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Biomedical subjects

F K Stevenson

Publications and source records attributed to F K Stevenson.

At least 145 records · Page 8Linked to original sources
PubMed1984

Consumption of monoclonal anti-idiotypic antibody by neoplastic B lymphocytes: a guide for immunotherapy.

A quantitative analysis in vitro of events which might occur on administration of mouse monoclonal anti-idiotypic antibody to a recipient with a B cell neoplasm has been made. The L2C leukaemic cells of guinea pigs, which closely resemble those of human lymphoma in expression and metabolism of immunoglobulin have been used as a model. Exposure of neoplastic B cells to antibody results in rapid binding of approximately 420,000 molecules of antibody per cell at saturation, and the amount consumed does not increase markedly over the next 4 h of exposure at 37 degrees C. This is in spite of the fact that secretion of idiotypic IgM continues unaffected by the presence of antibody, and reflects the fact that the amount of IgM secreted during this period is low compared to the amount displayed on the cell surface. If cells undergo lysis, however, the antibody consumed is approximately doubled: thus a recipient with an estimated tumour load of 10(12) cells would require 200 mg of monoclonal anti-idiotype for binding to surface and intracellular antigen. The effect of the soluble idiotypic IgM found in serum on the ability of antibody to bind target cells has been examined by means of the fluorescence activated cell sorter. Access of antibody to the cells is efficiently blocked by competing idiotypic IgM in the fluid phase, with no indication of preferential binding to cell surface idiotype. Immunotherapeutic doses should be designed therefore to overcome this additional antigenic load in secreting tumours, which form the majority of B cell neoplasms.

Animals↗
PubMed1984

Secretion of immunoglobulin by neoplastic B lymphocytes from lymph nodes of patients with lymphoma.

An investigation has been made into the ability of neoplastic B lymphocytes obtained from lymphoid tissue of patients with non-Hodgkin's lymphoma (NHL) to secrete immunoglobulin (Ig) in vitro. The majority of the cell populations secreted IgM (17/24 patients), identified as pentameric in three cases examined, and free monotypic light chains (23/24 patients) of the same type as the surface Ig. Secretion of IgD (6/21 patients) and IgG (3/21 patients) was found less frequently. The amounts of Ig secreted were variable and there was no significant difference in the patterns of secretion of cells from NHL patients when compared to previous studies of chronic lymphocytic leukaemia (CLL), nor was there any clear correlation with the histological type. For four of the patients, anti-idiotypic antibody was produced and was used to demonstrate the idiotypic nature of the secreted Ig, and also to show its presence in the serum. The level of idiotypic IgM was measured in one patient during chemotherapy and appeared to correlate well with disease. Such idiotypic Ig must be taken into account when planning treatment of B cell neoplasms with antiidiotypic antibody since it could act as a block to antibody attack. Assessment of the ability of tumour cells to secrete Ig in vitro provides a useful preliminary screen when choosing such patients since a high secretion rate together with extensive disease could lead to unacceptable levels of serum idiotypic Ig.

Antibodies, Neoplasm↗
PubMed1984

Immunoglobulin negative follicle centre cell lymphoma.

Immunoglobulin (Ig) could not be detected on the surface or in the cytoplasm of neoplastic cells from five cases of follicle centre cell lymphoma with centroblastic/centrocytic follicular histology when examined by immunohistology of frozen or wax embedded sections. Examination by fluorescein labelled antibodies of cells in suspensions prepared from the biopsies revealed a monotypic surface Ig positive population in one case and a surface or cytoplasmic Ig kappa:lambda light chain imbalance in a further two cases consistent with neoplastic B cell involvement: in all cases the proportion of cells failing to express Ig or T cell markers ranged from 24 to 75%. The monoclonal antibodies B1 (Pan B cell), FMC4 (HLA class II) and J5 (cALL antigen) stained the majority of cells in suspension with residual cells staining with UCHT1 or OKT11 (T cell monoclonal antibodies). In frozen sections, neoplastic follicular cells did not stain with UCHT1. However, in the one case tested these cells stained with the antibodies B1 and FMC4. In paraffin sections J chain could be demonstrated in the cytoplasm of three out of five cases. Cells from four cases were cultured in vitro for Ig production: two failed to produce Ig and monotypic light chains were the sole Ig product of the remaining two cases. The failure to express Ig by the majority of the neoplastic cells from the cases described in this report is at variance with the follicular histology of these neoplasms. Mechanisms responsible for this failure are discussed with reference to current models of B cell differentiation.

