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P Valent

Publications and source records attributed to P Valent.

At least 217 records · Page 12Linked to original sources
PubMed1990

Human blood basophils synthesize interleukin-2 binding sites.

Recent data suggest that basophils express receptors for a variety of lymphokines. In this study we present the biochemical characterization of the interleukin-2 (IL-2) receptor on the basophil surface membrane. Highly enriched populations (purity: 92% to 99%) of blood basophils were obtained from chronic granulocytic leukemia (CGL) patients (n = 3) by negative selection using monoclonal antibodies (MoAbs) and complement. CGL basophils were found to bind CD25 MoAbs (n = 4) directed against different epitopes of the 55- to 60-Kd subunit of the IL-2 receptor (= Tac peptide). Immunoprecipitation experiments with lysates of purified CGL basophils and CD25 MoAbs showed a protein with a molecular weight of 60 Kd, equivalent to the Tac peptide on human T blasts. Quantitative binding studies and Scatchard plot analysis using radiolabeled recombinant human (rh) IL-2 indicated the presence of 12,000 +/- 4,700 low affinity IL-2 binding sites (kd = 66 nmol/L) per purified CGL basophil. Northern blot analysis with enriched CGL basophils showed two messenger RNA bands of 3.5 and 1.5 kilobases hybridizing to radiolabeled Tac cDNA. Immunoprecipitation of the Tac peptide from enriched basophils metabolically labeled with 35S-methionine showed active synthesis of the IL-2 receptor. Our results show that human blood basophils synthesize and express receptors for IL-2.

Antibodies, Monoclonal↗
PubMed1990

Why clinicians should be interested in interleukin-3.

Interleukin-3 (IL-3), a product of activated immune cells has recently been cloned and introduced in preclinical and clinical trials. The biological target-cell spectrum of IL-3 is broad and includes progenitor cells of various hematopoietic lineages as well as multiple stages of stem cell differentiation. IL-3 also induces growth of most primitive hemopoietic progenitors (CFU-blast). Synergistic effects on growth of myeloid cells (i.e. macrophages, eosinophils and blood basophils) are obtained by sequential use of IL-3 and later-acting myelopoietic cytokines. In addition, IL-3 supports terminal maturation, prolongs survival and enhances the functional properties of myeloid cells through high-affinity binding sites. In vivo administration of IL-3 is followed by an increase in peripheral white blood cell counts as well as by an increase in the number of circulating progenitor cells giving rise to mature hemopoietic cells in response to more lineage-restricted growth factors. IL-3 also regulates growth of leukemic cells and primes them to become more sensitive to cell cycle specific cytotoxic drugs. IL-3 apparently represents a novel and unique hemopoietic growth factor. Its clinical use should offer new strategies in the treatment of cytopenia, leukemic disease and in stem cell transplantation.

Animals↗
PubMed1990

Further characterization of surface membrane structures expressed on human basophils and mast cells.

Recently, we were able to establish the immunologic surface marker profile of human basophils and mast cells. In the present study, the characterization of these cell types was extended by the use of monoclonal antibodies (mAbs) to hemopoietic differentiation antigens. Basophils and mast cells were enriched by mAbs and complement from chronic myeloid leukemia blood (n = 5) and dispersed lung tissue (n = 4), respectively. A panel of 80 mAbs was tested for being reactive with purified cell populations using flow cytometry and/or a combined toluidine blue-immunofluorescence staining procedure. In addition to previous findings, basophils were found to react with mAbs directed against the 126-kilodalton dipeptidylpeptidase IV (CD26), platelet glycoprotein IIa (CD31), CD40 antigen known to share sequence homology with nerve growth factor receptor, leukosialin (CD43), CD44 antigen, the ICAM-1 antigen (CD54) and VIM2-reactive gangliosides involving the sialofucooligosaccharide sequence (CDw65L). Bsp-1 was found to be a specific marker for human basophils, whereas mast cells were not stained by this reagent. Basophils apparently lack CD22 antigen, gangliosides detected by CDw65 mAbs (except CDw65L) and CD71 antigen (transferrin receptor). Mast cells were found to express CD43 and CD44 antigen. In contrast, mast cells lack CD22, CD26, CD31, CD40 and CDw65 antigen. These results provide further evidence that both blood basophils and mast cells express a unique immunologic surface marker profile including binding sites for a variety of immunomodulating ligands and adhesion molecules.

