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Biomedical subjects

W E Fibbe

Publications and source records attributed to W E Fibbe.

At least 109 records · Page 6Linked to original sources
PubMed1991

Clonal hematopoiesis in patients with acquired aplastic anemia.

To determine whether patients with acquired asplastic anemia (AA) exhibit clonal hematopoiesis, we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Of the 19 female patients studied, 18 (95%) patients were informative for at least one marker. Of these, eight patients (42%) were heterozygous for PGK1, two (11%) for HPRT, and 16 (84%) for M27 beta. In 13 (72%) patients, a monoclonal pattern was found. Analysis of purified cell suspensions of four of these patients showed that both myeloid and lymphoid cells were of monoclonal origin, indicating the involvement of an early stem cell. The four patients who were studied at presentation all showed a monoclonal pattern. One of these patients showed a spontaneous recovery despite persistent clonal hematopoiesis. The presence of either clonal or polyclonal hematopoiesis did not show a correlation with the response to antithymocyte globulin (ATG) treatment. A relapse after ATG was also seen in a patient exhibiting polyclonal hematopoiesis. Conversely, a monoclonal pattern did not preclude the occurrence of a partial or complete response to ATG. Other potential markers to study clonality, including cytogenetic abnormalities or point mutations of the N-ras protooncogene, were not found in any of the patients. It is concluded that patients with AA may exhibit clonal hematopoiesis. The significance with respect to evolution to disorders with clonal hematopoiesis like paroxysmal nocturnal hemoglobinuria, myelodysplasia, and acute leukemia remains to be determined.

Adolescent↗
PubMed1991

Growth inhibition of clonogenic leukemic precursor cells by minor histocompatibility antigen-specific cytotoxic T lymphocytes.

Minor histocompatibility (mH) antigens appear to play a major role in bone marrow transplantation (BMT) using HLA-identical donors. Previously, we reported the isolation of major histocompatibility complex (MHC)-restricted mH antigen-specific cytotoxic T lymphocytes (CTL) from patients with graft-vs.-host disease or rejection after HLA-identical BMT. We have demonstrated that mH antigens can be recognized on hematopoietic progenitor cells, and residual recipient CTL specific for mH antigens expressed on donor hematopoietic progenitor cells may be responsible for graft rejection in spite of intensive conditioning regimens in HLA-identical BMT. Here, we investigated whether mH antigen-specific CTL directed against the mH antigens HA-1 to HA-5 and the male-specific antigen H-Y were capable of antigen-specific inhibition of in vitro growth of clonogenic leukemic precursor cells. We demonstrate that mH antigen-specific CTL against all mH antigens tested can lyse freshly obtained myeloid leukemic cells, that these mH antigen-specific CTL can inhibit their clonogenic leukemic growth in vitro, and that this recognition is MHC restricted. We illustrate that leukemic (precursor) cells can escape elimination by mH antigen-specific CTL by impaired expression of the relevant MHC restriction molecule. We suggest that mH antigen-specific MHC-restricted CTL may be involved in vivo in the graft-vs.-leukemia reactivity after BMT.

Acute Disease↗
PubMed1991

Minor histocompatibility antigen-specific cytotoxic T cell lines, capable of lysing human hematopoietic progenitor cells, can be generated in vitro by stimulation with HLA-identical bone marrow cells.