Antibodies, Monoclonal↗
PubMed1984

Mechanisms of tumour cell escape encountered in treating lymphocytic leukaemia with anti-idiotypic antibody.

Four patients with chronic lymphocytic leukaemia were treated by one or more infusions of polyclonal antibody specific for the immunoglobulin idiotype expressed on their leukaemic cells. The antibody was in the form of IgG from sheep antiserum. Three of the 4 cases showed a significant fall in blood lymphocyte count. On one occasion most of the residual circulating lymphocytes were apparently dead. However on all occasions the cell counts rebounded to near pre-infusion levels within one week. Viable lymphocytes recovered from the blood after infusion always showed evidence of antigenic modulation: a diminished level of surface idiotype in a patched distribution, with an accompanying refractoriness to lysis by anti-idiotype plus complement. When cultured in vitro blood lymphocytes from three of the four patients revealed an appreciable export of idiotypic Ig. These 3 patients showed plasma levels of idiotypic Ig up to 400 micrograms ml-1, reduced by plasma exchange prior to infusion. The fourth patient had a level of less than 4 micrograms ml-1, and was the only one in whom free antibody could be found in the plasma after infusion. These cases demonstrate two major factors which thwart antibody attack on leukaemic cells--extracellular antigen and antigenic modulation--as well as problems relating to sparseness of surface antigen, recruitment of effectors, and exhaustion of effectors.

Aged↗
PubMed1983

The export of immunoglobulin D by human neoplastic B lymphocytes.

An investigation has been made into the ability of human neoplastic B lymphocytes expressing surface IgM and IgD to export IgD in culture. Cells that expressed surface Ig of the lambda light chain type frequently exported IgD (10/12 patients), whereas cells expressing surface Ig of the kappa light chain type exported no IgD, although most (8/11 patients) were able to export IgM. It appears, therefore, that in most of the 23 cases studied, cells synthesizing IgD with lambda light chains can both express and export IgD, whereas those synthesizing IgD kappa can only insert it into the surface membrane. This finding and the known preponderance of lambda in plasma IgD imply that the possession of a lambda chain facilitates the IgD secretory pathway, a conclusion that implicates a control mechanism subsequent to the surface/secretory dichotomy arising from different splicings of heavy chain messenger RNA.

B-Lymphocytes↗
PubMed1983

Monoclonal immunoglobulin light chain in urine of patients with B lymphocytic disease: its source and use as a diagnostic aid.

The presence of tumour-related monoclonal light chain has been sought in urine as an immunochemical aid in the diagnosis of B lymphocytic neoplasms. The technique of isoelectric focusing in agarose followed by immunofixation has been applied to concentrated urines from 41 patients. In chronic lymphocytic leukaemia involving neoplastic B lymphocytes, monoclonal light chain was detected in 14 out of 19 patients investigated. For 2 of the positive cases (one kappa light chain type and one lambda light chain type) the urinary light chains were compared directly with culture fluids obtained after incubation of the corresponding neoplastic cells obtained from the patient's peripheral blood: identity of the light chains from urine and cells was established by isoelectric focusing demonstrating for both patients that the tumour cells were the source of the urinary light chain. In patients with non-Hodgkin's lymphoma involving neoplastic B lymphocytes, urinary monoclonal light chains were found in 7/16 of those studied. Such light chains were not detected in 11 control subjects, in 3 patients with true histiocytic tumours or in 2 patients with enlarged reactive lymph nodes. The technique is simple to perform and provides information for diagnosis and possibly monitoring of B cell neoplasms.

Adult↗
PubMed1983

Antibodies against urinary light chain idiotypes as agents for detection and destruction of human neoplastic B lymphocytes.