Antibodies, Monoclonal↗
PubMed1990

Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia.

The prognostic significance of the expression of surface membrane antigens on the blasts of 123 consecutive patients with de novo acute myeloblastic leukemia (AML) was evaluated. For this purpose, reactivity of monoclonal antibodies (mAbs) CLB-ERY3 (antiblood-group H antigen), VIM-D5 (CD15), WT1 (CD7), MY7 (CD13), MY9 (CD33), VID-1 (antihuman leukocyte antigen locus DR [anti-HLA DR]), VIM-2 (CDw65L), VIM-13 (CD14), 63D3 (CD14) and anti-TdT with leukemic blast cell populations was prospectively analyzed with respect to the rates of complete remission (CR), continuous complete remission (CCR), and survival. The overall rate of CR was 65%, the 6-year rates of overall CCR and survival were 23% and 13%, respectively (median period of patient observation, 30 months). Of all Abs tested, four (CLB-ERY3, MY7, anti-TdT, and VIM-D5) were found to be of prognostic value. Reactivity of CLB-ERY3, MY7, and anti-TdT was predictive for CR (CLB-ERY3+, 43% v CLB-ERY3-, 73%, P less than .02; MY7+, 59% v MY7-, 91%, P less than .003; TdT+, 28% v TdT-, 71%, P less than .001, respectively) and probability of survival (significantly lower survival rates: CLB-ERY3+, P less than .02; MY7+, P less than .03; and TdT+ cases, P less than .001, respectively). Reactivity of VIM-D5 was significantly associated with a higher probability of CCR (P less than .01). Our results confirm earlier reports on the prognostic significance of expression of CD13 and TdT in AML and indicate CLB-ERY3 (antiblood-group H antibody) and VIM-D5 (CD15) as further markers predictive for the clinical outcome in patients with de novo AML.

Adolescent↗
PubMed1989

[Radioimmunometric determination of histamine in myeloproliferative syndromes].

Quantitative analysis of histamine is increasingly used in clinical haematology. The present study demonstrates the properties of and potential indication for a novel histamine radioimmunoassay (RIA) in clinical haematology. The sensitivity of this test assay corresponds to a histamine level of 0.1 to 0.5 nM, the non-specific cross reaction with endogenous histamine metabolites appears to be less than 0.1%. The total histamine levels in the peripheral blood of healthy donors (n = 10) ranged from 10 to 100 ng/ml, the plasma histamine values from 0.02 to 0.6 ng/ml blood. Increased levels of total histamine were measured in myeloproliferative syndromes, i.e. in patients with chronic myeloid leukemia (CML) (8 of 9), myelofibrosis (OMS) (2 of 4), and polycythaemia vera (PCV) (1 of 2). An excessive increase in total histamine was observed in healthy rhesus monkeys (n = 10) treated with recombinant human interleukin-3 (rhIL-3). The total histamine value correlated with the absolute number of circulating blood basophils (correlation coefficient: 0.9). The calculated content of histamine per basophil was found to be 0.5 to 1.5 pg. Plasma histamine values in patients suffering from myeloproliferative syndromes were within the normal range. In contrast, a moderate to marked increase in plasma histamine values was observed in monkeys during IL-3 treatment. The radioimmunometric analysis of histamine clearly represents a useful new test system in clinical haematology, especially in the follow up of malignant as well as IL-3-induced myeloproliferation.

Animals↗
PubMed1989

[Interleukin-3: a preclinical study].

