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Biomedical subjects

J C Cawley

Publications and source records attributed to J C Cawley.

At least 19 recordsLinked to original sources
PubMed1992

Role of Fc gamma RII in platelet activation by monoclonal antibodies.

mAb are being widely used to probe the function of cell-surface proteins. The cell stimulation that may be produced is often dependent on mAb interaction with both the target Ag and FcR. However, it remains unclear whether these interactions take place on the same cell or between adjacent cells and whether the FcR plays an anchoring or signaling role. Using the model of platelet activation, we demonstrate that two different Fc-dependent mAb, LeoA1 and ALB6, both activate the cell by forming intercellular links between Ag on one cell and FcR on the opposing platelet. We also show that the mAb differ with respect to the relative roles of target Ag vs FcR in provision of the stimulation signal. Thus Fc gamma RII played a mainly anchorage role in LeoA1 stimulation, whereas its role in ALB6 stimulation was mainly signaling. Therefore the precise contribution of each of these roles to the overall effect of a stimulatory antibody should be determined before the antibody is used as a specific functional probe.

Antibodies, Monoclonal↗
PubMed1992

Endolymphatic delivery of IL2 in patients with melanoma and lymphoma.

UNLABELLED: During this phase I/II study, enodolymphatic cannulae were placed in the iliac lymphatics under general anaesthesia. IL2 was then infused via this route at escalating doses until the highest tolerated dose was achieved; then, continuous infusion was maintained for 2 to 3 weeks. Seven patients with advanced cancer (3 lymphoma, 4 melanoma), resistant to all other modalities of treatment received such therapy. Most patients tolerated 4 to 5 x 10(6) u/day of IL2 for 2 to 3 weeks with less toxicity as compared to the equivalent dosage given intravenously. No severe perioperative morbidity was experienced. One melanoma patient had a minor clinical response. Changes in circulating lymphocyte numbers and cytotoxicity demonstrated a systemic effect of endolymphatic IL2 therapy. CONCLUSIONS: The endolymphatic administration of IL2 is associated with less toxicity than the intravenous route but still achieves a systemic effect; a lower tumour burden may prove more responsive to this therapy.

Adult↗
PubMed1992

Combination of GM-CSF and cytosine in myelodysplasia results in improved neutrophil function.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was given concurrently with low-dose cytosine arabinoside for 3 weeks to patients with myelodysplasia. Neutrophil activation as evidenced by increased chemiluminescence and reduced surface expression of CD16 was consistently seen during therapy. An attendant fall in chemotaxis was also observed. These effects occurred even when neutrophil counts did not rise significantly at lower doses of GM-CSF. Although no improvement in anaemia or thrombocytopenia was observed, the neutrophil counts became normal during therapy without significant expansion of marrow cellularity or colony-forming ability. No major toxicities were observed, even at higher dosages of GM-CSF.

Antigens, CD↗
PubMed1992

A method for clinical purging of myeloma bone marrow using peanut agglutinin as an anti-plasma cell agent, in combination with CD19 monoclonal antibody.

Previous studies have shown that the lectin peanut agglutinin (PNA) binds bone marrow plasma cells in the majority of patients with myeloma and does not bind to normal haemopoietic progenitors. This lectin has been used in combination with anti-CD19 monoclonal antibody (moAb) in a system for purging myeloma bone marrow. This has now been scaled up for application to ex vivo treatment of large volumes of bone marrow suitable for autologous bone marrow transplantation. Four bone marrow harvests from patients with myeloma containing 9.5 +/- 4.9% plasma cells were depleted of erythrocytes and mature granulocytes by Ficoll separation using the Haemonetics V50 cell separator. The mononuclear fraction was then purged with magnetic beads coated with PNA and anti-CD19 moAb. The system proved highly efficient with removal of all detectable plasma cells and CD19+ cells. Average mononuclear cell recovery following purging was 71% of the concentrated marrow with 78% yield of CFU-GM. Normal progenitor recovery related to patients' weight is predicted to be adequate for haemopoietic reconstitution following ablative chemoradiotherapy. This system is therefore feasible for large-scale clinical purging.