Patients with B cell neoplasms frequently have low levels of tumor-related light chains in their urine; these light chains can be isolated with the use of relatively simple methods and then used to raise antibodies to the idiotypic determinants. In this study, anti-light chain idiotypes were raised against monoclonal light chains from the urine of four patients with chronic lymphocytic leukemia. The antibodies reacted specifically with the tumor cells of the homologous patient, assessed by immunofluorescence, and can therefore be used for tumor cell detection. In one case for which serum idiotypic IgM was available, the anti-light chain idiotype was shown to bind whole idiotypic IgM, and such binding could be inhibited by idiotypic IgM or idiotypic light chains, which demonstrates recognition of similar antigenic determinants. The binding of antibody to tumor cells was also totally inhibited by idiotypic IgM. The analysis of separated sera from the four patients for free light chains demonstrated only low levels (3.0 to 8.6 micrograms/ml of serum with a mean of 5.8), which suggests that light chain is rapidly cleared and therefore does not present a major barrier to antibody attack. It should be feasible to use such antibodies for both analysis and therapy of B cell neoplasms.

Animals↗
PubMed1983

Immunization with idiotypic immunoglobulin protects against development of B lymphocytic leukemia, but emerging tumor cells can evade antibody attack by modulation.

Immunization of strain 2 guinea pigs with idiotypic IgM obtained from serum of animals in the terminal phase of the L2C leukemia produced high levels of circulating anti-idiotypic antibody that was cytotoxic for the tumor cells in the presence of syngeneic C. Such animals showed good protection against injected tumor cells, but after a long delay, leukemia did develop. As tumor cells appeared in the blood, anti-idiotype was consumed, but the cells displayed little or no surface Ig and could not be killed in vitro by anti-idiotype and C. However, as serum antibody levels fell, the cells displayed increasing amounts of surface IgM lambda of the same idiotype and regained their susceptibility to the antibody and C in vitro. It appears, therefore, that the ability of tumor cells to modulate their target idiotype can present a considerable problem for antibody-mediated attack.

Animals↗
PubMed1982

Polycythaemia rubra vera and hairy cell leukaemia in the same patient: studies on the spleen.

The first association of polycythaemia rubra vera (PRV) and hairy cell leukaemia (HCL) is reported. The secretion by spleen cells in short term culture of IfGlambda to the exclusion kappa demonstrated that despite aberrant surface marker studies the HCL was a monoclonal tumour of B cells. Chromosomal studies on splenic cells were not able to demonstrate the common clonal origin of the two tumours.

Chromosomes, Human↗
PubMed1981

The nature of the immunoglobulin G on the surface of B lymphocytes in chronic lymphocytic leukemia.

The nature of the immunoglobulin (Ig) G found associated with the neoplastic B lymphocytes in chronic lymphocytic leukemia that also express Igm and IgD had been investigated by absorption studies using anti-idiotypic antibodies raised against cell surface IgM from five patients. In all five cases, although cellular IgM and IgD behaved as idiotypic, the IgG did not. Thus the IgG frequently found associated with lymphocytes at this stage of differentiation is likely, at least in many cases, to be of extrinsic origin.

B-Lymphocytes↗
PubMed1981

A human b-cell lymphoma synthesizing and expressing surface mu-chain in the absence of detectable light chain.

Lymph node cells obtained from a case of non-Hodgkin's lymphoma, of follicular center cell histology, were seen by immunofluorescence to express immunoglobulin mu heavy chains but no detectable light chain on their surfaces. Antibody specific for determinants expressed only on uncombined mu-chain reacted with these cell surfaces, but not with normal or neoplastic cells expressing surface IgM. Analysis of radioiodinated surface material revealed mu-chains which, without reduction, migrated on SDS-gel electrophoresis as normal mu-chain monomers, and again failed to detect light chains. Lysates of cells incubated with 3H-leucine revealed the synthesis of mu-chains but not of light chains. The labeled mu-chains were not secreted into the culture supernatant, a finding confirmed in parallel cultures by radioimmunoassay. The findings are discussed with particular reference to current concepts of the "mu-chain only" phenotype.

Adult↗
PubMed1980

Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes.

