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Biomedical subjects

S Gillis

Publications and source records attributed to S Gillis.

At least 55 records · Page 3Linked to original sources
PubMed1994

Clinical and therapeutic experience in 712 Israeli patients with idiopathic thrombocytopenic purpura. Israeli ITP Study Group.

Idiopathic thrombocytopenic purpura (ITP) is a relatively common hematologic disorder. Steroids and splenectomy constitute the main modalities of treatment. Although the indications for these therapies are well established in the literature, the timing of splenectomy remains controversial. This report retrospectively reviews 712 consecutive patients with ITP hospitalised in 9 medical centers in Israel between the years 1977 and 1987. The clinical presentations, the time required for a response to steroids and the remission rate following splenectomy were all similar in children with ITP who were hospitalised and adults. There were however marked differences in associated conditions, predominantly viral infections in children, and autoimmune disorders, neoplasia or infections in adults. The overall response to initial steroid therapy was 82% in children and 74% in adults. Ninety-three percent of those responding did so within 60 days of starting treatment. One hundred and seventy-three patients underwent splenectomy; 123 (71%) achieved a prolonged complete remission. We recommend early splenectomy in patients not responding rapidly to corticosteroid treatment. This study demonstrates that chronic, more severe ITP in children requiring hospitalisation has a marked similarity to the disease in adults. Many children, however, present with mild transient thrombocytopenia that does not necessitate hospitalisation or a specific therapy.

Adolescent↗
PubMed1994

Activity of fludarabine in refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma--the Jerusalem experience.

Twenty four patients with refractory chronic lymphocytic leukemia (CLL) and advanced low grade lymphoma (LGL) were treated with Fludarabine given at a dose of 25 mg/m2, intravenously daily for 5 days, every 28 days. Ten of the patients with LGL were in terminal leukemic phase. All patients had received previous chemotherapy, most with multiple regimens. Patients received a mean of 5.1 cycles (range 1-9). 4 patients--one with CLL and 3 with LGL--achieved a complete remission, while 7 LGL and 3 CLL patients had a partial response. Two patients remain in complete remission 23 and 25 months after completion of therapy. One patient underwent successful autologous bone marrow transplantation after achieving a complete remission, while two others had marrow cryopreserved during complete remission. The drug was well tolerated and toxicity was mild. In 9 of the 122 given cycles patients required hospitalization. In conclusion, Fludarabine is active in refractory patients with CLL and LGL and induces complete and partial remissions in some. It seems that Fludarabine could be used as primary therapy in these disorders in the future.

Adult↗
PubMed1994

Hairy cell leukemia: results of 2-chlorodeoxyadenosine therapy in Jerusalem.

Since the introduction of adenosine deaminase analogues the vast majority of patients with Hairy cell leukemia obtain lasting complete remission. In this report we describe our experience with 2 CdA in 18 patients with Hairy cell leukemia (HCL). Ten of these had failed previous interferon therapy, 6 were splenectomized before and of these, 4 had also received interferon. Sixteen of the 18 patients receiving 2 CdA achieved complete remission (CR), 1 patient is in good partial response (GPR) and 1 patient has relapsed. These results are in keeping with those reported from other larger centers and confirm the efficacy of 2-CdA. In this report IL-2 receptor (sIL-2R) levels were performed in most of the patients and found to be an accurate indicator of disease activity. Mean levels prior to therapy were 17200 U/ml (+/- 2500) and after successful therapy 970 U/ml (+/- 160). We confirm that 2-CdA treatment is the treatment of choice in HCL and suggest that sIL-2 levels be used as a parameter of disease activity.

Adult↗
PubMed1993

Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice.

A recombinant human TNF receptor Fc fusion protein (rhuTNFR:Fc) was assessed for antiarthritic activity using murine type II collagen-induced arthritis in mice. DBA/1 mice were immunized with bovine type II collagen and treated with rhuTNFR:Fc either from day 21 to day 28 (preventative protocol), or after disease onset for fourteen days (therapeutic protocol). Control mice received either sterile saline or human serum albumin injections. rhuT-NFR:Fc treatment significantly reduced both the incidence and the severity of collagen-induced arthritis in the preventative protocol. Mice receiving rhuTNFR:Fc therapeutically progressed to less severe disease than did control animals, and the arthritis index in rhuTNFR:Fc treated mice was significantly lower than the index in control mice from 7.5 weeks after treatment. The antibody response to collagen was significantly reduced by treatment with rhuTNFR:Fc in both the preventative and therapeutic protocols. No difference was observed in the proliferative response to type II collagen or Con A, but the response to LPS was significantly lower in rhuTNFR:Fc treated mice at the conclusion of both the preventative and therapeutic trials. The results suggest that rhuTNFR:Fc may have both immunosuppressive and antiarthritic properties in this experimental model, and may represent a useful approach to the treatment of autoimmune arthritis.

