Beinart, Roy, Zeira, Michael, Ohana, Meir, Rabbani, Elazar, Engelhardt, Dean, and Nagler, Arnon
- Abstract
Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 × 107splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen α1(I) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFNγ was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD.
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- 2000
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37. TT Virus Infection in Israeli Patients with Fulminant Hepatic Failure
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Safadi, Rifaat, Ergunay, Koray, Ilan, Yaron, Klein, Athalia, Shouval, Daniel, Manny, Noga, Harush, Nissim, and Galun, Eithan
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- 2000
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38. Orally administered anti-eotaxin-1 monoclonal antibody is biologically active in the gut and alleviates immune-mediated hepatitis: A novel anti-inflammatory personalized therapeutic approach
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Khoury, Tawfik, Rotnemer-Golinkin, Dory, Zolotarev, Lidya, and Ilan, Yaron
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Personalized therapies are designed to optimize the safety-to-efficacy ratio by selecting patients with higher response rates based on specific biomarkers. Inflammation plays a vital role in the pathogenesis of non-alcoholic steatohepatitis (NASH), a common liver disorder. Eotaxin-1 plays a role in innate and adaptive immune responses. High eotaxin-1 levels are associated with diabetes and fatty liver disease and, therefore, serves as a biomarker for patient selection. The anti-eotaxin-1 monoclonal antibody is tailored for the personalized therapy of patients with inflammatory conditions due to high levels of eotaxin-1. To evaluate the biological activity and immunomodulatory effect of orally administered anti-eotaxin-1. C57B1/6 mice were treated with either oral or intra-peritoneal anti-eotaxin-1 antibody before induction of immune-mediated hepatitis using an injection of concanavalin A (ConA) and checked for liver injury and eotaxin-1 serum levels. Oral administration of anti-eotaxin-1 alleviated the immune-mediated liver injury. Serum alanine aminotransferase levels decreased to 1807 U/L, compared with 19025 U/L in untreated controls and 3657 U/L in mice treated with parenteral anti-eotaxin-1 (P< 0.005). A trend toward reduced serum eotaxin-1 levels was observed in treated mice, ranging from 594 pg/mL in the controls to 554 and 561 pg/mL in mice treated orally and intraperitoneally (P= 0.08, P= 0.06, respectively). Oral administration of anti-eotaxin-1 antibody shows biological activity in the gut and exerts a systemic immunomodulatory effect to alleviate immune-mediated hepatitis. The data suggest that testing for eotaxin-1 serum levels may enable screening patients with high-eotaxin-1 levels-associated NASH.
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- 2021
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39. The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways
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Ishay, Yuval, Rotnemer-Golinkin, Dvorah, and Ilan, Yaron
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Background:Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim:To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods:Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results:While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions:Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.
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- 2021
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40. Adenovirus-mediated Gene Therapy of Liver Diseases
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Ilan, Yaron, Saito, Hidetsugu, Thummala, Narsing R., and Chowdhury, Namita Roy
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- 1999
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41. IgA Deficiency Associated With Chronic Hepatitis C Virus Infection: A Cause or an Effect?
