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Biomedical subjects

R Levy

Publications and source records attributed to R Levy.

At least 631 records · Page 35Linked to original sources
PubMed1985

Heteroantibody duplexes target cells for lysis by cytotoxic T lymphocytes.

Antibodies to the clonally unique variable-region determinants (idiotype) of the antigen-specific alpha beta heterodimeric receptor of a clone of cytotoxic T cells (CTLs) were shown previously to render diverse cells, regardless of their own surface antigens, susceptible to lysis by that clone of CTLs. To extend these findings, we have sought to develop a general means for targeting cells for destruction by any CTL, without regard to its alpha beta idiotype and specificity for antigen. We explored the use of heteroantibody duplexes formed by joining covalently an antibody to the T3 complex (anti-T3), which is associated with the alpha beta receptors on all human mature T cells, and a second antibody, specific for an antigen on the intended target cell. The second antibody selected in this study was specific for the idiotype (Id) of the surface immunoglobulin of a human B-lymphoma (anti-Ig Id). In the presence of the anti-T3/anti-Ig Id heteroantibody duplex the B-lymphoma cells were lysed by a clone of human T8+ CTLs (of unrelated specificity) but not by a noncytotoxic clone of human T4+ helper T cells, and lysis by the CTLs was specifically blocked by the uncoupled anti-T3 or the uncoupled anti-Ig Id antibodies. The extent of the heteroantibody-dependent cytolysis depended both on the heteroantibody concentration and on whether the intended target cells or the CTL effectors were initially preincubated with the heteroantibody. Under optimal conditions, heteroantibody-dependent lysis of the surrogate target (B-lymphoma) cells by the CTLs compared favorably with lysis of their natural target cells by the same CTLs. Overall, our findings suggest that heteroantibody duplexes containing anti-T3 antibody may be capable of targeting selected cells, such as tumor cells, for destruction in vivo by the body's CTLs.

Animals↗
PubMed1985

Monoclonal anti-idiotype antibodies against the murine B cell lymphoma 38C13: characterization and use as probes for the biology of the tumor in vivo and in vitro.

To establish a murine model for the monoclonal anti-idiotype immunotherapy of B cell lymphoma, a panel of rat and murine monoclonal anti-idiotype antibodies of several different isotypes was generated against the surface immunoglobulin of the murine B cell tumor 38C13 (38C). Xenogeneic antibodies were made from fusions of rat spleen cells immunized with the 38C idiotype. Syngeneic monoclonal anti-idiotypes were generated from mice immunized with the idiotype conjugated to the protein carrier KLH. Small differences were noted in the ability of the antibodies to cross-block one another, but all appeared to be directed against the same or closely spaced idiotopes on the immunoglobulin molecule. The antibodies selectively precipitated surface Ig from 38C tumor cells and not from normal mouse spleen cells. They were used to selectively stain 38C tumor cells in cell suspensions for FACS analysis or immunohistochemical staining of tissue sections from mice bearing the tumor. As the malignancy progressed, the number of tumor cells found in all tissues examined increased. Thus, the anti-Id antibodies provided a specific probe for tumor cell detection. The antibodies had no detectable effect on cell growth in vitro; however, they did cause the rapid transient loss of the expression of cell surface Ig. This modulation was concentration and time dependent but not 100% complete. Re-expression of the Id occurred by 24 h following removal of the anti-Id antibodies. When these antibodies were used in sensitive radioisotope and enzyme linked immunoassays, the tumor cells were found to secrete small amounts of idiotype in vitro and in vivo. The level of idiotype detected in vivo correlated with tumor growth and inversely with survival. This work is an attempt to develop further an animal model system in which to test the diagnostic and therapeutic effects of monoclonal anti-idiotype antibodies.

Animals↗
PubMed1985

A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer's disease.

The first long-term double-blind placebo controlled trial of high dose lecithin in senile dementia of the Alzheimer type is reported. Fifty one subjects were given 20-25 g/day of purified soya lecithin (containing 90% phosphatidyl plus lysophosphatidyl choline) for six months and followed up for at least a further six months. Plasma choline levels were monitored throughout the treatment period. There were no differences between the placebo group and the lecithin group but there was an improvement in a subgroup of relatively poor compliers. These were older and had intermediate levels of plasma choline. It is suggested that the effects of lecithin are complex but that there may be a "therapeutic window" for the effects of lecithin in the condition and that this may be more evident in older patients.