Recipient-antidonor alloreactivity before HLA genotypically identical bone marrow transplantation (BMT) between donor-recipient pairs that are negative in the mixed lymphocyte reaction (MLR), the cell-mediated lympholysis (CML) assay, and the lymphocyte crossmatch was not detectable in the majority of cases, using recipient peripheral blood lymphocytes (PBL) collected before BMT as responder cells and donor PBL as stimulator cells. However, when donor bone marrow mononuclear cells (BMMNC) instead of PBL were used as stimulator cells, we could detect donor-specific alloreactivity in 7 of 10 HLA genotypically identical donor-recipient pairs. To demonstrate that this alloreactivity was minor histocompatibility (mH) antigen specific and not directed against HLA class I splits or variants, two cytotoxic T lymphocyte (CTL) lines were tested in further detail against phytohemagglutinin (PHA) blasts from pairs of HLA genotypically identical siblings positive for the HLA class I restriction molecule. Both CTL lines recognized mH antigens, as illustrated by the differential recognition of PHA blasts of one of the two siblings from several pairs. The potential role of these mH antigen-specific CTLs in bone marrow graft rejection was demonstrated by the mH antigen-specific growth inhibition of hematopoietic progenitor cells from the original bone marrow donor and from HLA class I restriction molecule-positive individuals who expressed the mH antigens on their PBL and BMMNC. Our assay can be used in HLA genotypically identical BMT to detect a recipient-antidonor response, directed against cellularly defined mH antigens expressed on donor HPC, BMMNC, and PBL, before transplantation.

Bone Marrow Transplantation↗
PubMed1991

Differential stimulatory and inhibitory effects of interleukin 4 on granulocytic and monocytic colony formation in human bone marrow cultures.

Both stimulatory and inhibitory effects of interleukin (IL) 4 on myelopoiesis have been described. In this paper we further define the specificity of these effects. IL-4 was added to cultures of bone marrow cells in which colony formation was stimulated with several colony-stimulating factors (CSFs): monocyte CSF (M-CSF), granulocyte CSF (G-CSF), IL-3, IL-5 and conditioned medium from phytohemagglutinin-stimulated peripheral blood cells (PHA-CM). Inhibition of monocytic colony formation by IL-4 was observed in cultures that were stimulated with IL-3 or with PHA-CM, similar to the inhibition in M-CSF- or GM-CSF-stimulated cultures. The enhancement of granulocytic colony formation by IL-4 was restricted to G-CSF-induced colony growth. No enhancement was observed in cultures that were stimulated with IL-5 or with PHA-CM from which the G-CSF was neutralized by anti-G-CSF antibodies. Both the inhibiting and enhancing effects of IL-4 were preserved in cultures that were stimulated with concentrations of CSF that exceeded more than tenfold the plateau concentrations. Enhancement of granulocytic and inhibition of monocytic colony formation by IL-4 occurred simultaneously in cultures stimulated with PHA-CM or with a combination of G-CSF and M-CSF. In summary, we show that the inhibiting effect of IL-4 on monocytic colony formation is independent of the growth factor used, whereas the stimulatory effect of IL-4 on granulocytic colony formation is restricted to G-CSF-induced cultures. Simultaneous occurrence of both effects results in preferential growth of granulocytes.

Bone Marrow↗
PubMed1991

Neutropenic enterocolitis following treatment with cytosine arabinoside-containing regimens for hematological malignancies: a potentiating role for amsacrine.

A retrospective clinical study was performed to determine the clinical impact of neutropenic enterocolitis (NE) in adult patients with acute leukemia and non-Hodgkin's lymphoma treated with cytosine arabinoside (Ara-C)-containing regimens. The diagnosis of NE was restricted to conditions with clinical signs of peritonitis, ileus, or intestinal hemorrhage. Forty episodes of NE were noted during 461 Ara-C-containing courses (8.6%) in 36 of 211 patients (17%) over a 6-year period. Clinically, 18 cases of ileus, 16 cases of peritonitis, and 6 cases of intestinal hemorrhage were recognized as the most important presentation of NE. NE started about 2 weeks after the initiation of the chemotherapy and lasted for an average of 1 week. All patients had a profound neutropenia. The incidence of septicemia was higher during courses complicated by NE (p less than 0.001). All cases of NE were treated with conservative measures. The mortality was 22.5% and represented one third of all therapy-related deaths during the pancytopenic period. The incidence of NE was significantly higher in courses consisting of high-dose Ara-C for 6 consecutive days when the drug was combined with amsacrine for 3 consecutive days (p less than 0.0001).

