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Biomedical subjects

M F Greaves

Publications and source records attributed to M F Greaves.

At least 127 records · Page 7Linked to original sources
PubMed1984

Human T-cell leukemia virus (HTLV) in the United Kingdom.

Ten out of 26 leukaemic patients who had emigrated from the Caribbean region to the United Kingdom had adult T-cell leukaemia with associated serum antibodies to HTLV I. Antibodies to HTLV were also detected in sera from a small proportion of non-leukaemic Caribbean immigrants but not in any sera from other (non-ATL) T-cell leukaemias or a variety of control groups. The long period between immigration to the UK and diagnosis of leukaemia (up to 30 years) suggests that an extensive latent period in disease development may exist. Cell lines were isolated from two patients with HTLV antibody-positive ATL and were shown to be virus-positive by electron microscopy and immunofluorescence using antibodies to the p19 and p24 viral proteins. HTLV1 provirus integration and active transcription were demonstrated by Southern blotting of DNA and in situ hybridization respectively using molecularly cloned HTLV1 probes. Virus from one of these cell lines could be transmitted to normal T cells by co-cultivation.

Adolescent↗
PubMed1984

Functional properties of neoplastic T cells in adult T cell lymphoma/leukemia patients from the Caribbean.

The neoplastic T cells from five patients with adult T cell lymphoma/leukemia (ATLL), born in the Caribbean, were studied with respect to immunoregulatory activity on pokeweed mitogen (PWM) driven immunoglobulin (Ig) synthesis as well as surface-marker phenotypes with monoclonal antibodies. The neoplastic T cells in all patients had an OKT1+4+8-11+M1-I1-3A1- phenotype, but differed in the reactivity with OKT3. None of the patients' cells exerted helper activity on PWM-induced Ig synthesis. The neoplastic cells of three patients had suppressor activity on PWM-induced Ig synthesis. All patients were positive for human T cell leukemia/lymphoma virus (HTLV) or had antibodies against HTLV antigens. It has previously been shown that the neoplastic cells in Japanese ATLL patients and in patients from the Caribbean are indistinguishable by morphology and marker phenotype. We now show them to be also similar with respect to their functional properties.

Adult↗
PubMed1984

An immunotoxin with therapeutic potential in T cell leukemia: WT1-ricin A.

A conjugate of the monoclonal antibody WT1 and ricin A-chain was studied for its suitability for purging marrow of leukemic T cells for autologous transplantation in T cell acute lymphocytic leukemia (T-ALL). The conjugate was powerfully cytotoxic to the human T-ALL cell line, GH1, which expresses the WT1 antigen at a high density. Treatment of the cells with the conjugate at 10(-11) M reduced their rate of protein synthesis by 50%, and the inclusion of 6 mM ammonium chloride in the cultures enhanced the potency of cytotoxic effect by 10-100-fold. Clonogenic assays indicated that less than 0.1% of GH1 cells survived 3-hr exposure to the conjugate in ammonium chloride. WT1 alone did not react with multipotent (CFU-GEMM) hematopoietic progenitors in normal human bone marrow, as measured by fluorescence-activated cell sorting. Under conditions giving maximal killing of GH1 cells, there was no toxicity to multipotential progenitors in normal human marrow.

Antibodies, Monoclonal↗
PubMed1984

Isolation and characterization of a human T lymphocyte-associated glycoprotein (gp40).

The biosynthetic and structural characteristics of the human thymocyte/T cell antigen defined by the monoclonal antibody WT1 have been studied. WT1 identified a monomeric cell surface glycoprotein of Mr = 40,000 ( gp40 ). Cross-absorption experiments and two-dimensional gel analyses indicate that WT1 and another monoclonal antibody, 3A1, react with the same structure. This glycoprotein was asymmetrically inserted into the rough endoplasmic reticulum as a transmembrane structure. At this stage, the polypeptide chain possessed two N-linked, "high-mannose" type glycans; these were subsequently processed into endo-H-insensitive, complex oligosaccharides during intracellular transport to the cell surface. Inhibition of N-linked glycosylation with tunicamycin failed to block the processing of the nonglycosylated Mr = 29,000 polypeptide to a glycoprotein of Mr = 33,000. Cleavage of the mature Mr = 40,000 form with endo-F yielded a similar Mr = 33,000 product. The kinetics of synthesis of the Mr = 33,000 intermediate in conjunction with gal-NAc oligosaccharidase digestion indicated the presence of O-linked glycans in the mature cell surface WT1 antigen. The fully processed cell surface form of the polypeptide also contains covalently associated fatty acid, and was labeled by 32P phosphate, the predominantly labeled phosphoamino acid being phosphoserine. We also demonstrate biochemically that the reactivity of WT1 with cells from a few patients with acute myeloid leukemia reflects genuine expression of the gp40 structure on myeloid cells.

Adult↗
PubMed1983

Rat AL2, AL3, AL4 and AL5 monoclonal antibodies bind to the common acute lymphoblastic leukaemia antigen (CALLA gp 100).

