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Biomedical subjects

W E Fibbe

Publications and source records attributed to W E Fibbe.

At least 127 records · Page 7Linked to original sources
PubMed1990

Interleukin-4. A regulatory protein.

Since its discovery in 1982, numerous biological activities of interleukin-4 (IL-4) have been described. Like other cytokines, IL-4 is highly pleiotropic, both with respect to the number of different target cells that are responsive to it and with respect to the number of different biological responses it elicits. Interleukin-4 was initially described as a costimulant for the proliferation of B lymphocytes stimulated with anti-IgM antibody. Synonyms for this cytokine are B cell growth factor-1 (BCGF-1) and B cell stimulatory factor-1 (BSF-1). After cloning of both the murine and human IL-4, the use of recombinant IL-4 enabled detailed studies of its biological functions. Many cell types, mainly of hematological origin, express receptors for IL-4. Accordingly, effects of IL-4 have been described on B lymphocytes, T lymphocytes, NK cells, mononuclear phagocytes, mast cells, fibroblasts and hematopoietic progenitor cells. Currently, there are three major areas in which IL-4 appears to play an important role: 1) regulation of B cell growth and of antibody isotype expression. In this context, a possible role for IL-4 in allergic reactions is of special interest. 2) Stimulation of T cell growth and the generation of cytotoxic T lymphocytes. In addition to the suppressive effects on the induction of non HLA-restricted cellular cytotoxicity by natural killer- (NK) and lymphokine-activated killer (LAK) cells, this suggests a role for IL-4 in the regulation of cellular immune responses. 3) Regulation of the growth and differentiation of hematopoietic bone marrow stem cells. IL-4 itself does not induce proliferation of hematological progenitor cells but it can modulate the growth-factor dependent proliferation of these cells. In this review the biological functions of IL-4, reported until present, are discussed.

Animals↗
PubMed1990

Increased numbers of circulating haematopoietic progenitor cells after treatment with high-dose interleukin-2 in cancer patients.

Immunotherapy with recombinant interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells has been applied to patients with metastatic cancers for its antitumour activity. In the present study we investigated the effects of in vivo administration of IL-2 (3 x 10(6) U/m2/d, continuously i.v.) on haematopoiesis. Six patients with disseminated renal cell carcinoma, treated with IL-2 and LAK cells, were monitored for the numbers of white blood cells and circulating haematopoietic progenitor cells (HPC). During IL-2 treatment lymphopenia developed, followed by lymphocytosis after discontinuation of IL-2 infusions. IL-2 administration also resulted in neutrophilia and eosinophilia. Absolute numbers of circulating HPC declined markedly during IL-2 treatment. However, after completing IL-2 infusions, the numbers of circulating erythroid (BFU-E), myeloid (CFU-GM) and multipotential progenitor cells (CFU-GEMM) strongly increased, reaching a maximum after 5 d (day 10 from the start of IL-2 treatment). This increase did not result from repeated leucaphereses, since patients treated with IL-2 alone showed a similar response. In comparison with pretreatment levels the pool of circulating HPC expanded about 20-fold. This study illustrates that IL-2 treatment has a biphasic effect on the frequency of circulating BFU-E, CFU-GM and CFU-GEMM, causing a decrease during IL-2 infusion, followed by an increase after IL-2 administration. The total number of progenitor cells harvested by four consecutive leucaphereses is in the range that is commonly used for peripheral blood stem cell autografting.

Carcinoma, Renal Cell↗
PubMed1990

Acquired severe aplastic anaemia in adults--a single centre study with 13 years follow-up.