Animals↗
PubMed1993

Identification of regions in interleukin-1 alpha important for activity.

Saturation mutagenesis of the mature human interleukin-1 alpha (IL-1 alpha) gene has been performed. Following expression in Escherichia coli, the biological and receptor binding activities of the mutant proteins were examined. Most of the molecule could be altered with little effect on either function. More than 3,500 mutants were examined, and only 23 unique amino acid sequences were identified which resulted in an altered ratio of biological to binding activity when compared with wild-type IL-1 alpha. These proteins possessed mutations at 38 of the 159 amino acid residues in IL-1 alpha. Random mutagenesis at several of these positions identified further substitutions that affected activity. Examination of a model for IL-1 alpha localized most of the residues which altered activity along one face of the molecule. This region appears to be distinct from areas of IL-1 which have been postulated to make contact with IL-1 receptor.

Amino Acid Sequence↗
PubMed1993

In a concerted action kit ligand and interleukin 3 control the synthesis of serotonin in murine bone marrow-derived mast cells. Up-regulation of GTP cyclohydrolase I and tryptophan 5-monooxygenase activity by the kit ligand.

Mouse bone marrow-derived mast cells (BMMC) store and release serotonin whose synthesis is initiated by tryptophan 5-monooxygenase. (6R)-H4biopterin serves as the natural cofactor for this reaction. GTP cyclohydrolase I catalyzes the first and rate-limiting step of its synthesis. In this study we demonstrate that among a panel of growth-promoting cytokines including kit ligand (KL), interleukin 3 (IL-3), IL-4, IL-9, and nerve growth factor, KL selectively enhances the synthesis of H4biopterin through up-regulation of GTP cyclohydrolase I activity to 6.2-fold levels. The activities of the subsequent enzymes 6-pyruvoyl-H4pterin synthase and sepiapterin reductase remain unaffected. The activity of tryptophan 5-monooxygenase was selectively enhanced 4.5-fold by the combination of IL-3 with KL. All other factors could not substitute for KL. The constitutive high activity of aromatic L-amino acid decarboxylase is not different in cells cultured in IL-3 and/or KL. In consequence, the concerted action of IL-3 and KL on the GTP cyclohydrolase I and the tryptophan 5-monooxygenase reaction enhances the production of serotonin to about 20-fold levels. Additionally, KL specifically causes the release of about half of total serotonin produced. Hence, our data demonstrate a novel role of these cytokines for the function of mouse BMMC and provide a coherent view of the regulation of serotonin synthesis in this cell type.

5-Hydroxytryptophan↗
PubMed1993

Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand.

Both human and mouse c-kit ligand induced differentiation of human mast cells in a long-term culture of the mononuclear cells of umbilical cord blood. Growth factor activity for human mast cells present in conditioned medium of BALB/3T3 fibroblasts was due to mouse c-kit ligand. Recombinant c-kit ligand induced differentiation and proliferation of mast cell progenitors in early stages of culture. However, apparent selective growth of mast cells by c-kit ligand in cord blood cell cultures is mainly due to the effect of the cytokine to selectively maintain survival of immature mast cells. Electron microscopic analysis indicated that human mast cells developed by c-kit ligand were similar to human mast cells in the lung and gut mucosa, while those developed in coculture of cord blood cells with Swiss albino/3T3 fibroblasts were similar to skin mast cells. This conclusion was supported by the fact that the majority of mast cells developed by c-kit ligand contained only tryptase in their granules, whereas those developed in the cocultures contained both tryptase and chymase. It was also found that mast cells developed by c-kit ligand were immature even after culture for 14 weeks. Nevertheless, these cells express Fc epsilon RI, and could be sensitized with human IgE for anti-IgE-induced release of histamine, prostaglandin D2, and leukotriene C4.

Animals↗
PubMed1993

[Transfusion-related acute lung injury].

Transfusion related acute lung injury develops a few hours after transfusion of blood products and is characterized by fever, chills, severe dyspnea and bilateral crepitations. Chest x-ray reveals diffuse patchy infiltrates and blood gas analysis shows severe hypoxemia. It is caused by an immunologic reaction of antileukocyte antibodies which, in most cases, are transfused with blood products. We present 2 patients with this syndrome who responded to large doses of corticosteroids (1 g methyl prednisolone) and made full recoveries within 96 hours. Medical personnel should be aware of this unique subtype of the adult respiratory distress syndrome, which responds to corticosteroids and has a favorable prognosis.