The peripheral blood lymphocytes of nine out of nine patients with typical surface Ig-positive chronic lymphocytic leukemia but no paraprotein visible on serum electrophoresis have been shown by radioimmunoassay to export small amounts of pentameric IgM during culture (in the range of 2.4-7.2 ng/10(7) cells per h); three out of nine also exported monomeric IgD (0.7-1.4 ng/10(7) cells per h). Immunoglobulin turned over on the cell surface did not appear to contribute to material in the culture fluid, except possibly as vesicle-bound Ig. In three cases, which included two of the IgD producers, anti-idiotypic antibody raised against the cell surface Fab mu was used to demonstrate the idiotypic nature of the exported Ig. Anti-idiotypic antibody was also used to measure levels of idiotypic Ig in the sera of these three patients as a proportion of the total Ig. Total serum IgM was depressed in all three patients, and the idiotypic IgM represented 43%, 65%, and 96% of the IgM. The findings suggest that in typical chronic lymphocytic leukemia involving B lymphocytes, the export of a small amount of idiotypic Ig by the neoplastic cells in a common or even usual occurrence.

Antibodies, Anti-Idiotypic↗
PubMed1980

Preliminary experience in treating lymphocytic leukaemia with antibody to immunoglobulin idiotypes on the cell surfaces.

Tumour-specific antiserum was raised in sheep against idiotypic determinants on the surface immunoglobulin of neoplastic lymphocytes from a patient with chronic lymphocytic leukaemia (prolymphocytic variant). The complement-activating IgG1 subclass of the anti-idiotype was prepared from the serum in monodisperse form for infusion. Two treatments of 480 and 1200 mg caused the white-cell count to fall by one-third and one-half respectively. However, there was a rapid resurgence, so that by 8 days after each treatment the counts were restored to approximately 85% of their former levels. No change was noted in the size of spleen or lymph nodes. Each treatment probably destroyed 4-8 X 10(11) cells, some 10% of the total tumour load. The antibody was rapidly consumed, and there was evidence of heavy utilization of complement.

Aged↗
PubMed1980

Immunoglobulin produced by guinea-pig leukaemic B lymphocytes: its source and use as a monitor of tumour load.

The cells of the B lymphocytic leukaemia (L2C) of strain 2 guinea-pigs have IgM on their surfaces but produce insufficient monoclonal IgM in vivo to be detectable by conventional serum electrophoresis. A radioimmunoassay, using anti-idiotypic antibody raised against the surface IgM of these cells, has been used to estimate levels of extracellular IgM produced both in vitro and in vivo. Analyses of the contributions to such IgM from the cell surface and from an export pathway have been made by examining the effect of prior removal of surface Fab mu by papain, and by following the fate of radio-iodinated surface IgM. Results suggest that the extracellular IgM arises predominantly from an export pathway, being exported in both pentameric and monomeric forms. Only a minute contribution, possibly in the form of vesicle-bound monomeric IgM, appears to derive from the cell surface. Radioimmunoassay was used to monitor the increasing levels of this leukaemic cell product during the course of the disease. Idiotypic IgM was detectable when the body load of neoplastic cells was approximately 4% of that detectable by an increased white cell count in the blood.

Animals↗
PubMed1978

beta2-Microglobulin from normal and leukaemic guinea-pig lymphocytes.

beta2-Microglobulin has been isolated in useful quantities from the urine of strain-2 guinea-pigs after either treatment with sodium chromate or induction of the L2C leukaemia. Antibodies raised against the beta2-microglobulin were used to set up a radioimmunoassay which measured its export into culture fluid by normal and leukaemic lymphocytes. Material containing beta2-microglobulin was also obtained by digestion of the lymphocytic surfaces with papain; fractionation demonstrated both free and combined forms, with no qualitative difference between those from normal and those from leukaemic cells.

Animals↗
PubMed1978

Mediation of cytotoxic functions by classes and subclasses of sheep antibody reactive with cell surface immunoglobulin idiotypic and constant region determinants.

Sheep antibodies, reactive with either the idiotypic or constant region antigenic determinants of the immunoglobulin light chain on guinea-pig L2C leukaemic cells, were separated into IgM and into the two subclasses of IgG, IgG1 and IgG2. Antibody of both IgG subclasses inhibited the migration of L2C cells along plastic surfaces; IgM was only weakly inhibitory. Antibody of class IgM and of subclass IgG1 mediated complement cytotoxicity against the L2C cells whereas only that of subclass IgG2 mediated K-cell cytotoxicity; the effector arms were rabbit complement and sheep peripheral leucocytes, respectively.

Animals↗