Adult↗
PubMed1991

Correction of neutropenia associated with chronic lymphocytic leukaemia following treatment with granulocyte-macrophage colony-stimulating factor.

A patient with chronic lymphocytic leukaemia (CLL) and severe persisting neutropenia due to marrow infiltration of his leukaemia, developed bilateral Legionella pneumophila pneumonia for which he was treated with erythromycin, rifampin and ciprofloxacin. To increase the number of circulating polymorphonuclear neutrophils, the patient was treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) at a dose of 2 micrograms protein/kg bodyweight s.c./12 h. GM-CSF therapy resulted in a sustained rise of the neutrophil count from the fifth day of treatment onwards, without showing an effect on the number of circulating leukemic cells. The patient completely recovered from his pneumonia. It is suggested that the rise of the neutrophil count, due to GM-CSF, contributed to the improvement of the infection of this patient. Our observation illustrates that GM-CSF can be given safely to CLL-patients and that it can be used effectively in CLL patients with severe bacterial infections to restore neutropenia.

Granulocyte-Macrophage Colony-Stimulating Factor↗
PubMed1991

The efficacy of itraconazole against systemic fungal infections in neutropenic patients: a randomised comparative study with amphotericin B.

In a randomised clinical trial, we compared the efficacy of the new triazole drug itraconazole (200 mg orally twice daily) with that of amphotericin B (0.6 mg/kg daily or 0.3 mg/kg in combination with flucytosine) in neutropenic (less than 500 x 10(6)/l neutrophils) patients with proven or highly suspected systemic fungal infections. Patients with unexplained fever alone were not included in the study. Of the 40 patients enrolled, 32 patients (16 males, 16 females) were evaluable. Sixteen patients (median age 49 years) were treated with itraconazole for a median period of 20 days and 16 patients (median age 32 years) received amphotericin B for a median period of 13 days. The overall clinical response was 10/16 (63%) for patients treated with itraconazole and 9/16 (56%) for patients treated with amphotericin B (P greater than 0.90). Itraconazole seemed to be more effective against Aspergillus infections, whereas amphotericin B seemed to be more effective against candidal infections, although the differences were not statistically significant.

Amphotericin B↗
PubMed1991

Effect of subcutaneously administered human recombinant erythropoietin on erythropoiesis in patients with myelodysplasia.

In a phase II study, 12 patients with a myelodysplastic syndrome (MDS) and anaemia (nine transfusion-dependent) were treated with recombinant human erythropoietin (rHuEpo) to assess the therapeutic effect on erythropoiesis and on transfusion requirement. Patients with a low risk of developing acute leukaemia were included, i.e. refractory anaemia (RA), RA with ringed sideroblasts (RARS) and RA with excess blasts (RAEB), providing the percentage of myeloblasts in the bone marrow did not exceed 10%. Recombinant HuEpo treatment was initiated at a dose of 50 units/kg body weight and administered subcutaneously three times weekly. At 3-week intervals the dose was increased with 50 units/kg per injection, until after 15 weeks a maximum dose of 250 units/kg three times weekly was reached. All patients completed the study. Recombinant HuEpo was well tolerated and no serious side effects were seen. There was no evidence of the emergence of a new malignant clone in response to rHuEpo as shown by sequential karyotyping. In none of the patients was an increase in haemoglobin level or a diminished red blood cell transfusion requirement seen. In four out of 10 evaluable sequential bone marrow smears, an increase in erythropoiesis was seen, suggesting stimulation of ineffective red cell production. One of these patients also showed a rise in reticulocyte count. The number of erythroid progenitor cells (BFU-E and CFU-E) in blood and bone marrow was not affected by rHuEpo treatment. Also no change in the number of myeloid progenitor cells (CFU-GM) in blood and bone marrow was noted. In conclusion, subcutaneous treatment with rHuEpo at dosages up to 250 units/kg body weight (three times weekly) fails to increase the haemoglobin level or to diminish the transfusion requirement in patients with MDS and anaemia. It is unclear whether higher doses of rHuEpo are effective or whether patients with less severe anaemia who are transfusion independent, have a higher likelihood of response.

