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Biomedical subjects

Y Ilan

Publications and source records attributed to Y Ilan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Downregulation of a tumor promotion immune response via induction of oral tolerance towards tumor-associated-antigens: can we 'eat the tumor'?

The mechanism by which hepatocellular carcinoma (HCC) develops and the role of the hepatitis B virus (HBV) in inducing tumors, are not yet well understood. Patients persistently infected with HBV tend to have a defective immune response against the virus, which fails to clear the virus and also induces liver injury. This defective response may also have an inducible effect on the virus and on cells that express HBV antigens, as well as play a role in the growth of neoplasm. It is possible that one of the mechanisms of tumor growth is related to a deviant immune response towards viral or tumor associated antigens. We describe two responses against the tumor. A 'good' response that would suppress the tumor and a 'bad' response that would promote it and theorize that the net balance between 'bad' and 'good' responses of the immune system towards a cancerous cell and/or antigen will predict whether a tumor grows or is suppressed. Oral tolerance involves the induction of immunological hyporesponsiveness towards specific antigens. It was shown that oral tolerance induces antigen-specific immune suppression towards tumor-associated-antigens by feeding of HBV or other tumor proteins. We hypothesize that induction of immune tolerance towards tumor-associated antigens will suppress the immune response towards these antigens, thus reducing the 'bad' response. The proposed new treatment strategy would redirect the focus from augmenting anti-tumor immune responses to inducing host tolerance towards the tumor.

Adaptation, Physiological↗
PubMed2001

Amelioration of steroid-resistant chronic graft-versus-host-mediated liver disease via tacrolimus treatment.

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.

Adolescent↗
PubMed2001

Pregnancy rate and embryo loss in the NK1.1+ T cell-depleted mouse.

OBJECTIVE: To determine the role of natural killer cell (NK) 1.1+ T cells in pregnancy and in embryo loss. STUDY DESIGN: Four groups of C57 mice, consisting of 20 animals each, were studied. Groups A and B included pregnant females treated with anti-NK1.1 monoclonal antibodies until they gave birth or non-NK1.1-depleted antibodies, respectively. In order to evaluate the role of NK1.1+ T cells in pregnancy, female mice in group C were treated with anti-NK1.1 monoclonal antibodies every seven days starting seven days prior to mating until they gave birth. Control mice in group D were not NK1.1-depleted. NK1.1+ T cell depletion was determined by flow cytometric analysis. RESULTS: Depletion of NK1.1+ T cells did not significantly change the pregnancy rate, nor did it significantly alter the number of live births. Numbers of live births tended to decrease in NK1.1-depleted mice, with a mean number of live births of 4.66 as compared with 6.09 in NK1.1-depleted and nondepleted mice, respectively. Similarly, mice treated with anti-NK1.1 monoclonal antibodies every seven days starting seven days prior to mating became pregnant at a rate of 40% as compared with 60% in non-NK1.1-depleted controls. A comparable trend was observed in the number of live births, with a mean number of live births of 5.0 as compared with 6.1 in NK1.1-depleted and non-NK1.1-depleted mice, respectively. CONCLUSION: In the NK1.1-depleted mouse model, NK1.1+ T cells do not have any direct effect on pregnancy rate or on early embryo loss.

Animals↗
PubMed2001

Amelioration of immune-mediated experimental colitis: tolerance induction in the presence of preexisting immunity and surrogate antigen bystander effect.

Oral tolerance is a recognized procedure for induction of antigen-specific peripheral immune hyporesponsiveness. Recently, it has been shown that oral tolerance can be used to prevent experimental colitis. The aim of this study was to test whether induction of oral tolerance toward proteins extracted from inflammatory and noninflammatory colons can alleviate preexisting experimental colitis. Colitis was induced in BALB/c mice by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-induced colitis or normal colons, before, or 7 days after colitis was induced. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin (IL)4 levels were measured by enzyme-linked immunosorbent assay. Feeding of colitis- or normal colon-extracted proteins before, or following colitis induction, ameliorated colonic inflammation as shown by decreased diarrhea, increased body weight, reduction of colonic ulcerations, intestinal and peritoneal adhesions, wall thickness, and edema. Histological parameters for colitis were markedly improved in tolerized animals, and there was a significant reduction in inflammatory response and mucosal ulcerations. Tolerized mice developed an increase in IL4 and a decrease in IFNgamma serum levels. The results show that induction of oral tolerance to colitis- or normal colon-extracted proteins down-regulated preexisting anticolon immune response, thereby ameliorating experimental colitis. Tolerance induction was mediated via a shift from a proinflammatory T helper (Th)1 to an anti-inflammatory Th2 immune response.