Recombinant hemopoietic cytokines play an increasing role in clinical hematology. The present preclinical study describes the biologic spectrum of a novel recombinant human cytokine, interleukin-3 (rhIL-3). In appropriate culture systems it could be demonstrated that interleukin-3 is a potent growth factor for hemopoietic stem cells. RhIL-3 induced, in addition, terminal differentiation of basophilic and eosinophilic granulocytes. Moreover, rhIL-3 was found to be an activation factor for mature blood basophils. Binding studies using radiolabelled rhIL-3 showed that the effects of interleukin-3 are mediated via specific cell surface membrane receptors. The in vivo effects of recombinant interleukin-3 were studied in a primate model (rhesus monkeys). In agreement with in vitro results interleukin-3 caused significant expansion of the functional stem cell pool. Moreover, interleukin-3 induced a marked increase in basophils and eosinophils. As side effects of recombinant interleukin-3 a slight to moderate elevation of plasma histamine levels was observed as well as the appearance of an erythematous exanthem. In summary, our studies provide evidence that IL-3 induces self renewal, growth and differentiation of human hemopoietic stem cells. Clinical indication areas for interleukin-3 obviously represent stem cell transplantation and the treatment of cytopenic disorders. Adverse side effects of this novel cytokine might arise from stimulation of growth and function of "allergic effector cells".

Animals↗
PubMed1989

The in vivo effects of recombinant human interleukin-3: demonstration of basophil differentiation factor, histamine-producing activity, and priming of GM-CSF-responsive progenitors in nonhuman primates.

Recently human interleukin-3 (IL-3) produced by molecular cloning was characterized as a growth factor for basophils and eosinophils in human bone marrow cultures. Since we found a similar activity of the human factor on simian bone marrow cells, we investigated the in vivo effects of recombinant human (rh) IL-3 in healthy rhesus monkeys (n = 10). rh IL-3 was administered subcutaneously (SC) to monkeys at different doses (11, 33, and 100 micrograms/kg/d) for 14 days followed by subsequent rh GM-CSF administration (5.5 micrograms/kg/d SC) for another two weeks. During the second week of rh IL-3 administration monkeys responded with a twofold to threefold increase of WBCs caused by a dose-dependent elevation of basophils (up to 40% of WBCs) and eosinophils. rh IL-3 also induced a dose-dependent increase of histamine (up to 700-fold above normal values) in monkey blood cells. Administration of rh GM-CSF to rh IL-3 pretreated monkeys resulted in a twofold enhanced increase in WBCs (due mainly to eosinophils and neutrophils) compared with animals treated with rh GM-CSF alone. Simultaneous administration of both cytokines (100 micrograms/kg rh IL-3 + 5.5 micrograms/kg rh GM-CSF SC) to two separate monkeys for 14 days induced a WBC elevation similar to that observed in monkeys treated with rh GM-CSF alone. In conclusion, our results indicate that rh IL-3 is a differentiation factor for blood basophils and primes the hematopoietic system for subsequent rh GM-CSF actions.

Animals↗
PubMed1989

Interleukin-3 is a differentiation factor for human basophils.

The effect of recombinant human (rh) cytokines, interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), granulocyte/macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), monocyte/macrophage colony stimulating factor (M-CSF), interferon-alpha (IF-alpha), interferon-gamma (IF-gamma), and the tumor necrosis factor-alpha (TNF-alpha) on differentiation and function of metachromatic cells (MCS) was studied. Among all cytokines tested, rh interleukin-3 (rhIL-3) selectively induced a significant formation of MCS (IL-3: 1.1 +/- 0.6 x 10(5) v control: 0.02 +/- 0.15 x 10(5) MCS/mL suspension) and dose dependent increase in formation of intracellular histamine (IL-3, 100 U/mL: 95 +/- 23 ng/mL v control: 1.8 +/- 0.8 ng/mL) in a bone marrow suspension culture system (analyzed on day 14 of culture). Besides MCS, formation of eosinophils was observed in this culture system in the continuous presence of rhIL-3, whereas IL-3 pulse-stimulation for three hours and subsequent exposure to control medium induced growth of MCS but not of eosinophils. By combined immunofluorescence/toluidine blue staining, MCS were found to express a cell surface marker profile that corresponds to the immunological phenotype of peripheral blood basophils (MY-7(CD13)+, VIM12(CD11b)+, VIM2+, MAX1-, MAX24- and YB5B8-). Furthermore, cultured MCS expressed surface membrane receptors for IgE and could be triggered for nontoxic histamine release by a monoclonal anti-IgE antibody. To evaluate a possible influence of IL-3 on basophil function, studies were extended to freshly obtained blood basophils (healthy volunteers, n = 3). However, like all other cytokines tested, rhIL-3 failed to induce basophil histamine release. Taken together, our studies demonstrate that IL-3 is a differentiation factor for human basophils.