Between 1974 and July 1987 the diagnosis of severe aplastic anaemia (SAA) was confirmed in 82 patients. Overall actuarial survival was 57% at 7 yr. Four patients recovered while receiving conventional therapy, and four died before treatment with antithymocyte globulin (ATG) or bone marrow transplantation (BMT) could be initiated. Nineteen patients (median age 19.6 yr) were treated with allogeneic BMT (11 as initial therapy, eight after ATG). Incidence of acute and chronic graft versus host disease was high, occurring in 14/16 and 4/11 patients at risk, respectively. Survival of BMT patients (18/19 transfused) was 32% at 7 yr. Of 63 patients treated with ATG, survival was 63% at 7 yr but decreased to 43% at 11 yr. The 2.5 yr survival following ATG was influenced by pretreatment disease severity (defined by percentage reticulocytes, granulocyte and platelet counts), age and--in patients under 45 yr of age--by sex. However, pretreatment disease severity was less in patients aged between 20 and 45 yr and in females. Concomitant androgen therapy, animal source of ATG, interval diagnosis--ATG (which was in general rather short) and aetiology did not influence survival. Thirty-four patients became transfusion independent for up to 26 months after ATG. A gradual increase in granulocyte and platelet counts could be observed over a period of many years, and 26 patients recovered to show a normal haemoglobin level, granulocytes greater than or equal to 1.0 X 10(9)/l and platelets greater than or equal to 100 X 10(9)/l). Late complications (paroxysmal nocturnal haemoglobinuria, myelodysplastic syndrome/acute leukaemia, hepatocellular carcinoma) were observed in nine patients who survived with autologous marrow function. Five died within 12 yr of initial therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Eosinophilic fasciitis after allogeneic bone marrow transplantation.

We describe a patient with eosinophilic fasciitis (EF) developing 8 months after an allogeneic bone marrow transplantation for acute myeloblastic leukemia. The patient responded to low dose prednisone. A full thickness skin-muscle-fascia biopsy detected the characteristic fascial changes of EF and distinguished it from other forms of chronic graft-versus-host-disease (GVHD). This distinction may be important since EF after bone marrow transplantation may occur more often and it may respond to treatment with low doses of prednisone whereas chronic GVHD usually requires more extensive immunosuppressive treatment.

Bone Marrow Transplantation↗
PubMed1989

Interleukin-1 synergizes with granulocyte-macrophage colony-stimulating factor on granulocytic colony formation by intermediate production of granulocyte colony-stimulating factor.

Interleukin-1 (IL-1) was found to act synergistically with granulocyte-macrophage colony-stimulating factor (GM-CSF) on granulocytic colony growth of normal human bone marrow cells, depleted of mononuclear phagocytes and T lymphocytes. Using CD34/HLA-DR-enriched bone marrow cells we demonstrated that this activity of IL-1 was not a direct action on hematopoietic progenitor cells, but an effect of an intermediate factor produced by residual accessory cells in response to IL-1. Neutralization experiments using an anti-IL-6 antiserum showed that IL-1-induced IL-6 did not contribute to the observed synergy. Furthermore, IL-6 by itself had neither a direct stimulatory effect on CFU-GM colony growth, nor did it act synergistically with GM-CSF on granulocytic or monocytic colony formation. Neutralization experiments with an anti-G-CSF monoclonal antibody showed that IL-1-induced G-CSF production was responsible for the synergy with GM-CSF. Using combinations of G-CSF and GM-CSF this synergistic activity could be detected at concentrations of G-CSF as low as 0.1 ng/mL (10 U/mL). Our results indicate that IL-1, but not IL-6, stimulates the GM-CSF-dependent proliferation of relatively mature myeloid progenitor cells in the presence of small numbers of accessory cells.

Antigens, CD34↗
PubMed1989

Inhibition of human macrophage colony formation by interleukin 4.

We investigated the effects of human rIL-4 on in vitro hematopoiesis. A profound inhibition of macrophage colony formation by IL-4 was observed, whereas colony growth of other lineages was not affected. Inhibition of macrophage colony growth was not restricted to GM-CSF-induced colony growth but was also present in cultures stimulated with M-CSF. This inhibition was not only observed in cultures of light density bone marrow cells, but also in cultures of monocyte- and T lymphocyte-depleted bone marrow cells. Since a similar inhibition was observed in cultures of CD34+HLA-DR+-enriched bone marrow cells, a direct action of IL-4 on monocyte-committed progenitor cells is suggested.

Antigen-Presenting Cells↗
PubMed1989

Normal hematopoietic progenitor cells and malignant lymphohematopoietic cells show different susceptibility to direct cell-mediated MHC-non-restricted lysis by T cell receptor-/CD3-, T cell receptor gamma delta+/CD3+ and T cell receptor-alpha beta+/CD3+ lymphocytes.