Acute Disease↗
PubMed1993

Recurrent transient bone marrow hypoplasia associated with pregnancy.

A 24-year-old female was admitted for evaluation of thrombocytopenia during her second pregnancy. During the second trimester of her first pregnancy, the patient developed aplastic anemia which resolved completely following termination of pregnancy. Three and a half years later she was admitted in the third trimester of pregnancy suffering from severe thrombocytopenia and hypoplastic bone marrow which improved after a normal delivery. To the best of our knowledge this is the first description of recurrent bone marrow hypoplasia associated with pregnancy.

Adult↗
PubMed1993

The response to treatment in chronic idiopathic thrombocytopenic purpura (ITP).

Immune thrombocytopenic purpura (ITP) is a relatively common illness. The initial recommended therapy is glucocorticoids, however due to low response rate and high rate of relapses, the second preferred line of therapy is splenectomy. About 60% of the patients respond to this therapy. A retrospective study performed in Israel in 226 children and 446 adults with ITP has evaluated the response to steroids and splenectomy. The response rates were similar to reported studies and no significant differences were observed between children and adults. The possibilities of treating patients who fail splenectomy and exhibit refractory disease are summarized.

Adolescent↗
PubMed1992

Low molecular weight heparin for Hickman catheter--induced thrombosis in thrombocytopenic patients undergoing bone marrow transplantation.

BACKGROUND: Patients with an indwelling central venous catheter are prone to development of thrombotic complications. Thrombocytopenia in patients undergoing bone marrow transplantation (BMT) generally is protracted. The management of thrombosis in thrombocytopenic patients is difficult because heparin and warfarin are relatively contraindicated because of the high risk of major bleeding. Low molecular weight heparin (LMWH) is a new class of antithrombotic drug. Enoxaparin (Rhone Poulenc Rorer, Antony, France) is an LMWH that has been shown to be effective in the treatment and prophylaxis of venous thrombosis. Enoxaparin, with its high antithrombotic to anticoagulant ratio, may be safer than standard heparin in patients at high risk of hemorrhagic complications. METHODS: The authors report the cases of five thrombocytopenic patients, undergoing autologous BMT, in whom venous thrombosis developed related to a Hickman catheter. RESULTS: All the patients were treated with Enoxaparin and recovered promptly without hemorrhagic complications. CONCLUSIONS: The authors suggest that Enoxaparin is an effective drug in treating thrombocytopenic patients in whom acute venous thrombosis develops.

Adult↗
PubMed1992

The human recombinant c-kit receptor ligand, rhSCF, induces mediator release from human cutaneous mast cells and enhances IgE-dependent mediator release from both skin mast cells and peripheral blood basophils.

The gene product of the steel locus of the mouse represents a growth factor for murine mast cells and a ligand for the c-kit proto-oncogene receptor, a member of the tyrosine kinase receptor class of oncogenes (for review, see O. N. Witte. 1990. Cell 63:5). We have studied the effect of the human recombinant c-kit receptor ligand stem cell factor (rhSCF) on the release of inflammatory mediators from human skin mast cells and peripheral blood basophils and compared its activity to that of rhIL-3, rhSCF (1 ng/ml to 1 microgram/ml) activated the release of histamine and PGD2 from mast cells isolated from human skin. Analysis by digital video microscopy indicated that purified human skin mast cells (84 +/- 5% pure) responded to rhSCF (0.1 to 1 microgram/ml) challenge with a rapid, sustained rise in intracellular Ca2+ levels that was accompanied by secretion of histamine. A brief preincubation (10 min) of mast cells with rhSCF (0.1 pg/ml to 1 ng/ml) significantly enhanced (100 +/- 35%) the release of histamine induced by anti-IgE (3 micrograms/ml), but was much less effective on IgE-mediated release of PGD2. In contrast, a short term incubation with rhSCF did not potentiate the secretion of histamine activated by substance P (5 microM). A 24-h incubation of mast cells with rhSCF did not affect the release of mediators induced by anti-IgE (3 micrograms/ml), probably due to receptor desensitization, rhSCF (1 ng/ml to 3 micrograms/ml) neither caused release of histamine or leukotriene C4 (LTC4) release from leukocytes of 14 donors, nor induced a rise in intracellular Ca2+ levels in purified (greater than 70%) basophils. Brief preincubation (10 min) of leukocytes with rhSCF (1 ng/ml to 3 micrograms/ml) caused an enhancement (69 +/- 11%) of anti-IgE-induced release of histamine that was significant at concentrations as low as 3 ng/ml (p less than 0.05), whereas it appeared less effective in potentiating IgE-mediated LTC4 release. In contrast, a prolonged incubation (24 h) with rhSCF (0.1 pg/ml to 100 ng/ml) did not enhance the release of histamine or LTC4 induced by anti-IgE (0.1 microgram/ml), whereas rhIL-3 (3 ng/ml) significantly potentiated the release of both mediators.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1992