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Ilan, Yaron, Shouval, Daniel, Ashur, Yaffa, Manns, Michael, and Naparstek, Yaakov
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OBJECTIVE: To evaluate the role of IgA in hepatitis C virus (HCV) infection. We have tested serum IgA levels in patients with antibodies to HCV. DESIGN: A retrospective study. PATIENTS: The IgA levels were tested in serum samples from 94 patients with antibodies to HCV examined during 1989-1990. RESULTS: Low IgA levels were found in 16/94 (17%) patients. In three of these 16 patients (3.2% of the original 94), no IgA was detected by radial immunodiffusion. In nine of 16 patients, previous pre-HCV infection serum samples with undetectable anti-HCV antibodies were available. In four of these nine patients, IgA deficiency was found in the preinfection serum, while in the remaining five patients, previous IgA levels were normal and the occurrence of anti-HCV was associated with the recent development of IgA deficiency. CONCLUSIONS: The results of this study indicate that IgA deficiency is a risk factor for HCV infection in some patients, whereas in others it might be caused by the viral disease.(Arch Intern Med. 1993;153:1588-1592)
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- 1993
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42. Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis B virus*
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Levy, Micha, Leibowich, Igal, Zylber-Katz, Ester, Ilan, Yaron, Granit, Liora, Sviri, Sigal, and Caraco, Yoseph
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Background: The pharmacokinetics of a number of drugs has been shown to be impaired in patients with acute or chronic viral liver disease.Objective: To examine the effect of the asymptomatic hepatitis B virus carrier state on the metabolism of dipyrone (INN, metamizole) as a model drug.Methods: The pharmacokinetics of the metabolites of dipyrone—4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine—after a 1.0 gm oral dose of dipyrone were evaluated in nine asymptomatic carriers of hepatitis B virus with normal liver function tests and nine healthy subjects. All subjects displayed the slow acetylator phenotype.Results: The nonrenal (metabolic) clearance of 4-methylaminoantipyrine was significantly reduced (mean ± SEM) (123.3 ± 15.8 versus 182.9 ± 15.1 ml · min−1, respectively; p < 0.02) in the carriers of hepatitis B virus compared with the healthy subjects, and the elimination half-life of this metabolite was significantly longer (3.69 ± 0.35 versus 2.64 ± 0.28 hours, respectively; p < 0.03). The formation clearances of 4-aminoantipyrine and 4-formylaminoantipyrine were significantly smaller in the carriers of hepatitis B virus compared with healthy subjects (33.8 ± 6.2 versus 55.2 ± 6.4 ml · min−1; p < 0.03, and 16.7 ± 2.2 versus 34.2 ± 4.2 ml · min−1; p < 0.002, respectively). However, the elimination half-life of 4-formylaminoantipyrine was found to be slightly shorter in the carriers of hepatitis B virus. No significant differences were noted between the groups in the pharmacokinetics of 4-acetylaminoantipyrine.Conclusion: The metabolism of dipyrone is impaired in asymptomatic carriers of hepatitis B virus. Clinically latent infection with hepatitis B virus seems to exert a differential effect on metabolism of the drug. Oxidative pathways to produce 4-aminoantipyrine and 4-formylaminoantipyrine were significantly affected, whereas acetylation remained intact. This study provided an additional example of the effect of a virus on the disposition of a drug.
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- 1997
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43. Case Series: Hyponatremia Associated With Moderate Exercise
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Zelingher, Julian, Putterman, Chaim, Ilan, Yaron, Dann, Eldad J., Zveibil, Fabio, Shvil, Yigal, and Galun, Eithan
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Exercise-induced hyponatremia is commonly believed to be associated only with extraordinary physical efforts, or particularly strenuous exercise. Hyponatremia complicating moderate exercise has not been described previously. The authors describe the characteristics of seven patients with life-threatening hyponatremia associated with mild to moderate exercise. All patients suffered from nausea, vomiting, agitation, and confusion, appearing during or after moderate physical activity. Grand mal convulsions occurred in five of the patients. In laboratory results, hyponatremia was as low as 115 mEq/L, with a relatively high sodium concentration in the urine. High serum creatine kinase activity levels were found in most of the patients. All patients were discharged in good condition, without neurologic sequela. The authors conclude that hyponatremia is a possible complication of moderate exercise, and not only of endurance sports, and that exercise-induced hyponatremia can produce severe neurologic manifestations. The mechanism of the hyponatremia is unclear, but may be due to a hemodynamically inappropriate stimulus for antidiuretic hormone secretion.
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- 1996
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44. Impaired liver function tests in patients treated with antithymocyte globulin: Implication for liver transplantation
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Toren, Amos, Ilan, Yaron, Or, Reuven, Kapelushnik, Joseph, and Nagler, Arnon
- Abstract
Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day — 1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 ± 37.7 U/l pre-treatment to 1394.4 ± 488.7 U/l 3 days post-treatment (n= 16;p< 0.029), and then declined to 561.4 ± 61.3 U/l 10 days post-treatment (n= 16;p< 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 ± 11.3 U to 184.6 ± 74.6 U (n= 16;p< 0.036), and then declined to 121.9 ± 61.3 U (n= 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 ± 5.7 U to 152.0 ± 67.0 U (n= 16;p< 0.44) and then declined to 46.0 ± 14 (n= 16;p< 0.049). The mean r-glutamyltransferase (GTP) levels increased from 93.0 ± 34 to 188.0 ±36 (n= 16;p< 0.02), and were 168.0 ± 37.0 at day +10 (n= 16; NS). The mean bilirubin levels increased from 18.0 ± 1.9μMI-1to 22.7 ± 2.8 (n= 16); NS), at day +3 and to 31.9 ± 6.9 at day +10 (n= 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.