Adult↗
PubMed1991

IL-2 abolishes fibroblast proliferation in long-term bone marrow culture by inhibition of an accessory cell.

Addition of interleukin-2 (IL-2 (greater than 250 U/ml) during the first 3 d of long-term bone marrow culture (LTBMC) permanently abolished the fibroblast component of the stromal layer, even when IL-2 was removed after the 3 d culture period. When IL-2 was added at more than 72 h after initiation of culture, no effect was observed. Stromal growth in IL-2-treated culture was restored by addition of irradiated bone marrow, indicating that the IL-2 inhibited an accessory cell rather than the fibroblast directly. Accessory cells were shown to be necessary for fibroblast proliferation at low cell densities and were also inhibited by IL-2. The accessory cell effect could not be replaced by LTBMC supernatants or extracellular matrix. It is suggested that these observations are relevant to the suppression of haemopoiesis observed in patients receiving IL-2.

Bone Marrow↗
PubMed1991

A monoclonal antibody to a 67 kD cell membrane glycoprotein directly induces persistent platelet aggregation independently of granule secretion.

The transition from reversible to persistent platelet aggregation has been difficult to study because of interference both from preceding primary aggregation and from the events associated with granule secretion during secondary aggregation. As a result it remains unclear whether the persistence of aggregation involves some secretion-independent specific platelet surface reactions. Here we show that a monoclonal antibody (MAb), LeoAl, against a newly described 67 kD platelet membrane glycoprotein induced active platelet aggregation consisting of two distinct phases. The first secretion-independent phase was in several respects (extracellular protein, divalent cation, and pH dependence) different from primary aggregation, but closely resembled the transition from primary to secondary aggregation observed at certain concentrations of physiological agonists. The second, faster phase was indistinguishable from secretion-dependent aggregation to various stimulants. It was shown that p67, GPIIb-IIIa and FC gamma RII are all involved in the observed aggregation, probably through their close topographical association. It is suggested that LeoAl-induced aggregation can be used as a model to study the receptors, ligands and metabolic pathways specifically involved in the transition from reversible to persistent platelet aggregation.

Antibodies, Monoclonal↗
PubMed1991

Peanut agglutinin in combination with CD19 monoclonal antibody has potential as a purging agent in myeloma.

Administration of high-dose chemotherapy to patients with myeloma, followed by rescue with autologous bone marrow transplantation (ABMT), sometimes induces complete disease remission but relapse is usual. We have attempted to reduce the risk of relapse by selective in vitro removal of myeloma cells from the autologous graft. A combination of the (gal-galNac)-binding lectin peanut agglutinin (PNA), which binds all plasma cells, and the pan-B monoclonal antibody CD19 was assessed for purging marrow of myeloma cells and their putative precursors using a magnetic bead method. Preliminary experiments performed on peripheral blood mononuclear cells spiked with fluorescent-labeled PNA+ Kirk tumor cells showed that a magnetic bead: target cell ratio of 40:1 resulted in a greater than 3-log reduction in PNA+ cells. This technique was then applied to 17 samples of myeloma bone marrow and to 18 samples of normal bone marrow spiked with PNA+ Kirk cells and CD19+ hairy cell leukemia cells. In each case all detectable plasma cells and CD19+ lymphocytes were effectively removed, and normal hemopoietic progenitor cell recovery was greater than 55%. This purging system deserves further study as a means of reducing relapse rates in myeloma patients treated by a combination of high-dose chemotherapy and ABMT.

Antibodies, Monoclonal↗
PubMed1990

VIM-D salvage chemotherapy in Hodgkin's disease.

A total of 15 patients with relapsed or resistant Hodgkin's disease were treated with a combination of etoposide (VP16), ifosfamide, mitozantrone and dexamethasone (VIM-D). The regime was well tolerated, the only major toxicity being myelosuppression. Complete remissions (CRs) were obtained in 4 patients and were maintained for 2, 4, 10 and 14 months. 10 subjects subsequently received an autologous bone marrow transplant with high-dose chemotherapy (ABMT). Previous exposure to VIM-D did not appear to predict for or prejudice the response to subsequent ABMT.

