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Biomedical subjects

M Greaves

Publications and source records attributed to M Greaves.

At least 217 records · Page 12Linked to original sources
PubMed1983

Receptor for transferrin may be a "target" structure for natural killer cells.

Human transferrin receptors detected by monoclonal antibody OKT9 appear to be well expressed on cell types known to provide sensitive targets for natural killer (NK) cells. The possibility that transferrin receptors are recognized by NK effector cells has been investigated by three series of experiments: (i) analysis of the correlation between sensitivity to natural killing and the proportion of transferrin receptor-positive cells in different cell lines, (ii) study of the relationship between levels of transferrin receptor expression in cell lines and their capacity to competitively inhibit recognition and killing of the target cell K562 by NK cells, and (iii) comparison of affinity-purified soluble proteolytic fragments of the transferrin receptor and HLA-A, -B molecules for their ability to inhibit the natural killing effect. The data indicate that the transferrin receptor can provide a "target" structure for NK cells. Because transferrin receptors are ubiquitously expressed on normal and malignant proliferating cells, these observations have interesting implications for the possible function of NK cells in vivo.

Antibodies, Monoclonal↗
PubMed1983

Acquired von Willebrand's disease: demonstration of a circulating inhibitor to the factor VIII complex in four cases.

We have studied four patients suffering from acquired von Willebrand's disease. All patients had a severe bleeding diathesis with recurrent life-threatening haemorrhages. Three of the patients had a monoclonal gammopathy and one of these developed multiple myeloma. In three patients tested, a plasma inhibitor to ristocetin cofactor activity was detected. In each case this was localized to the IgG fraction of plasma. In addition, VIII:C activity was found to be associated with the IgG fraction of patients' plasma and altered mobility of VIII:C was detected on Laurell immunoelectrophoresis. Furthermore, plasma from all four patients and the IgG fraction therefrom resulted in a dissociation of normal VIII:C into two components separable by gel-filtration on Sepharose 6B. Finally the circulating half-life of the three factor VIII activities was found to be markedly reduced in the patients with acquired von Willebrand's disease. We conclude that in the patients studied the coagulation defect was related to the presence of a circulating inhibitor to the factor VIII complex and that this inhibitor was associated with the IgG fraction of plasma.

Aged↗
PubMed1982

The human type-C retrovirus, HTLV, in Blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma.

Type-C RNA tumor viruses have been implicated in the etiology of naturally occurring leukemias and lymphomas of animals. Human T-cell leukemia/lymphoma virus (HTLV) is the first human virus of this class consistently identified in association with a specific type of human leukemia/lymphoma. The isolation of HTLV was made possible by the ability to grow mature T-cells in tissue culture usually with T-cell growth factor (TCGF). We now report a cluster of adult T-cell leukemia/lymphoma among Blacks from the Caribbean in which all eight cases are positive for HTLV virus and/or antibody. These patients have disease that appears indistinguishable from Japanese adult T-cell leukemia/lymphoma which, as we have also reported, is associated with HTLV in over 90% of cases. The finding of HTLV antibodies in some of the normal population in the Caribbean and Japan, and the clustering of a specific form of T-cell leukemia/lymphoma in these virus-endemic areas, suggest that HTLV infection may be associated with the occurrence of a distinctive clinico-pathologic entity.

Adolescent↗
PubMed1982

A study of the stimulation of human venous prostacyclin synthesis by dipyridamole.

The synthesis of prostacyclin by human venous tissue in vitro and the effects of aspirin and dipyridamole thereon were investigated. Dipyridamole significantly stimulated prostacyclin production in a concentration range of 25 to 100 microM. Dipyridamole significantly attenuated the inhibitory effect of 0.1 mM aspirin in a concentration range of 12.5 to 100 microM. Isobutylmethylxanthine 0.1 mM, an unrelated inhibitor of phosphodiesterase, had similar effects to dipyridamole. Cyclic AMP 3.0 mM had an inhibitory effect on prostacyclin synthesis in the presence of dipyridamole. Adenosine 0.1 mM and nitrobenzylthioguanosine 0.1 mM, an inhibitor of adenosine uptake, did not significantly influence prostacyclin synthesis in this system. We conclude that the stimulation of prostacyclin synthesis by dipyridamole is unrelated to the ability of this drug to block the high-affinity uptake of adenosine by endothelial cells and that the effect may also be independent of changes in the concentration of cAMP induced by the drug.

Aspirin↗
PubMed1982

Evidence for a platelet membrane defect in the myeloproliferative syndromes.

Bleeding and abnormal platelet aggregation occur in patients with myeloproliferative disorders. In this study, twenty patients were examined, some sequentially, and a proportion found to have defective aggregation toward adrenaline, adenosine diphosphate (ADP), and collagen. In these seven patients, the abnormality in platelet response with defective collagen-induced [14C]serotonin release correlated with poor collagen-stimulated thromboxane B2 (TXB2) production. In contrast, five of these patients showed a normal threshold aggregation response to arachidonic acid. The combined results suggest that in these patients, there is a defect between receptor-stimulus coupling and the mobilization of arachidonic acid from membrane phospholipid.