To evaluate the capability of NK cells and cytotoxic T lymphocytes to interact with normal hematopoietic progenitor cells (HPC), as compared to neoplastic lymphohematopoietic cells, we investigated inhibition of colony growth of these cell populations in semi-solid culture systems, after incubation with cloned cytotoxic effector cells. Three different types of cloned effector cells were investigated: TCR-/CD3- NK cells, TCR-gamma delta+/CD3+ cells, and TCR-alpha beta+/CD3+ cytotoxic T lymphocytes. Effector cells showed differential levels of tumor cell colony inhibition, but no MHC-non-restricted lysis of normal HPC was observed. Pre-stimulation of normal HPC by culturing on established stromal layers had no effect. Cell-mediated lysis of HPC only occurred by Ag-specific MHC-restricted lysis by CTL, or by antibody-dependent cellular cytotoxicity. In cell mixing experiments, irradiated tumor cells, but not normal bone marrow cells inhibited tumor cell lysis. Furthermore, cloned effector lymphocytes were able to specifically eliminate malignant cells from tumor contaminated bone marrow without damaging normal HPC. When fresh leukemic cells were used as targets, growth of acute myeloblastic leukemia colonies was inhibited after incubation with several cytotoxic effector clones, whereas chronic myeloid leukemia precursor cells showed limited sensitivity to MHC-non-restricted cytolysis. These results indicate that MHC-non-restricted cytolysis by NK cells is selectively directed against neoplastic cells and not against normal HPC.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1989

Simultaneous production of interleukin 6, interferon-beta and colony-stimulating activity by fibroblasts after viral and bacterial infection.

Different viruses were compared with the double-stranded RNA poly(rI).poly(rC) and interleukin (IL) 1 for their IL 6-inducing potential in several human and animal cell types. The laboratory viruses Sendai, Mengo and Newcastle disease virus were found to dose dependently stimulate IL 6 production in diploid fibroblasts. A similar effect was obtained with the human pathogens, measles and rubella virus. Concomitantly with IL 6, two other cytokine activities, i.e., interferon-beta and colony-stimulating activity for granulocytes and monocytes, were induced. In addition, these three activities were also produced by fibroblasts in response to Escherichia coli, whereas lipopolysaccharide was only marginally active. The specificity of the induction phenomenon was confirmed by the lack of IL 6 induction with inactivated infectious agents and by the complete neutralization of produced IL 6 by specific antibodies. This study indicates that the coordinate production of hemopoietic growth factors and interferon, originating from cells that do not classically belong to the immune system, can influence the local and systemic reactions observed during host defence against various infectious agents.

Animals↗
PubMed1989

The biological activities of interleukin-1.

Interleukin-1 (IL-1) refers to a hormone-like polypeptide that mediates a broad spectrum of activities in host defence as well as a variety of disease processes. Originally described as a substance produced by activated macrophages, IL-1 is now recognized as a polypeptide produced by many other cell types. Two distinct genes have been identified that code for two structurally related forms of the molecule, termed IL-1 alpha and beta. IL-1 is the primary mediator of the acute phase response and is responsible for many of the changes associated with the onset of infection. It is involved in the immune response to antigenic challenge. IL-1 induces fever and has profound endocrinologic, neurologic, metabolic and hematologic effects. Both forms of IL-1 bind to a common receptor that has been identified on a variety of cell types including lymphocytes, hepatocytes, endothelial cells and fibroblasts. Many of the activities of IL-1 are mediated by the induction of other cytokines like IL-2, IL-6, interferons, tumor necrosis factor, and colony-stimulating factors. In animals IL-1 protects against the effects of radiation, it enhances natural resistance of infection, and it stimulates bone marrow recovery after myelosuppression. These studies suggest that IL-1 may be used as a therapeutic agent.

Acute-Phase Reaction↗
PubMed1989

Interleukin 1 and poly(rI).poly(rC) induce production of granulocyte CSF, macrophage CSF, and granulocyte-macrophage CSF by human endothelial cells.