Adult↗
PubMed1990

The effects of alpha interferon on human long-term bone marrow culture.

The effect of alpha IFN on normal long term bone marrow culture (LTBMC) was assessed by measuring haemopoietic progenitor formation and stromal cell number and composition over the course of 5 weeks. When alpha IFN was added at the initiation of LTBMC, there was a marked inhibition of CFU-GEMM, BFU-E and CFU-GM formation from both adherent and non-adherent compartments of culture. There was a profound inhibition of stromal layer formation, especially the reticulo-fibroblast component, and this was not a result of TNF release from macrophages. When alpha IFN was added to established normal LTBMC, although haemopoietic progenitor formation was inhibited, there was little effect on the stromal layer in terms of number or composition. This suggests that the cytostatic effects of alpha IFN when added at commencement of LTBMC result from the anti-proliferative effects of alpha IFN on these actively dividing cells. It is concluded that in addition to the established inhibitory effects of alpha IFN on haemopoietic progenitors as previously demonstrated in semi-solid culture systems, alpha IFN has profound effects upon the marrow microenvironment. This is of particular relevance to bone marrow transplantation where such cytokines may be considered for clinical use.

Bone Marrow Cells↗
PubMed1990

gamma IFN receptor expression in haemic malignancies.

gamma Interferon receptor (gamma IFNR) expression was examined by Scatchard analysis in 49 patients with various haemic malignancies. In chronic lymphocytic leukaemia (CLL) (20 cases) expression was variable but generally low (0-1600 receptors/cell) and was not related to clinical stage. In hairy-cell leukaemia (HCL) (n = 6), prolymphocytic leukaemia (PLL) (n = 1) and acute lymphoblastic leukaemia (ALL) (n = 4) expression was again variable but was significantly higher than in CLL (500-4500 receptors/cell). In the myeloid proliferations (n = 18) receptor numbers were significantly higher than in the lymphoproliferative disorders as a whole (1000-30,000) and the highest level of expression was observed in primitive monocytoid proliferations.

Cell Differentiation↗
PubMed1990

The current status of interferon alpha in haemic malignancy.

Interferon-alpha (IFN alpha) has been extensively studied, both in clinical trials and in the laboratory. The cytokine has proved most effective in haemic malignancy, in particular hairy cell and chronic granulocytic leukaemia. This article deals with the current status of IFN alpha in these conditions and the possible basis of this sensitivity. Other less responsive haemic malignancies are also discussed.

Humans↗
PubMed1990

The effect of cytokines, including IL-1, IL-4, and IL-6, in hairy cell proliferation/differentiation.

IL-1, IL-4, and IL-6 had no effect on hairy cell (HC) proliferation in vitro. Anti-mu and low molecular weight B cell growth factor (LBCGF) and tumor necrosis factor alpha (TNF-alpha) stimulated the proliferation of a minor subpopulation of HCs detected by double immunocytochemical staining. None of these cytokines had any effect on HC differentiation as measured by immunoglobulin secretion. It is concluded that none of the above growth factors are central to HC proliferation in-vivo. Since alpha-interferon IFN-alpha, but not IFN-gamma, consistently inhibited any proliferation observed, it seems likely that this monokine has a direct antiproliferative effect in vivo.

Biological Factors↗
PubMed1989

IL-2 and myelopoiesis: IL-2 induces blast cell proliferation in some cases of acute myeloid leukaemia.

