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Biomedical subjects

F K Stevenson

Publications and source records attributed to F K Stevenson.

At least 127 records · Page 7Linked to original sources
PubMed1988

Idiotypic vaccination as a treatment for a B cell lymphoma.

To develop a model for the active immunotherapy of human B cell malignancy we vaccinated tumor-bearing animals with a well defined tumor associated Ag, the idiotypic Ig. The tumor used was the mouse B cell lymphoma BCL1, a highly malignant tumor in which transfer of a single tumor cell to a syngeneic mouse is capable of causing disease and eventual death. Varying doses (10(2) to 10(4] of BCL1 cells were given to mice on day 0 of the experiment, and treatment by active immunization was initiated on day 3. Immunization with purified, tumor-derived, idiotypic IgM (BCL1 IgM) coupled to keyhole limpet hemacyanin (KLH) was highly effective in treating mice challenged with 10(2) or 10(3) BCL1 cells, but less effective in mice that had received 10(4) tumor cells. Immunization with unconjugated BCL1 IgM showed no signficant therapeutic benefit. Coupling of the IgM to KLH led to higher levels of anti-idiotypic antibody after immunization; however, the higher levels were probably not responsible for the control of the malignancy as there was no correlation in healthy immunized animals between the levels of anti-idiotypic antibody, measured immediately before tumor challenge, and survival. This lack of correlation is due to the emergence of variant tumors in such protected mice. A more significant factor in the therapeutic advantage of KLH conjugation could be that immunization with BCL1 IgM-KLH led to an earlier induction of the anti-idiotypic response than immunization with BCL1 IgM and, as the BCL1, lymphoma divides rapidly, the speed of induction of the immune response may be important in outstripping tumor cell growth. Mice with BCL1 tumour showed some evidence of immunosuppression as indicated by a reduced ability to mount an immune response against KLH. Although it is not possible to model spontaneous human lymphoma accurately, the generation of a functional anti-idiotypic response capable o eliminating a malignant animal lymphoma in situ opens up the possibility of a limited trial of active immunotherapy in selected human patients.

Animals↗
PubMed1988

Idiotype vaccination leads to the emergence of a stable surface Ig-negative variant of the mouse lymphoma BCL1, with different growth characteristics.

Vaccination of mice with tumor-derived idiotypic IgM from the B cell lymphoma, BCL1, induces an anti-idiotypic immune response which suppresses tumor development. One of the mechanisms by which tumor cells can escape attack is by failing to express significant levels of idiotypic immunoglobulin at the cell surface, and a stable variant of this phenotype has been isolated. The variant, termed SNAG 1, continues to synthesize idiotypic IgM, which can be detected in the cytoplasm, but it neither secretes nor expresses IgM on the cell surface (less than 10% of the levels of the original BCL tumor), even though the H and L chains show no gross structural changes. The SNAG 1 cells resemble the parent BCL cells in morphology, in expression of MHC class I and II Ag and in bearing FcR. A significant difference between the BCL lymphoma cells and the variant cells is that the latter fail to respond to LPS by either DNA synthesis or secretion of IgM, suggesting that surface Ig might be required for such a response. The variant has a slower rate of division than the parent tumor both in vitro and in vivo, and a rather different organ distribution. Study of such variants might allow analysis of the mechanisms involved in surface Ig expression and its possible role in tumor cell growth and migration.

Animals↗
PubMed1988

Problems and prospects in the use of lymphoma idiotypes as therapeutic targets.

The infusion of anti-idiotypic antibody in patients with lymphoma has proved a relatively innocuous procedure, but in general had yielded only partial, short-lived remissions of disease. A major problem is that xenogeneic antibody is simply not well-fitted to destroying mammalian cells: complement and cellular effectors (K cells and phagocytes) are not efficiently recruited, and the target cells in any case present some excellent defense mechanisms. Antigenic modulation is particularly prominent among these defenses, and we present evidence here for modulation of idiotype being much more efficient in vivo than in vitro. Two broad types of antibody derivative are under development to improve the killing of neoplastic targets. One type relies on recruiting natural effectors, and is exemplified by univalent chimeric antibody. The other relies on delivering an exogenous effector such as a drug or toxin, and is exemplified by bispecific anti-Id/anti-saporin F(ab'gamma)2 antibody. Both types of derivative have been able to suppress animal lymphoma to the extent that tumor escape occurs largely through the emergence of idiotype-negative mutants.