Antibodies, Monoclonal↗
PubMed1989

Mast cell typing: demonstration of a distinct hematopoietic cell type and evidence for immunophenotypic relationship to mononuclear phagocytes.

The immunologic surface marker profile of human mast cells (MCs) was established using a combined toluidine/immunofluorescence staining procedure [49 monoclonal antibodies (MoAbs) tested]. Ascites (n = 9) MCs as well as enzymatically dispersed MCs from all organs tested (lung n = 11, skin n = 7, intestinum n = 10) exhibited an identical marker profile. MCs were recognized by MoAbs clustered as CD9 (anti-gp24), CD33 (anti-gp67), and CD45 (anti-gp220) as well as by MoAbs directed against membrane-bound IgE. MoAB YB5B8 (anti-gp145) selectively recognized MCs. Most significantly, however, MCs were stained by MoAbs MAX1 (anti-gp65), MAX3 (anti-gp68), MAX11 (anti-gp65), and MAX24 (anti-gp65). These antibodies bind to surface membrane antigens associated with a late stage of monocyte/macrophage differentiation. Thus, our results provide definite evidence that MCs share surface membrane markers with mononuclear phagocytes. In contrast, MCs are stained neither by lymphatic markers (CD1-8, 10, 19-24) nor by myelomonocytic markers (CD11-17). MCs also lack the interleukin-2 (IL-2) receptor (CD25), the T10 antigen (CD38), and most of the myelocytic markers expressed on peripheral blood (PB) basophils. Thus, MCs displayed a unique phenotype within the hematopoietic system. This new approach enabled us to enrich human lung MCs to a purity greater than 95% by means of negative selection with complement-mediated cell lysis. Purified MCs were subsequently stained with MoAbs and analyzed by flow cytometry, which confirmed the results obtained from the double-staining experiments. We next examined cultured metachromatic cells derived from bone marrow (BM) and peripheral blood colony-forming units (CFU). These metachromatic cells previously could not be classified by morphologic criteria alone and have therefore been termed basophil-like/MC-like cells. In this study, toluidine blue-positive cells obtained from either pooled multipotential colonies (day 14-CFU-GEM) or pooled myelocytic colonies (day 16/17-CFU-GM/G/M) were recognized by MoAbs MY7 (CD13), VIM12 (CD11b), and VIM2, as well as by an anti-IgE MoAb, after preincubation with IgE. In contrast, CFU-derived metachromatic cells were not stained by MoAb YB5B8. This marker profile corresponds to the immunologic phenotype of blood basophils and excluded a detectable formation of mature MCs in colonies derived from cultured hematopoietic stem cells.

Antigens, Surface↗
PubMed1989

Interleukin 3 activates human blood basophils via high-affinity binding sites.

Pure populations of human basophilic granulocytes were obtained from chronic myeloid leukemia (CML) blood by negative selection using a mixture of monoclonal antibodies and complement. 125I-radiolabeled recombinant human interleukin 3 (rhIL-3) bound to purified basophils in a specific manner. Quantitative binding studies and Scatchard plot analyses performed on samples from two donors revealed the presence of a single class of high-affinity IL-3 binding sites (500 and 2100 sites per cell; dissociation constant at equilibrium, 230 and 160 pmol/liter, respectively). Purified CML basophils maintained in suspension in the presence of rhIL-3 (100 units/ml) incorporated up to 12 times more [3H]thymidine than basophils in control cultures. Furthermore, after preincubation in vitro with rhIL-3 (100 units/ml) for 30 min, normal blood basophils released 2- to 3-fold more histamine than basophils pretreated with control medium when exposed to various concentrations of an anti-IgE antibody. Together, these results show that rhIL-3 binds to a specific receptor on blood basophils and is a regulator of basophil function.

Antibodies, Monoclonal↗
PubMed1988

T cell receptor alpha mRNA transcription in T-lymphoblastic transformation of chronic myelocytic leukemia.