Four distinct rat monoclonal antibodies against the common ALL antigen (CALLA, gp 100) were obtained in a single fusion. Rat AL2, AL3, AL4, AL5 and the previously reported mouse J5 monoclonal antibodies identified the same subsets of leukaemic cells. AL2 and AL3 reacted weakly with terminal transferase-positive cells in normal bone marrow and foetal liver, as well as with a minority of mature granulocytes in blood. Immunoprecipitation experiments and competitive binding assays demonstrated that the four rat antibodies and J5 bound to the same glycoprotein of approximately 100,000 mol. wt. This set of rat monoclonal antibodies directed against CALLA has not only a diagnostic usefulness but may also be of therapeutic value.

Animals↗
PubMed1983

In vitro biosynthesis of the human cell surface receptor for transferrin.

The human cell surface receptor for transferrin is a transmembrane phosphoglycoprotein composed of two disulphide linked and apparently identical subunits of Mr 90 000. Using an affinity purified, polyclonal rabbit antibody, we have studied the in vitro biosynthesis of this receptor. The primary translation product, synthesised in a rabbit reticulocyte lysate programmed with human placental RNA, appears to have the same Mr (78 000) as the unglycosylated molecule immunoprecipitated from tunicamycin-treated cells. In the presence of a dog pancreatic microsomal system the cell free system accurately reproduces the glycosylation and the asymmetric transmembrane integration.

Animals↗
PubMed1983

Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma.

The proportion of lymphocytes from patients with non-Hodgkin lymphoma (NHL) expressing transferrin receptors in biopsy material from lymph-nodes assayed by binding of the monoclonal antibody OKT9 correlated significantly with the histological class of the tumour. High-grade lymphomas contained 22.5% (range 3-57%) OKT9-positive lymphocytes, and low-grade lymphomas contained 2.5% (range less than 1-22). Since histological class of lymphoma is an important factor in survival, it was expected and confirmed that OKT9 levels were related to survival in these patients. Transferrin receptor is expressed by growing cells. The correlates observed in this series of NHL suggests a relation between transferrin receptor and either the growth fraction, or factors affecting the growth fraction, of the tumour.

Antibodies, Monoclonal↗
PubMed1983

Differential expression of HLA-DR and DR-linked determinants on human leukemias and lymphoid cells.

Leukemic and normal hemopoietic cells were examined with the monoclonal anti-bodies DA2 and Genox 353 for the presence of HLA-DR and DR-linked (DC/MB) determinants, respectively. Although most non-T acute leukemias and leukemic cell lines expressed the monomorphic DR determinant detected by DA2, fewer than expected expressed the DR-linked polymorphic specificity detected by Genox 353. TdT+ lymphoid precursors from normal bone marrow were also DA2+ but Genox 353-. T cells and thymocytes which were DA2-, Genox 353- became DA2+, Genox 353+ after activation in vitro. Immunoprecipitation using DA2 and Genox 353 gave bands on polyacrylamide gel-electrophoresis which were of different molecular weights. In addition, DA2 could absorb out Genox 353 determinants from a cell lysate whereas Genox 353 could not absorb out DA2 determinants. It is concluded that DA2 and Genox 353 detect HLA-DR and DR-linked (DC1/MB1) determinants, respectively, and that these are differentially expressed on hemopoietic cells during differentiation.

Antibodies, Monoclonal↗
PubMed1983

Immunoglobulin gene organisation and expression in haemopoietic stem cell leukaemia.

We have analysed the organisation and expression of mu genes in the granulocytic phase and in the lymphoid and myeloid blast crises of Philadelphia chromosome (Ph1) chronic granulocytic leukaemia (CGL), a leukaemia which is known to arise in multipotential stem cells. We find that mu chain gene rearrangement occurs exclusively in lymphoid blast crisis leading in some, but not all, cases to the synthesis of small amounts of cytoplasmic mu chains characteristic of early pre-B lymphocytes. In Southern blots, only one or two rearranged mu chain genes are seen, suggesting that a clonal event leading to blast crisis can occur in a committed B cell precursor rather than in the multipotential stem cell precursor, in which the Ph1 chromosome originated. The pattern of mu gene rearrangement observed in Ph1 CGL blast crisis is compared with that in normal B cells, other B lineage malignancies, myeloid leukaemias and T cell leukaemias.

B-Lymphocytes↗
PubMed1983

Significance of glucocorticoid receptors and responses in leukaemia.

Glucocorticoid receptor levels and cellular responses to glucocorticoid treatment in vitro were evaluated for the malignant cells from patients with leukaemia. Cells from all cases of lymphoid and myeloid leukaemia contained glucocorticoid receptors; receptor levels and the extent of in vitro responses appeared to depend primarily on cell type and differentiation status. For acute lymphoblastic leukaemia (ALL), high receptor levels were associated with the common ALL phenotype, intermediate levels with null (unclassified) ALL and low levels with T-ALL. Considerable variation in receptor levels and in responses in vitro was observed for acute myeloid leukaemia; receptor levels measured by whole-cell assay did not relate to patient survival.

Antineoplastic Agents↗