Animals↗
PubMed2001

[Hepatic and hematological complications following ecstasy usage].

"Ecstasy" (3,4-Methylenedioxymethamphetamine), is used as a mood enhancer. We describe a case of a 23 year-old male suffering from thrombotic thrombocytopenic purpura (TTP), and severe hepatitis following ingestion of ecstasy. We describe the various hepatic complications, including hepatitis, cirrhosis, and hepatic failure, in addition to the hematological complications including DIC and TTP secondary to ecstasy abuse. Ecstasy abuse should be considered in every patient with unexplained hepatic or hematologic complications.

Adult↗
PubMed2000

Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model.

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 x 10(7) splenocytes 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 alpha1(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 IFNgamma 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.

Administration, Oral↗
PubMed2000

Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice.

In chronic graft versus host disease (cGVHD), an immune attack by transplanted donor lymphocytes results in damage of host target organs. A disbalance between proinflammatory (Th1) and anti-inflammatory cytokines (Th2) plays an important role in the pathogenesis. Immune hyporesponsiveness induced by oral antigen administration has been shown to suppress autoimmunity. We evaluated the efficacy of oral tolerization in preventing cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ in minor histocompatibility antigens. The transplantation resulted in cGVHD, with characteristic hepatic and small bowel inflammation, and increased skin collagen content and fibrosis. Oral tolerance was induced by feeding donor B10.D2 mice with proteins extracted from BALB/c splenocytes at 50 microg/d per mouse for 11 days before transplantation. Tolerization was evidenced by reduction in mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against BALB/c target splenocytes. Liver and small bowel biopsy specimens revealed much less inflammation. Oral tolerization prevented weight and subcutaneous fat loss, reduced thickening, and skin collagen deposits. Reduction of collagen alpha1 (I) gene expression was shown by in situ hybridization. Serum interleukin 10 (IL-10) levels measured significantly higher in tolerized mice than in controls, whereas interferon gamma (IFN-gamma), IL-2, and tumor necrosis factor alpha (TNF-alpha) were reduced significantly. Oral tolerization of splenocyte donors towards recipient-strain splenocytes ameliorated cGVHD of the liver, small intestine, and skin. A cytokine shift from a proinflammatory to an anti-inflammatory pattern may play a role in down-regulation of the immune-mediated target organ damage.

Animals↗
PubMed2000

Induction of oral tolerance towards hepatitis B envelope antigens in a murine model.

BACKGROUND: Hepatitis B virus (HBV) is a non-cytopathic virus, and the hepatocellular injury that occurs as a consequence of HBV infection is mediated by the host antiviral immune response. Subjects with natural tolerance to HBV have minimal or no liver injury despite chronic viremia. We have shown that immune tolerance towards viruses can be induced by oral administration of viral proteins. AIMS: To test whether oral induction of tolerance can be induced towards HBV antigens, and whether oral tolerance induction downregulates preexisting anti-HBV immune response. METHODS: Oral tolerance was induced via feeding of five low oral doses of HBV proteins (HBsAg+preS1+preS2, BioHepB). This was followed by two inoculations with the BioHepB vaccine. Humoral immune tolerance was evaluated by measuring serum levels of anti-HBs antibody titers at monthly intervals. To determine if oral tolerance induction downregulates pre-existing anti-HBs immunity, mice were inoculated twice with the BioHepB vaccine, followed by feeding of BioHepB-HBV proteins. RESULTS: Feeding of HBV proteins markedly inhibited production of anti-HBs antibodies in naive mice. Anti-HBs titers were 45 versus 135 mIU/ml, in tolerized versus non-tolerized controls (P<0.005). Moreover, oral tolerance induction effectively down-regulated pre-existing immunity and reduced the anti-HBs titers in previously immunized mice to 112 versus 223 mIU/ml, in tolerized compared with non-tolerized controls (P<0.01). CONCLUSIONS: Induction of oral tolerance towards HBV proteins downregulates the antiviral humoral immune response in naive mice, and in the presence of preexisting anti-HBV immunity. This approach should be further investigated as a method for alleviation of antiviral-mediated liver injury in chronic HBV hepatitis.

Administration, Oral↗
PubMed2000

Enhancement of immune tolerance via induction of NK1.1 positive liver-associated-lymphocytes under immunosuppressive conditions.

