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Israel Gotsman

Publications and source records attributed to Israel Gotsman.

9 recordsLinked to original sources
PubMed2006

Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule.

BACKGROUND: T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses. METHODS AND RESULTS: Bone marrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4+ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4+ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3+ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3+ Treg and impaired in vitro Treg suppressive function compared with control mice. CONCLUSIONS: ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.

Animals↗
PubMed2005

Alleviation of chronic GVHD in mice by oral immuneregulation toward recipient pretransplant splenocytes does not jeopardize the graft versus leukemia effect.

Chronic graft versus host disease (cGVHD) is the result of an immune-mediated attack by transplanted donor lymphocytes, entailing inflammatory damage to host target organs. Clinically, the post-bone marrow transplantation (BMT) graft versus leukemia (GVL) effect may be associated with GVHD. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of cGVHD in a murine model. To evaluate whether amelioration of cGVHD in mice by induction of oral immune regulation in donors toward recipient pretransplant lymphocyte antigens is associated with attenuation of the GVL effect donor B10.D2 mice were fed with Balb/c splenocytes, B10.D2 splenocytes, bovine serum albumin (BSA), or regular chow, every other day for 10 days. Subsequently, transplantation of 2 x 10(7) splenocytes from donor B10.D2 mice to recipient Balb/c mice was undertaken, followed by inoculation of 3 x 10(3) BCL-1 leukemia on the day of BMT. Control groups were fed identically without leukemia inoculation. Mice were followed for survival and leukemia progression. Induction of tolerance was assessed by a mixed lymphocyte reaction (MLR). Cutaneous GVHD was assessed macroscopically. To elucidate the mechanism of any observed effect, serum interferon (IFN), interleukin (IL-2), IL-12, IL-4, and IL-10 were determined by enzyme-linked immunosorbent assay and flow cytometry analysis for CD4+, CD8+, and NK1.1+ lymphocyte subpopulations was performed. There was no significant difference in leukemia progression manifested by survival or white blood cell counts of orally immune-regulated mice compared with control animals. Cutaneous cGVHD was significantly ameliorated in Balb/c mice transplanted from tolerized B10.D2 mice. This effect was associated with a significant reduction in the mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against Balb/c target splenocytes; significantly decreased serum IFN-gamma and IL-2; increased serum IL-12 levels; increased peripheral NK1.1+ cells; and CD4+/CD8+ lymphocyte ratio. Oral tolerization of BMT donors toward recipient antigens ameliorates cGVHD without hampering the GVL effect.

Adjuvants, Immunologic↗
PubMed2004

Clinical manifestations of pyoderma gangrenosum associated with inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition associated with inflammatory bowel disease. PG occurs rarely in IBD patients and there are insufficient data on the clinical manifestations of this disease with IBD. OBJECTIVE: To determine the incidence, clinical manifestations and treatment of PG in patients with IBD and the connection to IBD, its activity and extent. METHODS: All patients hospitalized with IBD at a university hospital during a 20 year period were evaluated for the occurrence of PG. RESULTS: Of 986 patients hospitalized for IBD 6 suffered from PG (0.6% incidence). Their average age was 37 with equal sex distribution and equal distribution of Crohn's disease and ulcerative colitis. PG appeared 6.5 years on average after diagnosis of IBD in all patients. The development of PG correlated with significant clinical exacerbation of IBD, the majority having active colitis at the onset of the PG. Extraintestinal manifestations of IBD occurred in half the patients (sacroillitis, peripheral arthritis and erythema nodosum). Pathergy was not elicited in any patients. Four patients had multiple skin lesions, frequently on the lower extremities. Diagnosis was made by skin biopsy in four patients. There was little correlation between amelioration of IBD and the skin lesions. Treatment consisted of high dose steroids and immunomodulatory drugs (cyclosporine, azathioprine and dapsone) in conjunction with topical treatment. CONCLUSIONS: PG is a rare extra-intestinal manifestation of IBD that coincides with the exacerbation of the intestinal disease but does not always respond to treatment of the bowel disease.

Adult↗
PubMed2003

Clinical manifestations and outcome of acute myocardial infarction in very young patients.

BACKGROUND: Acute myocardial infarction is rare in people under the age of 30. OBJECTIVE: To determine the clinical features and outcome in young patients presenting with AMI. METHODS: All patients aged 30 years and younger hospitalized with AMI during a period of 8 years (1993-2000) were evaluated for clinical features and outcome. RESULTS: Of the 3,758 patients with AMI, 15 were 30 years old or younger (0.4%). The mean age was 28 (range 21-30 years) and all were male. Eight had normal coronary arteries on angiogram; seven had obstructive coronary artery disease. Patients with OCA had more classical risk factors for coronary disease. A complete diagnostic workup was abnormal in four patients with NCA: thrombophilia in two patients, spasm due to alcohol withdrawal and hyperthyroidism in one patient each. All patients presented with typical new-onset chest pain. None had a previous history of angina. All patients with OCA received reperfusion therapy as compared to one patient with NCA. Peak creatine phosphokinase in NCA and OCA was 504 +/- 547 and 1,328 +/- 440 respectively (P < 0.01). All patients with NCA had good left ventricular function on follow-up echocardiography, compared to only three in the OCA group (P = 0.02). There was one death due to cardiogenic shock in a patient with OCA. Follow-up of 4 +/- 2 years demonstrated recurrent acute coronary syndromes in four of seven patients with OCA versus none in the NCA patients (P = 0.02). CONCLUSIONS: AMI is rare in very young patients, and more than half NCA. A thrombophilic tendency or spasm should be considered. Young patients with NCA have an excellent prognosis.

Adult↗
PubMed2002

Pleural effusion.

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Exudates and Transudates↗
PubMed2002

Inducing oral immune regulation of hepatitis B virus envelope proteins suppresses the growth of hepatocellular carcinoma in mice.

BACKGROUND: 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. METHODS: Recipient athymic Balb/c mice were irradiated sublethally and injected with 10(7) human hepatoma cells followed by the adoptive transfer of 2 x 10(6) 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 alpha-fetoprotein (aFP) 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 gamma (IFNgamma) ELISPOT assays as well as cytokine expression by reverse transcriptase-polymerse chain reaction assays. RESULTS: 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 aFP 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 IFNgamma ELISPOT assays in mice orally immune regulated with HBV proteins compared with naïve mice. Tumor suppression was mediated through increased IFNgamma production in immune regulated and immunized mice. CONCLUSIONS: 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.

Administration, Oral↗
PubMed2002

Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice.

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 microg HBV antigens or HCC-extracted proteins (50 microg protein) before vaccination with recombinant HBsAg. Splenocytes (2 x 10(6)) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 10(7) 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 mm(3) 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-IFN gamma 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.

Adoptive Transfer↗