In vitro culture of common acute lymphoblastic leukemia blasts: effects of interleukin-3, interleukin-7, and accessory cells.

We investigated the effects of interleukin-3 (IL-3), IL-7, IL-1, and IL-6, of irradiated bone marrow-derived fibroblasts (Fb) and of in vitro matured peripheral blood macrophages (M phi), on the survival, proliferation, and maturation of purified blasts from nine common acute lymphoblastic leukemias (cALLs) in 7-day suspension culture. Exposure to IL-3, IL-7, IL-1, and IL-6 resulted in a mean 2.8-, 1.5-, 1.4-, and 1.6-fold stimulation of 3H-thymidine (3H-TdR) incorporation, respectively. Cocultures of cALL blasts with irradiated M phi, either allowing direct cell-cell contact or preventing it by membrane filters, or with irradiated Fb, resulted in a mean 31.7-, 4.1-, and 11.2-fold increase of 3H-TdR incorporation, respectively. Southern blot analysis of immunoglobulin and T-cell receptor (TCR) gene rearrangements before and after culture indicated exclusive proliferation of the leukemic clone in three of eight samples, whereas additional generation of nonleukemic cells was found in five samples. Polyclonal growth pattern corresponded to the detection of heterogeneous cell populations using FACS analysis. Survival of cALL blasts as defined by the detection of cells coexpressing both CD10 and CD19 after culture was supported by accessory cells in five of eight samples. No evidence of induced lymphoid maturation was found under any culture condition. Our data demonstrate supportive effects of stromal cells on cALL growth, which cannot be replaced by IL-3 or IL-7.

Blotting, Southern↗
PubMed1992

Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand.

It is now established that the subclasses of mast cells (MC) that reside in mucosal and serosal environments can be distinguished from one another in terms of their expression of specific secretory granule-localized proteases and proteoglycans. Further, the hematopoietic- and connective tissue-derived cytokines that regulate expression of the genes that encode these constituents of the granule can now be identified using recently developed gene-specific probes and recombinant cytokines. When bone marrow-derived MC (BMMC) were developed with recombinant interleukin 3 (rIL-3) and maintained with this cytokine in the absence or presence of recombinant c-kit ligand (rKL), they remained safranin-, produced almost no 35S-labeled heparin proteoglycans, and contained greater levels of mouse MC protease (MMCP) -5 mRNA and mast cell carboxypeptidase A (MC-CPA) mRNA than MMCP-6 mRNA. They did not contain MMCP-4 or -2 mRNA, genes expressed late in the differentiation of progenitor cells into serosal and mucosal MCs, respectively. In contrast, BMMC developed with rKL alone or by sequential culture in medium containing rIL-3 followed by rKL expressed high levels of MMCP-4 and -6 mRNA, as well as the transcripts that encode MMCP-5 and MC-CPA. Although rKL-developed BMMC were safranin+ and produced substantial amounts of 35S-labeled heparin proteoglycans, they contained only minimal amounts of histamine and MC-CPA enzymatic activity relative to serosal MC. These are the first studies to characterize the transcriptional granule phenotype of a population of BMMC derived using any recombinant cytokine, to demonstrate a dissociation between histochemical staining and granule maturation, and to demonstrate antagonistic regulation of late expressed protease genes by a cytokine.

Animals↗
PubMed1992

The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor.

Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are multifunctional cytokines with many similar activities. LIF is structurally and functionally related to another cytokine, Oncostatin M (OSM), that binds to the high-affinity LIF receptor but not to the low-affinity LIF receptor. A complementary DNA was isolated that encodes the high-affinity converting subunit of the LIF receptor. The converter conferred high-affinity binding of both LIF and OSM when expressed with the low-affinity LIF receptor and is identical to the signal transducing subunit of the IL-6 receptor, gp130. The gp130 subunit alone confers low-affinity binding of OSM when expressed in COS-7 cells. This receptor system resembles the high-affinity receptors for granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5, which share a common subunit.

Animals↗