Interleukin-2 (IL-2) stimulated H-thymidine incorporation in the blasts of six of 21 cases of acute myeloid leukaemia (AML). An IL-2 induced increase in cell numbers was directly demonstrated in the two patients studied in this way, and T-cell contamination was rigorously excluded. The IL-2-induced proliferation was usually less marked than that caused by granulocyte-macrophage colony stimulating factor (GM-CSF), and IL-2 moderately enhanced GM-CSF-induced stimulation in five of the six patients; in the sixth, IL-2 and GM-CSF were strongly synergistic. IL-2-induced proliferation was observed only in AML with a monocytic component (M4/M5), but not all M4/M5 leukaemias responded to IL-2. There was no correlation between expression of the light-chain of the IL-2 receptor and IL-2-induced stimulation. It is suggested that IL-2 is involved at a restricted stage of early myelopoiesis, perhaps when cells are becoming committed to the monocytic lineage; and that IL-2 is a growth factor for early myeloid cells in a proportion of cases of AML.

Bone Marrow↗
PubMed1989

Mechanism of action of alpha interferon in chronic granulocytic leukaemia: evidence for preferential inhibition of late progenitors.

The effect of alpha interferon (alpha IFN) on colony forming unit, granulocyte-macrophage (CFU-GM) formation by normal bone marrow (BM) as compared with chronic granulocytic leukaemia (CGL) BM and peripheral blood (PB) was tested in semi-solid assay systems employing either 5637CM or recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) to support growth. alpha IFN (greater than 125 U/ml) caused consistent inhibition (P = 0.02) of day-7 (late progenitor) colonies, but had little or no effect on either day-7 clusters or day-14 colonies/clusters. This selective effect on day-7 colonies was quantitatively similar for both normal and CGL (P greater than 0.5). Similar results were obtained whether or not the mononuclear preparations were depleted of potential accessory cells, suggesting that the alpha IFN-suppression is directly mediated. Morphological examination of colonies and clusters showed that IFN had no effect on cell maturation and that colony inhibition is not, therefore, a consequence of blocked maturation. Since the late-progenitor compartment is preferentially expanded in CGL, we suggest that our demonstration that alpha IFN selectively inhibits this compartment is relevant to the clinical effects of the cytokine in the disease.

Bone Marrow↗
PubMed1989

The beneficial effects of alpha IFN in CGL are probably not mediated by NK cells.

Natural killer (NK) cells in CGL were measured phenotypically (by Leu7 and CD16 Mab staining) and functionally (by a standard chromium-release cytotoxicity assay) in eight patients before and during alpha-IFN therapy. Before alpha IFN therapy, phenotypic NK cells were normal in relative and absolute numbers but were consistently defective functionally; this defect was partially corrected by in vitro exposure to alpha IFN. During alpha IFN therapy, there was no change in NK function in five patients and enhanced (two patients) or reduced (one patient) activity was observed in the other three. Cold-target inhibition experiments showed no evidence of NK binding to normal or CGL myeloid progenitors. It is concluded that alpha IFN-enhanced NK function, a known anti-tumour mechanism in animal models, is probably not the basis of the responsiveness of CGL to alpha IFN therapy.

Cytotoxicity Tests, Immunologic↗
PubMed1989

Phenotypic changes on hairy cells exposed in vitro to interferons: a quantitative FACS study.

In vitro culture of hairy cells (HC) (five patients) with alpha IFN (100 U/ml) significantly enhanced MHC and CD22 antigen expression and reduced CD25, sIg and FMC7 positivity, together with consistent but not significant reductions in CD9, 19 and HC2. A sixth patient, who was refractory to the effects of alpha IFN in vivo, was also studied and none of these changes were seen in her HC when cultured with alpha IFN in vitro. gamma IFN (100 U/ml) produced a much less marked increase in MHC and reduced sIg. TPA (100 ng/ml) induced changes very similar to those observed with alpha IFN. alpha and gamma IFN had no effect on a range of other antigens in HCL (including CD23 and 38, and transferrin receptors) and also produced no significant antigenic changes in CLL cells. It is concluded that these findings are compatible with partial activation/maturation of HC by alpha IFN. It is suggested that the specificity of the phenotypic changes induced on HC by alpha IFN is a consequence of HC representing a stage of B-cell development at which alpha IFN has specific immunomodulatory effects.

Antigens, Differentiation↗