Aged↗
PubMed1988

CD3+ CD8+ T cell lymphocytosis masking B cell leukaemia.

A patient with CD3, CD8 positive lymphocytosis presented with features consistent with T cell chronic lymphocytic leukaemia/proliferations of large granular lymphocytes. The marrow and blood lymphoid populations (19.4 x 10(9)/l) contained more than 80% CD3 and CD8 positive cells with no evidence of a monotypic B cell population. A biopsy specimen of a vasculitic rash showed a diffuse infiltrate of CD3, CD8 positive cells into the upper dermis, consistent with T cell lymphocytic disease. After follow up for two years without treatment the blood lymphocyte count was 53 x 10(9)/l and was composed of cytologically small lymphocytes. A monoclonal SIg M D k lymphoid population (more than 90%) was demonstrable in sample blood and marrow aspirate. Gene rearrangement studies carried out on DNA extracted from peripheral blood lymphocytes at presentation and at two year follow up exhibited JH and Ck immunoglobulin gene rearrangement but no rearrangement of T cell receptor TcR gamma and beta genes. It is thought that this is the first well documented case of an aggressive CD8 positive lymphocytosis preceding, or in response to, an underlying B cell neoplasm.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Lymphokine-activated killer cells from normal and lymphoma subjects are cytotoxic for cells coated with antibody derivatives displaying human Fc gamma.

Lymphokine-activated killer (LAK) cells were successfully generated in all cases from blood mononuclear cells obtained from six patients with lymphoma. The LAK cells from three of these patients and from five normal adult donors were tested for their effector abilities in antibody-dependent cellular cytotoxicity (ADCC) against guinea pig leukemic lymphocytes coated with various antiidiotype antibodies. Cells from all the donors behaved similarly. Mouse monoclonal antibodies of IgG1, IgG2a, and IgG2b isotypes invoked no ADCC. However, substantial ADCC was invoked by the chimeric antibody FabFc, in which Fab'gamma from mouse antiidiotype is thioether-bonded to human normal Fc gamma. Similar results were obtained on testing LAK cells from a normal donor against uncultured human lymphoma targets coated with native or chimeric antiidiotype. The ADCC invoked by the mouse-human chimeric antibodies appears to depend on the human Fc gamma they display and not on the univalency of the derivatives used. The findings imply that LAK technology could usefully augment serotherapy that uses antibody derivatives displaying human Fc gamma.

Adult↗
PubMed1988

Use of a cross reacting anti-idiotype to identify normal counterparts of neoplastic cells.

We have established that 9G4, a cross reacting monoclonal anti-idiotype identifies an epitope close the binding site of anti-I cold agglutinins. 9G4 positive lymphocytes comprise around 5% of B cells and are widely represented in all lymphoid tissue. They may be detected in 15 week fetal spleen at the time of the earliest appearance of B cells and thus form part of the basic B cell repertoire. Such antibodies are derived largely from CD5 positive B cells. 9G4 is thus a useful tool to investigate the normal counterpart of the CLL cell.

Adult↗
PubMed1987

Whole ricin and recombinant ricin A chain idiotype-specific immunotoxins for therapy of the guinea pig L2C B cell leukemia.

The therapeutic efficacy of whole ricin, or recombinant ricin A chain, coupled to a monoclonal antibody that reacts with the idiotype of the surface IgM expressed on guinea pig L2C lymphoblasts, was assessed. In vitro studies were done to characterize the immunotoxins (IT) and to demonstrate their specificity before use in vivo. The concentration of whole ricin IT (M6-Ricin) that inhibited protein synthesis by 50% (IC50) in L2C cells was 1.4 X 10(-9) M, in a 5-hr assay, in the presence of lactose to block non-antibody-directed toxicity. M6-Ricin did not inhibit protein synthesis in two control guinea pig cell lines that did not express the idiotype, nor did a whole ricin IT prepared with an isotype-matched monoclonal antibody of irrelevant specificity inhibit protein synthesis in L2C cells. Two recombinant ricin A chain IT, which differed from one another by a factor of 2 to 3 in the number of A chains conjugated per antibody molecule, were less effective in vitro than M6-Ricin (IC50 of greater than 5 X 10(-8) M). For in vivo experiments, the IT were given by the i.p. route 24 hr after the i.p. inoculation of 1 X 10(5) L2C cells. The highest doses of M6-Ricin and M6-Ricin A chain IT tested, 30 micrograms/kg and 3000 micrograms/kg, respectively, were within fourfold to fivefold of their maximum tolerated doses; no deaths or ill effects due to ricin toxicity were noted. These doses increased the median survival time of L2C-bearing guinea pigs to 31 to 34 days, compared with 15 days for untreated animals. This magnitude of increase in survival indicates that 99.999% (5 logs) of injected tumor cells were eliminated, thus accounting for the 12% long-term survival rate obtained. Median survival times for guinea pigs treated with 30 micrograms/kg of the A chain IT were 18 and 21 days for the two conjugates tested, and the median survival for guinea pigs treated with 3000 micrograms/kg of unconjugated antibody was 18 days. Our data demonstrate that recombinant A chain IT are active in vivo and that the B chain of ricin can potentiate IT activity in vivo. Although the potency differs by 100-fold, the therapeutic index of the intact ricin IT is similar to that of the ricin A chain IT.

