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Y Ilan

Publications and source records attributed to Y Ilan.

At least 55 records · Page 3Linked to original sources
PubMed1999

Liver-associated lymphocytes expressing NK1.1 are essential for oral immune tolerance induction in a murine model.

Oral tolerance is the induction of immunological hyporesponsiveness towards orally administered antigens. Tolerance initiation involves induction of anti-inflammatory (Th2) lymphocytes, with downregulation of pro-inflammatory (Th1) lymphocytes. The liver was previously shown to play a critical role in oral tolerance induction. The aim of the present study was to test whether liver-associated-lymphocytes expressing the NK1.1 marker (NK1.1+ LAL) are substantial for induction of oral tolerance in an experimental colitis model. Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzensulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Anti-NK1.1 monoclonal antibodies were injected before tolerance induction. Colitis was assessed by standard clinical, macroscopic, and microscopic scores. Serum IFN-gamma, TGF-beta1, and IL4 levels were measured by enzyme-linked immunosorbent assay. To evaluate the role of NK1.1+ LAL in keeping the balance between immunogenic and tolerogenic subsets of cells, we tested whether peripheral lymphocytes harvested from tolerized and NK1.1-depleted nontolerized mice can adoptively transfer the tolerance into naive irradiated rats. Depletion of NK1.1+ LAL prevented immune tolerance induction in the experimental colitis model. NK1.1+ LAL-depleted nontolerized mice, disclosed severe clinical, macroscopic, and microscopic parameters of colitis. These mice had significantly lower TGF-beta1, IL4, and higher IFN-gamma serum levels, and their lymphocytes failed to transfer the tolerance into naive animals. In contrast, the feeding of colitis-extracted proteins, without NK1.1+ LAL depletion, markedly alleviated the disease. Tolerized mice had higher IL4 and TGF-beta1 and lower IFN-gamma serum levels, and adoptive transfer of their suppressor splenocytes markedly alleviated colitis in naive recipients. NK1.1+ LAL plays a critical role in oral tolerance induction. Depletion of this subset of LAL prevents a shift from Th1 to a Th2 type of immune response, hindering the ability to induce immune tolerance.

Administration, Oral↗
PubMed1999

Induction of tolerance to hepatitis B virus: can we 'eat the disease' and live with the virus?

Hepatitis B virus (HBV) is a major health problem, with over 300 million HBsAg carriers worldwide. The HBV itself is non-cytopathic, and it is widely accepted that the mechanism of hepatocellular injury is the host anti-viral immune response. Current treatments, including the newly developed therapeutic modalities, are either based on antiviral drugs or focus on attempts to augment the anti-viral immune response. The results of these approaches have been largely disappointing. There is evidence, however, that subjects with a natural tolerance to HBV or a down-regulated immune response develop little or no liver injury, despite chronic viremia. Lately, it has been shown that it is possible to induce tolerance toward viruses by oral administration of major viral structural proteins. Here, we discuss the pathogenesis of HBV-mediated liver disease and approaches to down-regulate the immune response directed against liver cells by orally inducing tolerance toward the virus. We hypothesize that this acquired tolerance should turn chronic active hepatitis patients with deteriorating disease into 'healthy' virus carriers. The proposed new treatment strategy would redirect the focus from augmenting anti-viral immune response to inducing host tolerance towards the virus.

Animals↗
PubMed1999

Adenovirus-mediated gene therapy of liver diseases.

Recombinant adenoviruses can infect nondividing cells with high efficiency and are rapidly concentrated in the liver after systemic administration, making them attractive for use in liver-directed gene therapy. However, there are two hurdles to clinical application of these vectors. First, adenoviruses are episomal and have limited life spans within the cell. Second, host antiviral immune responses reduce the duration of vector persistence and preclude long-term transgene expression by repeated injection of the vector. Several strategies have been designed for abrogation of the specific antiadenoviral immune responses by modification of the host immune system or alteration of the vector. These strategies and the use of adenoviral vectors for the treatment of hereditary, infectious, and malignant diseases of the liver are discussed in this review.

Adenoviridae↗
PubMed1999

Oral tolerance: a new tool for the treatment of gastrointestinal inflammatory disorders and liver-directed gene therapy.