Electrophoretically pure human interleukin 1 (IL-1) beta was found to stimulate human endothelial cells in monolayer culture to elaborate colony-stimulating activity (CSA). Supernatant fluids from cultures stimulated with increasing concentrations of IL-1 were found to stimulate colony formation of myeloid (CFU-GM), erythroid (BFU-E), and multipotent (CFU-GEMM) progenitor cells in a dose-dependent fashion. The effect on mixed colony formation, however, was less than on CFU-GM and BFU-E growth. Similar to IL-1, the double-stranded RNA polyriboinosinic-polyribocytidilic acid (poly[rI].poly[rC]) also stimulated release of CSA by endothelial cells in a dose-dependent manner. The kinetics of IL-1-induced CSA release as opposed to poly(rI).poly(rC)-induced release were found to be different, in that poly(rI).poly(rC)-induced CSA production occurred more slowly. An anti-IL-1 beta antiserum was able to completely neutralize the IL-1-induced CSA release, but had no effect on poly(rI).poly(rC)-dependent CSA production, indicating that the latter effect was mediated by other mechanisms than intermediate production of IL-1 beta. Using specific immunologic assays, IL-1- as well as poly(rI).poly(rC)-inducible production of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, and macrophage CSF was found. The release of CSF from endothelial cells in response to IL-1 may be a mechanism for stimulating production of neutrophils and mononuclear phagocytes, and for attracting and activating these cells at sites of inflammation.

Bone Marrow↗
PubMed1989

Interleukin-6 is not involved in the interleukin-1-induced production of colony-stimulating factors by human bone marrow stromal cells and fibroblasts.

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a role in regulation of hematopoiesis. Because IL-6 is coinduced with colony-stimulating factors (CSFs) by various cell types in response to stimulation with IL-1, we investigated whether IL-6 is involved in the IL-1-induced production of CSF by human bone marrow (BM) cells in long-term culture or human fibroblasts. We showed that IL-6 does not induce CSF production by these cells. Neither addition of exogenous IL-6 nor neutralization of endogenous production of IL-6 by an anti-IL-6 monoclonal antibody (MoAb) diminished the IL-1-induced colony-stimulating activity (CSA), indicating that IL-6 did not act synergistically with IL-1. Finally, IL-6 did not influence the kinetics of IL-1-induced CSA production by human fibroblasts. We conclude that IL-6, either alone or in combination with IL-1, does not induce CSF production by human BM stromal cells or fibroblasts.

Bone Marrow↗
PubMed1989

CD3+, 4+ and/or 8+ T cells and CD3+, 4-, 8- T cells repopulate at different rates after allogeneic bone marrow transplantation.

The antigen receptors of the majority of peripheral blood T lymphocytes are constituted of alpha- and beta-chains in association with CD3. The phenotype of those T cell receptor-alpha, beta cells is CD3+, 4+ and/or 8+. The small subset of CD3+, 4-, 8- T cells includes TCR-gamma, delta cells. These two T cell subsets have different TCR gene rearrangement patterns, tissue distributions and mechanisms of antigen recognition. We studied the repopulation of both T cell subsets in 20 allogeneic marrow graft recipients in relation to the type of graft (T cell-depleted versus non-depleted) and the occurrence of active cytomegalovirus (CMV) infection, using three-color immunofluorescence and flow cytometry. The CD3+, 4+ and/or 8+ and CD3+, 4-, 8- T cells had clearly different repopulation patterns. At 1 month post-BMT, they had repopulated the blood to similar levels. Thereafter, the CD3+, 4+ and/or 8+ T cells increased further in number, whereas the CD3+, 4-, 8- T cells stabilized on average between 100 and 200 x 10(6)/l. The nine recipients of T cell-depleted marrow grafts showed a relatively delayed repopulation of their CD3+, 4+ and/or 8+ T cells compared with the 11 recipients of non-depleted marrow. In contrast, the repopulation rate of the CD3+, 4-, 8- T cells was similar in both groups. The occurrence of active CMV infection post-BMT was associated with an increased rate of repopulation of the CD3+, 4+ and/or 8+ T cells, particularly those expressing HNK1, but did not affect the repopulation of the CD3+, 4-, 8- T cells.

Adolescent↗