- Published
- 1997
- Full Text
- View/download PDF
45. MASSIVE REPOPULATION OF RAT LIVER BY TRANSPLANTATION OF HEPATOCYTES INTO SPECIFIC LOBES OF THE LIVER AND LIGATION OF PORTAL VEIN BRANCHES TO OTHER LOBES1
- Author
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Ilan, Yaron, Roy Chowdhury, Namita, Prakash, Renu, Jona, Vinod, Attavar, Preeti, Guha, Chandan, Tada, Kouji, and Roy Chowdhury2, Jayanta
- Abstract
An important consideration in application of hepatocyte transplantation is whether the number of engrafted hepatocytes is sufficient to achieve the desired effect. Here we have evaluated the proliferative potential of transplanted primary hepatocytes during regeneration of hepatic lobes. Two million hepatocytes isolated from congeneic normal Wistar-RHA rats were injected into the main portal vein of deficient, jaundiced Gunn rats. The right branch of the portal vein was ligated 24 hr before hepatocyte transplantation (group A) or transiently clamped during hepatocyte injection (group B) or 24 hr after hepatocyte injection (group C). In these groups, the three lobes supplied by the right branch of the portal vein rapidly atrophied and disappeared in 4 days, whereas the remaining lobes proliferated, as shown by size increase and 5-bromo-2-deoxy-uridine uptake. Two control groups received 2 million (group D) or 20 million hepatocytes (group E) without ligation. Hepatocyte engraftment occurred in all groups. The greatest hypobilirubinemic effect was observed in group A, in which serum bilirubin concentrations were reduced to 1.7±0.45 mg/dl from pretransplantation levels of 6.9±1.2 mg/dl. This effect was even greater than that observed after transplantation of 20 times more hepatocytes without ligation (group E). Specific endonuclease digestion of a polymerase chain reaction-amplified segment of the ugt1gene from hepatic DNA showed that up to 25% of the DNA was of donor origin. This paralleled the hepatic bilirubin-UDP-glucuronosyl-transferase activity, which was above 50% of normal. The results indicate that the transplanted hepatocytes proliferate preferentially within the regenerating lobes, replacing more than 20% of the liver mass with the progency of the transplanted phenotypically normal hepatocytes.
- Published
- 1997
46. SYSTEMIC CHIMERISM IN SEXMISMATCHED LIVER TRANSPLANT RECIPIENTS DETECTED BY FLUORESCENCE IN SITU HYBRIDIZATION
- Author
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NAGLER, ARNON, ILAN, YARON, AMIEL, ALISA, EID, AHMED, and TUR-KASPA, RAN
- Abstract
Fluorescent in situ hybridization (FISH) is a reliable, rapid, sensitive, and quantitative method for detection of residual host cells following sex-mismatched bone marrow transplantation. Recently, donor-derived long-term multilineage hematopoiesis was detected in a sex-mismatched liver transplant recipient. We therefore assessed chimeric status in 12 patients (F 9, M 3), mean age 42.5 years (range 16–57), for a median period of 18 months (range 7–32) following sex-mismatched liver transplantation. Peripheral blood he-matolymphoid cells were hybridized with Y- or X-chro-mosome fluorescently labeled specific probes, and the donor-typed hematopoietic cells were enumerated. In two F recipients 4–5 male hematolymphoid cells were detected in the peripheral blood at 15 and 22 months after sex-mismatched liver transplantation, respectively. These two patients with systemic chimerism suffered from primary biliary cirrhosis and fulminant Wilson's disease before transplantation. One of them had evidence of graft rejection only once during the posttransplant course and the other had no episode of graft rejection. Two other female patients who were found to have ∼2 male hematolymphoid cells, which is considered to be in the false-positive range, also had no signs of graft rejection during the post-transplant follow-up period. Among the remaining eight patients, in whom systemic chimerism was un-detectable, there was at least one episode of acute cellular rejection during the posttransplant period. In summary, the FISH technique enables us to detect systemic chimerism following sex-mismatched liver allografts. Inasmuch as balanced systemic chimerism after organ transplantation is of major importance for self tolerance, our findings may enable us to treat patients after liver transplantation without the need for immunosuppression.