Animals↗
PubMed1987

Anti-idiotypic mechanisms involved in suppression of a mouse B cell lymphoma, BCL1.

Immunization of BALB/c mice with idiotypic IgM rescued by hybridization from the syngeneic BCL1 lymphoma protects specifically against challenge with tumor cells, with 83% surviving greater than 100 days compared with controls (38 +/- 10 days). Spleens from long-term survivors (greater than 6 mo) with no macroscopically visible tumor, when examined with anti-idiotypic antibody, showed a range of apparently dormant tumor with BCL1 cells present at 2 to 50% of total. A spectrum of protection against tumor resulted from immunization, and tumor emerging in the period 53 to 173 days postpassage was investigated for expression of idiotype. It was found that cells from individual mice expressed variable amounts of idiotypic IgM at the cell surface, although it was always detectable in the intracellular compartment. Unlike typical BCL1 cells, tumor cells developing in immune spleens often secreted little idiotypic IgM either in vitro or in vivo. This modulation of expression and secretion of idiotype was detected even in the apparent absence of serum anti-idiotypic antibody. On passage of spleen cells from the long-term survivors into naive animals, BCL1 tumor developed and killed the recipients in a way indistinguishable from routine tumor passage. These tumor cells, however, both expressed and secreted IgM of the same idiotype as the original tumor. It appears therefore that tumor development in immunized mice is suppressed by a process that includes modulation but not selection of the tumor cell idiotypic determinants. Analysis of possible mechanisms of suppression revealed the presence of cytotoxic anti-idiotypic antibody at variable levels in sera of immunized mice, and splenic T cells that proliferated specifically in response to idiotypic IgM. Only low levels of cytotoxic T cells were found. Passive transfer studies demonstrated a major role for antibody in protection against tumor, with no significant enhancement by immune lymphocytes.

Animals↗
PubMed1987

Monoclonal anti-light chain idiotype as a tumor-specific probe for human neoplastic B lymphocytes.

Tumor cells from patients with B cell neoplasms often secrete small amounts of free monoclonal light chains that can be found in the urine. Such tumor-derived light chains of the lambda type from a patient with typical chronic lymphocytic leukemia have been used to raise mouse monoclonal antibodies (MoAbs). A hybridoma-secreting antibody that recognized the idiotypic lambda chain but not normal lambda chains by a preliminary screen but which also reacted with idiotypic IgM from the patient's tumor cells was selected. This MoAb in fact recognized 1 in 20 X 10(3) molecules of pooled normal lambda chains, thus establishing its specificity for a private idiotypic determinant. It failed to give a detectable reaction with normal IgM, normal serum, or a panel of IgM paraproteins. The antibody bound to the patient's neoplastic B cells but not to normal tonsillar cells. The site of binding of the antibody to idiotypic IgM is clearly separate from that of another MoAb specific for idiotypic determinants on heavy plus light chains, since the two showed additive binding curves. The determinant also appeared to be less available in dimeric lambda chains than in monomeric lambda chains or in idiotypic IgM. Antibodies to idiotypic determinants on light chains show some technical advantages and should be useful for monitoring and possibly treating B cell tumors, either alone or together with the more conventional anti-idiotypic antibodies that usually recognize the heavy and light chain combination.

Antibodies, Anti-Idiotypic↗
PubMed1987

Initial experience in treating human lymphoma with a chimeric univalent derivative of monoclonal anti-idiotype antibody.