Aged↗
PubMed1985

Familial membranous subaortic stenosis.

Familial occurrence of membranous subaortic stenosis (MSS) is described in three families. The defect was found in 2 siblings in two of these families, and in 3 siblings of the third family. The importance of early diagnosis and treatment of MSS is emphasized. We suggest early evaluation of first-degree relatives of patients with MSS for the possibility of this defect.

Adolescent↗
PubMed1985

Discordance between surface and cytoplasmic expression of the Leu-4 (T3) antigen in thymocytes and in blast cells from childhood T lymphoblastic malignancies.

We have examined the expression of the Leu-4 (T3) antigen on the cell surface and in the cytoplasm of blast cells from 23 patients with T cell acute lymphoblastic leukemia and T cell lymphoblastic lymphoma. In the majority of cases (17), the Leu-4 antigen was absent from the cell surface; however, in 16 of these 17 cases, blast cells demonstrated cytoplasmic expression of Leu-4. This discordance between surface and cytoplasmic expression of Leu-4 was also found in thymocytes and appeared to be restricted to Leu-4, in that tests of other T cell antigens rarely revealed discordance between surface and cytoplasmic expression. To study further the cytoplasmic determinant identified by anti-Leu-4 in malignant T lymphoblasts, immunoprecipitation studies were performed that utilized biosynthetic labeling of established T cell lines derived from T lymphoblastic malignancies. By one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, identical Leu-4 polypeptide families were immunoprecipitated from surface Leu-4+ and surface Leu-4-/cytoplasmic Leu-4+ cell lines. Because T lymphoblastic malignancies represent proliferations of immature T cells, and because the cases studied demonstrated surface phenotypes corresponding to all of the proposed stages of T cell ontogeny, it appears that cytoplasmic expression of Leu-4 occurs early in T cell development. The reason for the failure of these immature T cells to transport the Leu-4 molecule to their surface remains to be elucidated.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1985

Long-term experience with pergolide therapy of advanced parkinsonism.

Nine patients with idiopathic Parkinson's disease were treated with pergolide to a daily maintenance dose of 2.2 +/- 0.9 mg (mean +/- SD) for 17.3 +/- 8.3 months. After 1 month, there was an average 68% increase in mobile on-time, but the improvement declined to 30% by 6 months, 23% by 1 year, and virtually disappeared by 18 months of therapy. Pergolide was discontinued in seven patients because of loss of efficacy (4 patients), confusion (1 patient), or myocardial infarction or ventricular ectopy (2 patients). Partial but temporary restoration of mobility was observed in seven patients who were switched to an alternate-day dosing schedule after 9.2 +/- 2.4 months. Two patients with advanced Shy-Drager syndrome were treated with pergolide without benefit.

Aged↗
PubMed1985

Differences in "host infiltrates" among lymphoma patients treated with anti-idiotype antibodies: correlation with treatment response.

To correlate treatment responses with numbers and types of "host cell infiltrates," lymphoid tissues from 10 patients with low-grade B cell malignancies were stained before, during, and after anti-idiotype therapy with a panel of monoclonal antibodies applied to frozen sections. Tissue penetration by the anti-idiotype antibodies was confirmed in five patients by these immunoperoxidase methods. Large numbers of phenotypic T helper cells were the main component of the "host infiltrate" in most patients. Two patients showed a complete and a near-complete clinical remission, four others had partial responses, and four did not respond to therapy. The two patients that developed clinical remission demonstrated the largest number of T cells, T helper cells, TAC+ cells, Leu-7+ cells, and in general the smallest number of proliferating cells as measured by the Ki-67 antibody. Other major differences in host cells were not evident among the patients. These preliminary data suggest that the type and amount of "host infiltrate" in low-grade B cell lymphomas may predict which patients will respond to anti-idiotype therapy.

Animals↗
PubMed1985

Antiproliferative monoclonal antibodies: detection and initial characterization.