Adult↗
PubMed1991

Detection of trisomy 8 in hematological disorders by in situ hybridization.

An alphoid repetitive DNA (D8Z2) probe specific for the pericentromeric region of chromosome 8 was used to detect extra copies of chromosome 8 in bone marrow cells obtained from 10 patients with hematological disorders and five controls. Numerical aberrations of chromosome 8 were established by conventional banding techniques. Trisomy 8 was found in four patients with myelodysplastic syndrome (MDS) and three with acute myeloid leukemia (AML). Three additional patients with MDS exhibited an extra chromosome 8 in only one metaphase. In five of the seven trisomy cases, the presence of the trisomy 8 clone was confirmed by in situ hybridization (ISH). In one case of AML with trisomy 8, detected by GTG-banding, no significant numbers of cells containing three spots were found using the alphoid repetitive probe; however, hybridization with a chromosome 8-specific library revealed that the alleged extra chromosome 8 was a translocation chromosome containing only the long arm of chromosome 8. Due to a lack of material, it was not possible to achieve optimal ISH results on the trisomy 8 bone marrow cells of patient 7. In the three MDS patients with a single trisomy 8 metaphase, a slight, albeit significant, increase of trisomy 8 interphase cells was found with ISH. We conclude that this probe is useful for cytogenetic studies. Moreover, ISH, in general, is a powerful tool for precise classification of chromosomal aberrations and can also contribute significantly to the clinical evaluation of patients with hematological disorders.

Chromosome Aberrations↗
PubMed1991

The role of interleukin-1 in hematopoiesis.

The polypeptide interleukin 1 (IL-1) is the primary mediator of the acute-phase response and is responsible for many changes that are associated with the onset of infection. It induces fever and has profound endocrinologic metabolic and hematologic effects. Two structurally related forms of IL-1 have been described, termed IL-1 alpha and IL-1 beta. Both forms of IL-1 bind to a common receptor that is present on a variety of target cells. Recently, IL-1 has been recognized as a molecule that is important in the regulation of hematopoiesis. IL-1 induces the production of several different hematopoietic growth factors including granulocyte-macrophage, granulocyte and macrophage colony-stimulating factors and interleukin 6 by a variety of accessory cells. In addition, IL-1 acts synergistically with colony-stimulating factors in the proliferation of primitive hematopoietic progenitor cells. In vivo, the administration of IL-1 accelerates hematopoietic reconstitution after chemotherapy or radiation induced myelosuppression. In untreated animals, IL-1 may induce a shift of hematopoietic progenitor cells into the peripheral blood, and these cells may be used to repopulate the bone marrow of lethally irradiated recipients. These studies suggest that IL-1 may be used as a therapeutic agent to accelerate bone marrow recovery after myelosuppression.

Animals↗
PubMed1991

[Therapy of systemic mycoses in neutropenic patients using itraconazole. A comparative, randomized study with amphotericin B].

Systemic mycosis constitute a serious threat for the patient with granulocytopenia. The most important causative agents are Candida spp., Aspergillus spp. and, to a lesser extent, Cryptococcus neoformans, Mucoraceae and Pseudoallescheria boydii. Treatment of such infections with amphotericin B is difficult, because of the many side-effects of this medicine, such as hypotension, fever, shivering, thrombophlebitis, nephrotoxicity, renal tubular acidosis, hypokalaemia, anaemia and thrombocytopenia. In addition, the efficacy of amphotericin B in the treatment of proven mycotic infections in granulocytopenic patients is not very great. Itraconazole is a new, oral antifungal agent which is active in vitro and in animal experiments against both Candida and Aspergillus. In patients without granulocytopenia, itraconazole appeared to be effective in the treatment of deep Candida and Aspergillus infections. On the basis of the above data, a randomized comparative investigation was carried out unto the efficacy of amphotericin B and itraconazole in the treatment of systemic mycoses in neutropenic patients.