Murine monoclonal anti-idiotype antibody was raised against the surface IgM on the neoplastic cells of a patient with widespread follicular lymphoma. For therapy, a chimeric antibody derivative, FabIgG, was constructed by thioether-linking Fab'gamma, from the monoclonal antibody, to human normal IgG. FabIgG is univalent and thereby avoids rapid antigenic modulation. Its human IgG component is intended to optimize recruitment of effectors and metabolic survival while minimizing immunogenicity. Four intravenous (IV) infusions of 380 to 580 mg of anti-idiotype FabIgG were given over a period of 11 weeks. There was no significant toxicity. On each occasion, the antibody disappeared from the plasma with a half-life (t1/2) of less than 24 hours. The brief survival was evidently due to uptake by tumor, as infused control FabIgG, containing Fab'gamma from an irrelevant antibody, yielded a plasma t1/2 of greater than 10 days. With each therapeutic infusion, there was a fall in the number of circulating neoplastic cells over a 24-hour period. The numbers were largely replenished over the next week, but a net fall became discernible over the entire period of treatment. Four days after each infusion, nodal masses were swollen and tender, subsiding over approximately 8 days. At the end of the treatments, the blood lymphocyte count and nodal and splenic swellings continued to subside, so that by 6 weeks a partial remission with removal of greater than 50% of tumor was judged to have occurred. We did not detect any qualitative change in surface idiotype nor any antibody response to the infused Ig.

Animals↗
PubMed1986

Analysis of soluble HLA class II antigenic material in patients with immunological diseases using monoclonal antibodies.

A quantitative assay for soluble human HLA Class II antigenic material is described. The method is a double-determinant ELISA using 2 monoclonal antibodies which recognize different epitopes on the antigen. The first rat monoclonal antibody captures antigen onto the microplate where it is then recognized by a second mouse monoclonal antibody. Bound mouse immunoglobulin is then detected by an enzyme-linked rat polyclonal antibody. The assay has been used to measure soluble HLA Class II antigen in the sera from healthy individuals and patients with leukaemia, and has shown raised levels in acute lymphoblastic but not in chronic lymphocytic leukaemia. Similar material has been identified in synovial fluid of patients with active rheumatoid arthritis. The assay is specific and simple to perform and should be applicable to probing the nature of the soluble material and its mechanism of release.

Antibodies, Monoclonal↗
PubMed1986

Urinary monoclonal free light chains in primary Sjögren's syndrome: an aid to the diagnosis of malignant lymphoma.

Three patients, two with typical primary Sjögren's syndrome (SS) and the third with several features of SS, including abnormal sialography and reduced tear secretion, developed B cell non-Hodgkin's lymphoma (NHL) of parotid or lung, or both. Isoelectric focusing of concentrated urine specimens in agarose, followed by immunofixation, demonstrated the presence in each patient's urine of monoclonal free light chains of the same class as that shown on the tumour cells. In one patient the level of urinary free light chains was monitored and found to correlate with disease activity. Similar techniques showed no monoclonal light chains in the urine from a further 26 cases of SS with no clinical evidence of lymphoma. The detection of monoclonal urinary free light chains may provide an early diagnostic clue to the development of lymphoma in patients with SS and be a means of tumour monitoring.

Aged↗
PubMed1986

Therapeutic strategies for B cell malignancies involving idiotype-anti-idiotype interactions.

The therapeutic use of unmodified monoclonal anti-idiotypic antibody for human B cell malignancies has met with limited success. Some factors thwarting antibody attack can be identified, such as the presence of extracellular idiotypic immunoglobulin (Ig), and the escape of the target cell by antigenic modulation. Another possibility is a change in idiotypic determinants due to somatic mutation. For direct attack on tumor cells in vivo it might be necessary to use antibody derivatives: univalent antibodies will avoid modulation, and chimeric univalent antibodies consisting of mouse Fab' gamma linked to host Ig of appropriate subclass can be engineered to mediate particular effector functions while reducing immunogenicity. Another approach is to use toxin or isotope-bearing antibodies. However, the final eradication of tumor might involve the natural non-specific, and specific anti-idiotypic mechanisms of the host which should not be damaged by antibody therapy, and which appear to be involved in control of tumor progression in patients in long-term remission. Rapidly growing animal lymphomas presently available as models cannot mimic more than a small fraction of human lymphoma but they provide useful information for design of passive anti-idiotype therapy. However host anti-idiotypic immunity must be induced in such models by pre-immunization with purified idiotype. Such a procedure can generate effective anti-idiotypic immunity which is highly protective in mouse and guinea pig lymphomas. Analysis of mechanisms involved should give insight into the role of the idiotype networks in the behavior of human disease.