Oral tolerance is a method of downregulating an immune response by feeding antigens. The use of oral tolerance toward adenoviruses and colitis-extracted proteins for long term gene therapy and alleviation of experimental colitis, and the mechanisms of tolerance induction are presented. Adenoviruses are efficient vectors in liver-directed gene therapy; however, the antiviral immune response precludes the ability to achieve long term gene expression and prohibits the ability to reinject the recombinant virus. Oral tolerance induction via feeding of viral-extracted proteins prevented the antiadenoviral humoral and cellular immune responses, thus enabling long term gene therapy using these viruses. Moreover, pre-existing immune response to the virus was overcome by tolerance induction, enabling prolonged gene expression in a presensitized host. Inflammatory bowel diseases are immune-mediated disorders where an imbalance between proinflammatory (T helper cell type 1) and anti-inflammatory (T helper cell type 2) cytokines are thought to play a role in the pathogenesis. In the experimental colitis model, the feeding of colitis-extracted proteins downregulated the anticolon immune response. Tolerance induction toward colitis-extracted proteins ameliorated colonic inflammation as shown by decreased diarrhea and reduction of colonic ulcerations, intestinal and peritoneal adhesions, wall thickness and edema. Histological parameters for colitis were markedly improved in tolerized animals. In both models, tolerized animals developed an increase in transforming growth factor-beta, interleukin-4 and interleukin-10, and a decrease in the mRNA of interferon-gamma lymphocytes and serum levels. Adoptive transfer of tolerized lymphocytes enabled the transfer of tolerance toward adenoviruses and colon-extracted proteins. Thus, oral tolerance induces suppressor lymphocytes that mediate immune response downregulation by induction of a shift from a proinflammatory T helper cell type 1 to an anti-inflammatory T helper cell type 2 immune response.

Adenoviridae↗
PubMed1999

Technology evaluation: naked DNA.

Vical and Merck are investigating vaccines against hepatitis B which use Vical's patented naked DNA technology. Both therapeutic and prophylactic vaccines are under development [177132], [268397]. The technology, and subsequent collaboration, stems from the observation by Vical that by directly injecting exogenous cDNA into muscle tissue, protein is expressed which gives rise to a strong immune response and protective immunity [163222].

Animals↗
PubMed1998

Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenoviruses.

Exposure to wild-type adenoviruses is common in humans and results in immune response against adenoviruses. The pre-existing antibodies and a strong secondary humoral and cellular immune response would interfere with gene transfer using recombinant adenoviral vectors. To test whether the secondary immune response can be abrogated by oral tolerization to adenoviral antigens, we immunized bilirubin-UDP-glucuronosyltransferase (BUGT)-deficient jaundiced Gunn rats with a recombinant adenovirus (5 x 10(9) pfu/rat) expressing the human UDP-glucouronosyltransferase (BUGT1) gene (Ad-hBUGT). Transgene expression was shown by reduction of mean serum bilirubin levels from 7.0 mg/dL to 2.3 mg/dL in 14 days, which then increased gradually to pretreatment levels in 6 weeks. All recipients developed antibodies (1:2[10]) and cytotoxic lymphocytes against the adenovirus. For oral tolerization, we administered to the immunized rats protein extracts of a recombinant adenovirus type 5 (1-1.5 mg/day) via duodenostomy tubes 10 to 40 days after the initial virus injection; control rats received bovine serum albumin. In rats fed adenoviral proteins and the BSA-fed controls, the antibody titers decreased to 1:2(7) and 1:2(9), respectively, in 70 days. Lymphocytes from the tolerized rats expressed TGF-beta1 upon exposure to antigen-presenting cells primed with adenoviral antigens, whereas IFN-gamma expression was undetectable. In contrast, lymphocytes from the BSA-treated control rats expressed IFN-gamma but not transforming growth factor beta1 (TGF-beta1). Seventy days after the first injection in the orally tolerized rats, but not in the controls, a second Ad-hBUGT injection caused human BUGT1 expression again, reducing serum bilirubin levels to those observed after the first injection. In the tolerized rats, serum antibody titers and anti-adenoviral cytotoxic lymphocyte activities continued to decline despite the second injection, whereas the antibody levels were boosted in the non-tolerized group. This results show that by preventing the secondary booster response, oral tolerization permits repeated adenovirus-directed gene transfer despite the presence of a residual antibody titer from a previous adenoviral exposure.

Adenoviridae↗
PubMed1998

Cavoatrial shunt: a graft salvage procedure for suprahepatic caval anastomosis obstruction after liver transplantation.

A liver transplant recipient developed the Budd-Chiari syndrome because of an obstruction of the suprahepatic inferior vena cava anastomosis. Percutaneous balloon dilatation angioplasty was not feasible. On exploration, dense retrohepatic fibrotic reaction was observed. The patient underwent successful retrohepatic cavoatrial shunt placement by means of a 16-mm, ring-enforced polytetrafluoroethylene graft. We conclude that this shunt should be considered an additional graft salvage procedure for this complication.