Analysis at the DNA and RNA level revealed a mature genetic marker profile in a case of T type blast crisis of chronic myelocytic leukemia. T cell receptor beta chain gene rearrangement as well as T cell receptor alpha mRNA transcription was demonstrated in blasts of the malignant clone. Corresponding findings were obtained from immunological phenotyping. Blasts were found to be CD7+, CD1+, CD3+, CD4+, CD8+, and TdT- and classified as common/mature thymocytes. The presence of the breakpoint cluster region gene on chromosome 22 excluded the possibility of a second neoplastic process.

Adult↗
PubMed1984

The Ash Wednesday bushfires in Victoria.

The Ash Wednesday bushfires were one of the worst natural disasters in Australia's history. This paper documents observations of human reactions to the disaster started immediately after the bushfires. Two frameworks were used for classification of observations: biopsychosocial and temporal. Biological, psychological and social reactions in adults and children are described as they occurred before, during, immediately after, and two months after the disaster. Some reactions in animals are noted. Victims of the bushfires were seen to have reacted during the various phases of the experience in a predictable way: during the acute danger, when survival was paramount, and immediately afterward, the usual patterns of hierarchical structure within families and in the wider community broke down and new social structures emerged. These reverted to previously existing patterns in the ensuing months. Feelings of disorientation, unreality and anger at outside agencies, which were viewed as hostile and unhelpful, were commonplace. The findings have implications for the development of everyday stress reactions and clinical syndromes presenting to clinical practitioners. Lastly, the role of intervention for disaster reactions is examined and its usefulness noted.

Aged↗
PubMed1984

The experience of a mental health team involved in the early phase of a disaster.

The reactions of a volunteer mental health team which convened in the aftermath of the 1983 Ash Wednesday bushfires are reported. A questionnaire designed to explore psychological and physical responses was completed by the 19 staff who made up the team. Using both open-ended and closed questions, the questionnaire tapped such areas as motivation, goals, expectations and observations, initial and later emotional and physical reactions, fantasies and evoked memories; an evaluation of the service and the experience was also included. Analysis of responses indicated that team members experienced considerable stress during their post-disaster work but also gained a great deal at both professional and personal levels. Sources of stress are discussed as are recommendations for their alleviation.

Adaptation, Psychological↗
PubMed1978

Issues with dying patients.

Doctors have the privilege of looking after patients from the moment of birth to the moment of death. Yet, the holistic approach to patients is interfered with by the doctor's role as a warrior against death, where death's everpresent claim on our lives, and its final victory, are ignored. This paper attempts to explore why doctors are in their current position, the mechanisms for ignoring death which are shared by doctors and patients, the nature of the fear of death, and practical implications for the treatment of dying patients. More and more patients die now in medical settings. It is incumbent on doctors to understand the dying process, if much unnecessary suffering is to be prevented.

Adult↗
PubMedDate not supplied

A case of bone marrow mastocytosis associated with multiple myeloma.

Mastocytosis is a term used for a spectrum of disorders characterized by abnormal growth and accumulation of mast cells. The cutaneous variants of the disease have to be distinguished from systemic mastocytosis (SM), in which at least one extracutaneous organ is involved. In contrast to cutaneous mastocytosis, SM is often associated with another hematologic neoplasm. In most cases clonal myeloid malignancies such as a myeloproliferative or myelodysplastic syndrome occur. In a few cases of SM, however, clonal lymphoid disorders have been described. We here report on a case of SM associated with multiple myeloma. At first presentation, the 48-year old female patient showed monoclonal IgGlambda gammopathy and bone marrow (BM) mastocytosis, but no BM plasma cell infiltrates. Eight years later, the patient presented with BM mastocytosis and overt multiple myeloma. The co-existence of myeloma and mastocytosis was demonstrable by staining serial BM sections with antibodies against mast cell tryptase, CD68R, and the plasma cell marker VS38c. Interphase FISH analysis of BM sections revealed a numeric gain of chromosome 5 and chromosome 7 in the plasma cells but not in the mast cell infiltrates, thereby confirming the presence of two different neoplastic cell populations. To our knowledge, this is the first report describing the co-existence of multiple myeloma and mastocytosis.

Antineoplastic Combined Chemotherapy Protocols↗