Blood Platelets↗
PubMed1982

Low-dose aspirin inhibits platelet and venous cyclo-oxygenase in man.

In a group of normal subjects we have compared rates of recovery of venous prostacyclin (PGI2) and platelet thromboxane B2 (TXB2) production after a single 300 mg dose of aspirin. Marked inhibition of both venous PGI2 synthesis and platelet TXB2 synthesis persisted for the 72 hours duration of the study. We also examined the effect of four daily doses of 40 mg aspirin on platelet and vessel wall prostaglandin biosynthesis. This produced a cumulative inhibitory effect on TXB2 production with 98.6 per cent mean inhibition at 72 hours. At this time 81-100 per cent inhibition of PGI2 was demonstrated in the four subjects studied. We conclude that the cyclo-oxygenase enzyme in human vein is sensitive to inhibition by very low doses of aspirin. No evidence was found to substantiate the view that rapid recovery of vessel wall cyclo-oxygenase activity occurs after inhibition by a single dose of aspirin.

Aspirin↗
PubMed1982

Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9.

The monoclonal antibody OKT9 reacts specifically with the receptors for transferrin on human cells (Sutherland, D. R., Delia, D., Schneider, C., Newman, R. A., Kemshead, J., and Greaves, M. F. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 4515-4519; in Leukemia Markers (Knapp, W., ed) pp. 157-160, Academic Press, New York) and has been used to isolate and characterize this receptor. The receptor is a dimeric glycoprotein (Mr = 180,000) composed of two subunits (Mr = 90,000) and has a pI of approximately 5.2. The transferrin receptor appears to be a transmembrane molecule and is phosphorylated, the phosphate group being predominantly on serine residues. The cell surface form of the molecular possesses both complex and high mannose oligosaccharide chains, which do not appear to have a direct role in antibody (OKT9) binding. The molecule can be cleaved into a Mr = 70,000 fragment from the cell surface, suggesting that the major part of the receptor is exposed to the extracellular environment. The released Mr = 70,000 fragments are not disulfide-linked and possess the antibody (OKT9)- and transferrin-binding sites. Cross-linking studies using radiolabeled transferrin suggest that two molecules of transferrin are bound to each Mr = 180,000 receptor dimer.

Antibodies, Monoclonal↗
PubMed1982

Plasma 6-keto-prostaglandin F1alpha: fact or fiction.

A radioimmunoassay for 6-keto-prostaglandin F1alpha was developed and validated. The apparent concentration of 6-keto-prostaglandin F1alpha in human venous plasma was found to be less than 50 pg/m1. A rise in plasma 6-keto-prostaglandin F1alpha was detected on infusion of prostacyclin or of DDAVP in human subjects. Various methods of organic extraction were applied to plasma samples prior to radioimmunoassay. Organic extraction and silicic acid chromatography introduced marked and unacceptable nonspecific interference on subsequent radioimmunoassay. This interference was abolished by high pressure liquid chromatography of eluates and extracts prior to assay. Using these methods, a very low concentration of 6-ketoprostaglandin F1alpha in human venous plasma was confirmed.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Vincristine inhibits the synthesis of malondialdehyde by human platelets in vitro.

When platelet-rich plasma was preincubated with vincristine, a depression in malondialdehyde production was seen when compared with saline controls. Colchicine caused an increase in malondialdehyde production. If prostaglandins are important in tumor-cell metabolism, then vincristine might exert some of its cytotoxic effect by depressing prostaglandin production.

Adult↗
PubMed1982

Expression of human transferrin receptor is controlled by a gene on chromosome 3: assignment using species specificity of a monoclonal antibody.

The monoclonal antibody OKT-9 has been shown to recognize the human transferrin receptor. We have exploited the species specificity of OKT-9 to map a gene controlling human transferrin receptor expression to chromosome 3, using human-mouse somatic cell hybrids. The gene for the human transferrin receptor and the gene controlling transferrin expression may be linked in humans.

Animals↗
PubMed1982

Relationship between platelet aggregation, thromboxane synthesis and albumin concentration in nephrotic syndrome.

Increased platelet aggregability on stimulation with sodium arachidonate (NaAA), collagen and ADP was found in a group of 14 patients with nephrotic syndrome when compared with age and sex matched controls. Five of the group also exhibited spontaneous platelet aggregation (SPA), associated with synthesis of thromboxane B2 (TxB2), and which appeared to correlate with a markedly increased serum triglyceride concentration. Thromboxane B2 generation in response to NaAA was increased and reflected both the low serum albumin concentration and the platelet aggregation response to this agent. Addition of albumin in vitro decreased the amount of TxB2 generated for a given dose of NaAA and increased NaAA and collagen-induced platelet aggregation thresholds. However, albumin had no significant effect on collagen-induced TxB2 production. The results suggest that the hypoalbuminaemia and associated reduced binding of arachidonic acid and increased synthesis of TxA2 account in part for the increased platelet aggregability seen in the nephrotic syndrome but that other mechanisms are also involved.