Adolescent↗
PubMed1991

Interleukin 4 down-regulates the expression of CD14 and the production of interleukin 6 in acute myeloid leukemia cells.

On normal monocytes, interleukin 4 (IL-4) down-regulates the production of several proteins that are produced in response to bacterial cell wall lipopolysaccharides (LPS), among others IL-6. In addition, IL-4 was shown to down-regulate the expression of the monocytic differentiation marker CD14, recently identified as a receptor for LPS. Since (autocrine) IL-6 is possibly involved in the proliferation and differentiation of acute myeloid leukemia cells with myelomonocytic differentiation (AML-M4/M5), we studied the effects of IL-4 on IL-6 production and CD14 expression by these cells. We found that IL-4 down-regulates both the expression of CD14 (n = 6) and the production of IL-6 (n = 9) in AML cells. Using Northern blot analysis, we found that IL-4 down-regulates the level of steady-state mRNA for both CD14 (two of three cases tested) and IL-6 (three cases tested).

Acute Disease↗
PubMed1991

Cytokine production by the bladder carcinoma cell line 5637: rapid analysis of mRNA expression levels using a cDNA-PCR procedure.

We have studied cytokine expression by the human bladder carcinoma cell line 5637 using a cDNA-PCR procedure. Transcripts for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-7, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, tumor-necrosis factor-alpha (TNF-alpha), and TNF-beta were constitutively present, whereas IL-3, IL-4, IL-5, and IL-9 mRNA sequences could not be detected. This expression pattern was not altered after 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulation (4 and 8 h) of 5637 cells. Relative expression levels of cytokines were assessed by limiting dilution of the cDNA pool. This procedure proved to be a semiquantitative technique when compared to Northern blot analysis.

Actins↗
PubMed1990

[Chimerism pattern following allogeneic bone marrow transplantation; a retrospective study of the connection with post-transplantation complications].

Allogeneic bone marrow transplantation is generally followed by disappearance of all host haematopoietic cells and replacement by donor cells, resulting in complete chimerism. In some cases, however, residual host cells can be detected after transplantation; this is called partial chimerism. We have analysed the chimerism pattern in 106 patients, by erythrocyte antigen typing, erythrocyte and leucocyte isoenzymes, immunoglobulin allotyping and karyotyping of bone marrow and blood. Recipients of a T cell-depleted marrow transplant exhibited partial chimerism significantly more often. In most cases this involved T lymphocytes, sometimes in combination with other cell populations. Persisting B lymphocytes of host origin were detected only in recipients of a T cell-depleted marrow graft. No relationship was found between chimerism pattern and GVHD, interstitial pneumonitis, relapse of the underlying disease or disease free survival.

Adult↗
PubMed1990

Rejection of bone-marrow graft by recipient-derived cytotoxic T lymphocytes against minor histocompatibility antigens.

A female patient showed rejection of a T-lymphocyte-depleted bone-marrow graft from her phenotypically HLA-identical father. Before bone-marrow transplantation, there was strong recipient anti-donor cellular cytotoxic reactivity directed against several minor histocompatibility (mH) antigens, including the male-specific H-Y antigen. After conditioning treatment, no recipient anti-donor cytotoxic activity could be detected, and good graft function was shown a month after transplantation. Thereafter, however, graft function deteriorated rapidly, while recipient-derived anti-donor cellular cytotoxic reactivity, against similar mH antigens, reappeared. The recipient-derived cytotoxic T lymphocytes could completely inhibit growth of donor haemopoietic progenitor cells both before and after bone-marrow transplantation. Thus, cytotoxic T lymphocytes can survive very intensive conditioning regimens, and residual recipient cytotoxic T lymphocytes directed against mH antigens expressed on donor haemopoietic progenitor cells may cause graft rejection after HLA-identical T-lymphocyte-depleted bone-marrow transplantation.

Adult↗