Arteriovenous Shunt, Surgical↗
PubMed1998

Increased serum CA 19-9 antibodies in Sjögren's syndrome.

A 67-year-old woman with a history of thyroiditis presented with recent intermittent epigastric pain and nausea. Hyperamylasaemia, oedema of the pancreas, and high serum levels of lipase and CA 19-9 were found. Xerostomia and dry eyes developed later, accompanied by an abnormal Schirmer's test. The diagnosis of Sjögren's syndrome was confirmed by increased anti-Ro and anti-La antibodies and the histological findings of parotid gland biopsy. Two additional cases of Sjögren's syndrome with elevated serum CA 19-9 are also described. These observations of elevated serum lipase and serum CA 19-9 in Sjögren's syndrome without evidence of malignancy may reflect pancreatic involvement in this disorder.

Adult↗
PubMed1997

Massive repopulation of rat liver by transplantation of hepatocytes into specific lobes of the liver and ligation of portal vein branches to other lobes.

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 ugt1 gene from hepatic DNA showed that up to 25% of the DNA was of donor origin. This paralleled the hepatic bilirubin-UDP-glucuronosyltransferase 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 progeny of the transplanted phenotypically normal hepatocytes.

Animals↗
PubMed1997

[Solid organ retransplantation].

The need for solid organ retransplantation is a major factor in the shortage of available organs. Between 1972 and 1992, 56 out of 309 kidney transplants and 2 out of 20 liver transplants performed in our hospital were retransplantations. The present study evaluates local and world experience with organ retransplantations in terms of the medical and ethical issues.

Humans↗
PubMed1997

Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression.

Recombinant adenoviruses (Ads) are highly efficient at transferring foreign genes to the liver in vivo; however, the duration of gene expression is limited by the host antiviral immune response, which prevents expression upon readministration of the virus. To test whether overexpression of the immunomodulatory products of the early Ad genome region 3 (E3) could prevent the antiviral immune response and prolong expression of foreign genes delivered by Ad vectors, we injected a recombinant Ad (Ad-E3-hBUGT), containing both E3 and the human bilirubin-uridine-diphosphoglucuronate-glucuronosyltransferase (BUGT) genes, into BUGT-deficient hyperbilirubinemic Gunn rats. Control Gunn rats received Ad-hBUGT, which expresses human BUGT alone. An initial injection of either virus resulted in hepatic expression of human BUGT as evidenced by excretion of bilirubin glucuronides in bile and a reduction of mean serum bilirubin levels from 7.0 mg/dl to 1.9-2.7 mg/dl within 7 days. In Ad-E3-hBUGT-injected rats, serum bilirubin levels increased to 4.5 mg/dl by 84 days after infection, but a second administration of the virus on that day resulted in a hypobilirubinemic response similar to that seen with the first injection. In contrast, rats receiving Ad-hBUGT had serum bilirubin levels of 7 mg/dl on day 84 after infection, but showed no reduction of serum bilirubin by reinjection of the virus on that day. In the rats injected with Ad-E3-hBUGT, but not in the ones injected with Ad-hBUGT, there was a marked inhibition of the antiviral antibody and Ad-specific cytotoxic T lymphocyte responses. This is the first demonstration that insertion of E3 genes in recombinant Ads facilitates readministration of a functional vector for long-term correction of an inherited metabolic disorder.

Adenoviridae↗
PubMed1997

Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors.

Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limited by the host immune response which precludes gene expression upon readministration of the virus. To test if this immune response can be abrogated by oral tolerization, we instilled protein extracts of a recombinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin-UDP-glucuronosyltransferase-1 (BUGT1)-deficient jaundiced Gunn rats. Control rats received BSA. Subsequent intravenous injection 5 x 10(9) pfu of a recombinant adenovirus-expressing human BUGT1 (Ad-hBUGT1) resulted in hepatic expression of human BUGT1 (hBUGT1) with reduction of serum bilirubin levels by 70%. After 2 mo serum bilirubin increased gradually. In orally tolerized rats, but not in controls, a second dose of the virus on day 98 markedly reduced serum bilirubin again. In the tolerized rats, the development of antiadenoviral neutralizing antibodies and cytotoxic lymphocytes were markedly inhibited, and transplantation of their splenocytes into naive Gunn rats adoptively transferred the tolerance, indicating a role for regulatory cells. Lymphocytes from the tolerized rats hyperexpressed TGFbeta1, IL2, and IL4 upon exposure to viral antigens, whereas IFNgamma expression became undetectable. Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adenoviruses.

Adenoviridae↗