Antibodies, Monoclonal↗
PubMed1986

Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors.

Monoclonal anti-idiotypic antibodies generated against idiotypic immunoglobulin (Ig) of neoplastic B lymphocytes can be selected from growing hybridoma clones by their ability to recognize idiotypic but not normal IgM. This group of antibodies can be subdivided into those that bind to the target tumor cells in the presence of normal human serum (approximately 85% of the clones) and those in which binding is inhibited by serum (approximately 15%). The former appear to be specific for private idiotypic determinants whereas the latter recognize cross-reacting idiotypic determinants. Such cross-reactivity is reflected both in recognition of a small percentage of normal Ig and also in binding to other lymphomas. The anti-idiotypes specific for private determinants can be used for therapy, with only idiotypic Ig secreted by tumor cells able to block its access to cells. The cross-reacting anti-idiotypes will face in addition the barrier of the proportion of normal Ig with which it reacts. The attraction of using a single monoclonal reagent for more than one patient has led us to develop an assay that measures the level of such blocking and to propose that those recognizing less than 30 micrograms/mL of normal Ig could be placed in a panel for possible therapy for several patients; less restriction need apply to antibodies for monitoring tumor progress. The assay is described, and examples of such antibodies raised against lymphoma cells from two patients are given together with comparisons with them of anti-idiotypes specific for private determinants.

Aged↗
PubMed1986

Lymphoma in Sjögren's syndrome: urinary monoclonal free light chains as a diagnostic aid and a means of tumour monitoring.

Non Hodgkins lymphoma (NHL) is reported to be at least 40 times more common in Sjögren's syndrome (SS). Diagnosis may be difficult as blood and bone marrow haematology can remain normal, with no evidence of a serum paraprotein band or Bence-Jones proteinuria by routine electrophoresis. Using the technique of isoelectric focusing in agarose, followed by immunofixation, monoclonal free light chains can be found in the urine of 44% and 74% respectively of patients with NHL and B cell chronic lymphocytic leukaemia, but not in normal individuals. Three patients, two with typical severe primary SS and the third with several features of SS including abnormal sialography and reduced tear secretion, developed B cell NHL of parotid and/or lung. Using the above method on concentrated urine specimens, monoclonal free light chains of the same class as that demonstrated on the tumour cells were found to be present in each patient's urine. In one patient the level of urinary free light chains was monitored and found to correlate with disease activity. Using similar techniques no monoclonal light chains could be found in the urine from a further 10 cases of primary SS and 18 cases of SS secondary to rheumatoid arthritis, all of whom had no clinical evidence of lymphoma. Screening of SS patients' urine by the method described for monoclonal urinary free light chains may provide an early diagnostic clue to the development of lymphoma and be a means of tumour monitoring.

Adult↗
PubMed1985

Secretion of idiotypic IgM by the mouse B-cell leukaemia (BCL1) occurs spontaneously in vitro and in vivo.

An analysis has been carried out to investigate the ability of neoplastic cells from the mouse B-cell leukaemia (BCL1) to secrete idiotypic IgM. Tumour cells taken from the spleen and placed in short-term culture without stimulation secreted quite large amounts of idiotypic IgM with a mean value for six animals +/- SD of 11,5000 +/- 6800 molecules of pentamer/cell/hr, with levels increasing steadily over a 7-hr period. Tumour cells from the blood of matched animals also secreted idiotypic IgM in amounts generally less than the spleen cells (4100 +/- 2000 molecules/cell/hr. The IgM produced was found to be mainly pentameric, with some material of lower molecular weight. This idiotypic IgM could also be detected in the serum of leukaemic animals as pentameric IgM, and amounts increased during tumour development to 1-2 mg/ml in the terminal phase of disease. Since binding of anti-idiotypic antibody to tumour cells is inhibited by this material, it should be taken into account in immunotherapeutic schedules involving such antibody. However, it also presents a useful marker of disease, and perhaps of response to therapy.

Animals↗