BACKGROUND/AIMS: The liver was previously shown to play a critical role in oral tolerance induction. A subset of liver-associated-lymphocytes expressing NK1.1 marker (NK1.1+ LAL) have killing activities and it has been suggested that they play a role in immune modulation. FK506 is a powerful immunosuppressive agent affecting T-cell differentiation and function. The exact pathway involved in peripheral tolerance induction using this drug remains unknown. The aim of the present study was to determine the interaction between FK506 and NK1.1+ LAL in induction of peripheral immune tolerance in the experimental colitis model. METHODS: Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall with and without FK506 treatment. The effect of FK506 treatment on NK1.1+ LAL was tested by cell-sorting and cytotoxicity assay. Colitis was assessed by standard clinical, macroscopic and histologic scores. RESULTS: Both FK506 treatment and oral tolerance induced a significant increase in NK1.1+ LAL number and cytotoxicity function. FK506 treatment enhanced the effect of oral tolerance on amelioration of disease activity. Orally tolerized mice treated with FK506 had no mortality nor increase in body weight, and manifested significant improvement in disease macroscopic and microscopic scores. CONCLUSIONS: This study shows for the first time that immune tolerance induced by both oral administration of an antigen and by FK506 treatment may be mediated via enhancement of NK1.1+ LAL. This subset of lymphocytes may play an immunoregulatory role in immune tolerance induction.

Animals↗
PubMed2000

Maintenance of immune memory to the hepatitis B envelope protein following adoptive transfer of immunity in bone marrow transplant recipients.

Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) has been documented in mice and humans. In the present study, we report long-term follow-up of antibodies to HBsAg in humans who received allogeneic bone marrow transplantation (BMT) from donors immunized with HBsAg. BM donors were immunized with recombinant HBsAg. BM or PB cells were transplanted to HLA matched recipients. Recipients were followed for anti-HBs seroconversion. Control groups included non-immunized or rHBsAg immunized healthy adults as well as individuals that had had hepatitis B and recovered spontaneously. PBLs were stimulated in vitro with rHBsAg and stimulation was expressed as stimulation index. Adoptive transfer of immunity to HBsAg was initially documented in 12 recipients of BM from anti-HBc+/anti-HBs+ donors. An almost 4 year follow-up showed detectable protective anti-HBs levels (>10 mIU/ml) in 50% of patients. Immunity to HBV was also documented in 22/35 BMT recipients (62%), who received their bone marrow from actively immunized donors. In 7/9 of these BMT recipients, anti-HBs antibodies levels were documented 25 months following BMT. In 6/8 (75%) of patients who received only PBLs from HBV immune donors, adoptive transfer of immunity to HBV, and seroconversion to HBsAg+, were documented within 2 months of i.v. injection. Evidence for specific cellular immune response with increased SIs was documented for healthy vaccinees, and BMT recipients, and in none of the healthy non-vaccinated controls. These results suggest that adoptive transfer of immunity to HBV is a useful method for providing long-lasting protection for BM recipients.

Adult↗
PubMed2000

A balanced 5:1 carbohydrate:protein diet: a new method for supplementing protein to patients with chronic liver disease.

BACKGROUND AND AIMS: Protein malnutrition in patients with chronic liver disease contributes to bone and muscle weakness and compromises immune function and survival. In contrast, high-protein diets may induce or exacerbate hepatic encephalopathy. The aim of the present study was to test whether increased amounts of protein, balanced by dietary carbohydrate in a 1:5 ratio, may be given to chronic liver disease patients in order to minimize postprandial increases in plasma amino acid (AA) concentrations. METHODS: Eight patients with chronic liver disease were studied. Each received, in a randomized order, three different diets of 2510 kJ of either high protein (37:50:28, carbohydrate:protein:fat), high carbohydrate (126:10:6) or a balanced 5:1 carbohydrate:protein diet (105:21:11). All patients were followed for plasma AA, glucose and insulin levels, as well as for cognitive and behavioral changes. RESULTS: Following the high protein diet, AA concentrations were significantly increased. In contrast, after the balanced diet, AA levels were practically constant enabled. All diets was well tolerated and no cognitive or behavioral changes appeared. CONCLUSION: The administration of a balanced 5:1 carbohydrate:protein diet may enable patients with chronic liver disease to tolerate increased amounts of dietary protein, without altering plasma amino acid concentrations.

Adult↗
PubMed2000

A replication-deficient rSV40 mediates liver-directed gene transfer and a long-term amelioration of jaundice in gunn rats.