- Published
- 1994
47. Ablation of persistent hepatitis B by bone marrow transplantation from a hepatitis B-immune donor
- Author
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Ilan, Yaron, Nagler, Arnon, Adler, Ruth, Tur-Kaspa, Ran, Slavin, Shimon, and Shouval, Daniel
- Abstract
Chronic hepatitis B virus (HBV) infection is still a major cause of liver disease for which no definite therapy is available. We describe here a hepatitis B surface antigen (HBsAg) carrier patient with active viral replication (HBV DNA positive) who was treated for leukemia by bone marrow transplantation (BMT) from an HBV immune donor. Following BMT from the antibody to hepatitis B core antigen (anti-HBc) positive/anti-HBs positive bone marrow donor, immune reconstitution of the recipient's bone marrow resulted in clearance of the circulating HBsAg, as well as HBV DNA. The patient acquired immunity against HBV, which lasted for more than 8 months posttransplantation. Therefore, this report provides evidence that adoptive transfer of specific immunity against HBV through allogeneic BMT may lead to clearance of persistent HBV infection. Furthermore, the data support the hypothesis that the HBsAg carrier state is most probably the result of an inefficient immune response against HBV, implying that clearance of HBV may be facilitated by adoptive cellular immunotherapy.
- Published
- 1993
- Full Text
- View/download PDF
48. A Novel 13C-Urea Breath Test Device for the Diagnosis of Helicobacter pyloriInfection
- Author
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Israeli, Eran, Ilan, Yaron, Meir, Shimon Bar, Buenavida, Claudia, and Goldin, Eran
- Abstract
The aim of this study is to determine the accuracy of a novel laptop sized 13C-Urea breath test analyzer that continuously measures expired breath and to use its advantages to decrease testing time.
- Published
- 2003
49. Exacerbation of Pulmonary Sarcoidosis After Liver Transplantation
- Author
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Shibolet, Oren, Kalish, Yossi, Wolf, Dana, Pappo, Orit, Laxer, Uri, Berkman, Neville, Shaham, Dorit, Ashur, Yaffa, and Ilan, Yaron
- Abstract
Patients with hepatic sarcoidosis rarely require orthotopic liver transplantation (OLT). Progression of granulomatous activity involving other organs after OLT has rarely been described. We describe a 32-year-old woman who underwent liver transplantation for sarcoidosis-associated end-stage liver disease. She presented 4 years later with shortness of breath, hilar lymphadenopathy, and interstitial lung abnormalities. Liver functions were normal. Open lung biopsy results revealed granulomata compatible with sarcoidosis. The patient made a complete recovery after corticosteroid treatment. To the best of our knowledge, this is a first description of severe exacerbation of pulmonary sarcoidosis in an immunosuppressed patient who underwent liver transplantation for sarcoidosis-associated liver disease.
- Published
- 2002
50. Etiology, Treatment, and Prognosis of Large Pericardial Effusions
- Author
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Ilan, Yaron, Oren, Ran, and Ben-Chetrit, Eldad
- Abstract
During the last 20 years, only a few studies have been published concerning large pericardial effusion. We recently reviewed 34 patients who presented with large pericardial effusion not associated with trauma. Our analysis revealed that half of the patients (52 percent) had pericardial effusion of unknown origin. Four patients had postmyocardial infarction pericardial effusion, three had associated malignant neoplasms, three suffered from collagen diseases, and two had infectious agents. Uremia and irradiation accounted for a single case each. Twenty-seven (79 percent) of the patients underwent pericardiocentesis and two (5.8 percent) had a pericardial window operation. The overall prognosis of the patients was excellent.
- Published
- 1991
- Full Text
- View/download PDF
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