Adenosine Diphosphate↗
PubMed1982

Leukaemia of platelet precursors: diverse features in four cases.

Four patients are described with malignant cells of definite or probable megakaryocytic lineage in the bone marrow and blood. Megakaryocytic features were defined by morphological and cytochemical studies using light and electron microscopy, and in two cases by reaction with a monoclonal anti-platelet antibody, AN51. All patients had increased bone-marrow reticulin, which developed in less than 15 months in two cases. One of these fitted the clinical pattern of acute myelosclerosis of Lewis and Szur (now widely referred to as acute megakaryoblastic leukaemia). Three cases had unique clinical features which are described in detail. There may be several variants of megakaryocytic leukaemia, including chronic forms. One variant is associated with Down's syndrome (trisomy 21).

Adult↗
PubMed1981

P-24: a human leukemia-associated and lymphohemopoietic progenitor cell surface structure identified with monoclonal antibody.

This study was directed at surface structures that are found on human lymphohemopoietic progenitor cells in normal and leukemic bone marrow. A monoclonal antibody was produced against an acute lymphoblastic leukemia (ALL) cell line of the pre-B phenotype; this antibody (BA-2) was used to demonstrate a cell surface polypeptide of approximately 24,000 mol wt that migrates similarly in both reduced and nonreduced form. This polypeptide, p24/BA-2, was shown by immune precipitation and gel electrophoresis and cell distribution studies to be different from HLA-DR and gp 100/cALLa. p24/BA-2 was present on the surface of 77% (54/70) of cases of non-T, non-B ALL; BA-2 staining was less bright or nondetectable in surface Ig+ (SIg+) chronic lymphocytic leukemia (CLL) and T ALL and nondetectable on peripheral T and B lymphocytes. Approximately 3% of bone marrow mononuclear cells were p24/BA-2+, and these cells were E rosette-, surface (SIg-), and nonphagocytic. Marrow TdT+ progenitor cells were frequently p 24/BA-2+. Results suggest that p24/BA-2 represents a surface structure present on lymphohemopoietic bone marrow progenitor cells and that most common types of ALL bear the p25/BA-2 structure.

Antibodies↗
PubMed1981

Expression of cell-surface HLA-DR, HLA-ABC and glycophorin during erythroid differentiation.

The unexpected discovery that Ia-like (HLA-DR) antigens in humans were present on blast cells from acute myeloblastic leukaemia led to the finding that normal granulocytic progenitors, in contrast to their mature descendents, also expressed HLA-DR antigens. Thus, anti-Ia sera stain a proportion of myeloblasts in normal bone marrow, inhibit myeloid progenitor (CFU-GM) colony formation in the presence of complement and can be used to label and separate CFU-GM on a fluorescence-activated cell sorter (FACS). Winchester et al. subsequently reported that erythroid progenitors (BFU-E and CFU-E) were also inhibited or killed by anti-Ia (p28,37) and complement. These observations raised the possibility that HLA-DR (or presumptive I-region equivalent) products might have a regulatory role in early haematopoiesis. We have now analysed HLA-DR and HLA-ABC antigen expression on normal erythroid progenitors using monoclonal antibodies to non-polymorphic determinants and fluorescence-activated cell sorting. In parallel experiments, we tested a monoclonal antibody to glycophorin, a well defined erythroid-specific cell-surface membrane glycoprotein. We report that HLA-DR, HLA-ABC and glycophorin are all expressed at various stages during erythroid differentiation.

Bone Marrow↗
PubMed1981

Mapping cell surface antigen expression of haemopoietic progenitor cells using monoclonal antibodies.

A library of monoclonal antibodies which show selective reactivity with particular cells or gene products (e.g. HLA-DR, glycophorin) of different cell lineages in the haemopoietic system has been compiled. Using these probes in conjunction with the fluorescence-activated cell sorter (FACS) the pattern and sequence of cell surface antigenic expression on haemopoietic progenitor cells have been mapped. A cell is identified in bone marrow which has a unique membrane phenotype and the nuclear enzyme terminal deoxynucleotidyl transferase. Its composite phenotype is identical to that seen in the common variant of acute lymphoblastic leukaemia (ALL). It is suggested that this cell is a putative B lineage progenitor which provides the major target for ALL. Detailed analysis of erythroid differentiation with monoclonal antibodies on the FACS reveals an intriguing pattern of antigenic expression in which HLA-DR, glycophorin and band III appear in sequence. HLA-DR (Ia-like antigen) may be present on all or most committed haemopoietic progenitor cells and could play an important role in cell interactions regulating early haemopoiesis.

Animals↗