BACKGROUND & AIMS: In the quest for a recombinant viral vector for liver-directed gene therapy that would permit both prolonged and efficient transgene expression in quiescent hepatocytes in vivo and repeated administration, we evaluated a recombinant simian virus 40 (rSV40). METHODS: The rSV40 was generated through replacement of the DNA encoding for the T antigens (Tag) by the coding region of human bilirubin-uridine 5'-diphosphate-glucuronosyl-transferase (BUGT) complementary DNA (SV-hBUGT). Helper-free rSV40 units were generated at infectious titers of 5 x 10(9) to 1 x 10(10) infectious units (IU)/mL in a Tag-producing packaging cell line (COS-7 cells). RESULTS: After 1, 3, or 7 daily infusions of 3 x 10(9) IU of SV-hBUGT through an indwelling portal vein catheter in bilirubin-UGT-deficient jaundiced Gunn rats, mean serum bilirubin concentrations decreased by 40%, 60% and 70%, respectively, in 3 weeks and remained at those levels throughout the duration of the study (40 days). Results of liver biopsies from SV-hBUGT-treated Gunn rats, but not from controls, were positive for human BUGT DNA, messenger RNA, and protein. Bilirubin-UGT activity in liver homogenates was 8%-12% of normal, and bilirubin glucuronides were excreted in bile. Immunostaining showed that >50%-60% of hepatocytes stably expressed the transgene. Portal vein infusion of an rSV40 expressing hepatitis B surface antigen (HBsAg) in a naive Gunn rat and a Gunn rat that had received 7 injections of SV-BUGT resulted in approximately equal levels of hepatic expression of HBsAg, indicating that multiple inoculations of SV-BUGT did not elicit neutralizing antibodies. Plasma alanine aminotransferase levels and liver histology remained normal despite repeated injections of rSV40. CONCLUSIONS: rSV40 vectors may represent a significant advance toward gene therapy for metabolic diseases.

Animals↗
PubMed2000

Treatment of experimental colitis by oral tolerance induction: a central role for suppressor lymphocytes.

OBJECTIVE: Inflammatory bowel diseases (IBD) are immune-mediated disorders wherein an imbalance between proinflammatory (Th1) and antiinflammatory (Th2) cytokines is thought to play a role in the pathogenesis. The aim of this study was to test whether induction of oral tolerance to proteins extracted from inflammatory colon alleviates experimental colitis, and whether oral tolerization mediated by suppressor cells can induce immune tolerance. METHODS: Colitis was induced in rats by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Rats received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Splenocytes harvested from tolerized and control rats were transplanted into irradiated naive rats. RESULTS: Feeding of colitis-extracted proteins ameliorated colonic inflammation, as shown by reduction of colonic ulcerations, as well as decreased diarrhea, intestine and peritoneal adhesions, wall thickness, and edema. A marked reduction of the fraction of injured colonic area and colon weight, and decrease in colon weight, were observed in tolerized rats versus controls. Histological parameters for colitis were markedly improved in tolerized animals that showed significant reduction in inflammatory response and mucosal ulcerations. Tolerized rats developed an increase in TGFbeta1 and a decrease in IFNgamma serum levels. TNBS-induced colitis was significantly attenuated in naive recipients of splenocytes from tolerized rats, compared with rats that received splenocytes from control donors. CONCLUSIONS: Induction of oral tolerance to colitis-extracted proteins downregulates the anticolon immune response, thereby ameliorating experimental colitis. Suppressor lymphocytes mediate the tolerance by induction of a shift from a proinflammatory to an antiinflammatory immune response.

Administration, Oral↗
PubMed1999

[Neurological manifestations of non A-G viral hepatitis].

Guillain-Barre and other neurologic syndromes rarely occur as complications of viral hepatitis (A, B and C). Other neurologic syndromes have also been reported in serologically defined viral hepatitis, including mononeuritis, auditory neuritis, and seizures. Chronic hepatitis B and mononeuritis multiplex are found together in 31-54% of patients with periarteritis nodosa. The mechanisms of these associations are unknown, but may include direct cytotoxicity of the virus or immune-mediated damage. Vasculitis of the vasa nervorum plays an intermediate role, at least in some cases. We describe a 36-year-old man with acute non A-G hepatitis complicated by Guillain-Barre syndrome. The neurological manifestation resolved completely without specific therapy within 6 days, as the hepatitis resolved.

Adult↗