Two monoclonal antibodies (MAB) are described which inhibit in vitro cellular proliferation in the absence of complement or effector cells. These MAB were produced by hybridomas made from mice immunized against human B lymphoma cells. The MAB were detected by using a colorimetric assay that quantifies proliferation based on the conversion of a yellow tetrazolium salt to a purple formazan product, a reaction that occurs only in metabolically active cells with intact mitochondrial enzymes. A human B lymphoblastoid cell was used as the screening target. RBC4 is an IgM MAB that modulates and immunoprecipitates the transferrin receptor. RBG5 is an IgG1 that binds to a nonmodulating cell surface determinant different from the transferrin receptor. Both MAB are active at low concentrations (RBC4, 0.5 microgram/ml and RBG5, 0.01 microgram/ml). Immunofluorescence staining of cell lines by RBC4 and RBG5 shows little correlation with inhibition by the antibodies. They differentially inhibit the proliferation of a panel of T, B, and myeloid cell lines. Both antibodies inhibit the proliferation of alloantigen or mitogen-activated human peripheral blood lymphocytes (PBL). Unstimulated PBL are not affected by either MAB. The RB MAB each cause different morphologic changes of target cells. Whereas RBC4-inhibited cells exhibit nonspecific changes, RBG5 causes a progressive increase in the size and nuclear number of a subset of inhibited cells.

Animals↗
PubMed1985

Monoclonal antibody therapy of lymphoid malignancy.

Monoclonal antibodies which bind to tumour cell surface antigens have produced regressions of malignancies in an increasing number of clinical trials. The largest experience to date is in the treatment of refractory B and T lymphoid tumours using a variety of intravenously administered mouse monoclonal antibodies. Treatment with antibodies against common differentiation antigens or very specific anti-idiotype antibodies has been effective in both cases. Toxicity has been acceptably low. A number of problems which limit the application and efficacy of monoclonal antibody therapy of lymphoid malignancy have been identified. Most prominent among these are tumour heterogeneity, which allows non-antibody binding subpopulations of the tumour to escape therapy, and the patient's immunological response to the monoclonal antibody-tumour cell complex. As more experience is accumulated, solutions to these problems will be found.

Antibodies, Monoclonal↗
PubMed1985

A clinical trial of anti-idiotype therapy for B cell malignancy.

Eleven patients with B lymphocytic malignancy were treated with mouse monoclonal anti-idiotype antibodies. All but one of the patients in this study had received extensive prior treatment with conventional lymphoma therapy. All antibodies were prepared against, and uniquely reactive with, the patient's own tumor. Ten patients were treated with a single antibody, but one patient received three antibodies concurrently. The treatment protocol initially used an escalating dose schedule that was intended to evaluate toxicity, pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last two patients received substantial initial doses. Tumor sampling was performed before and during therapy to evaluate tissue penetration by antibody. None of the patients had serum paraproteins by routine clinical testing, but six had idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/mL, two of which were greater than 200 micrograms/mL. Plasmapheresis was capable of reducing these levels temporarily. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig, which occurred in five of the 11 patients. Once an immune response had begun, further infusions of antibody were not capable of reaching the tumor or inducing tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 42 months after receiving antibody. Five of ten additional patients have had objective remissions that were also clinically significant. However, these remissions were not complete and were of relatively short duration. This therapy shows promise as an alternative modality for the treatment of B cell malignancy. Further study will be needed to determine the mechanisms of the antitumor effect and to improve the clinical results.

Adult↗
PubMed1985

Co-expression of cytokeratin and vimentin filaments in mesothelial, granulosa and rete ovarii cells of the human ovary.

The intermediate filament (IF) system of the various cells of human, pig and rat ovaries was studied by electron microscopy, by immunolocalization using antibodies to cytokeratins, vimentin, desmin and desmoplakin, and by two-dimensional gel electrophoresis of cytoskeletal proteins from microdissected tissue samples. In human ovaries, surface epithelial cells (mesothelium) were stained by antibodies against cytokeratins, desmoplakins and vimentin. Biochemical analysis revealed cytokeratins Nos. 8, 18 and 19, together with variable amounts of No. 7. Granulosa cells of follicles of all stages were also positive for cytokeratins, desmoplakins and vimentin, in agreement with the electron microscopic finding of desmosomes in these cells. As the follicle matured, the cytokeratin content usually appeared to decrease, whereas vimentin remained unchanged. On gel electrophoresis, granulosa cells presented cytokeratins Nos. 8 and 18 and vimentin. Rete ovarii cells were also positive for both cytokeratins, desmoplakins and vimentin, and the electron microscopy revealed numerous desmosome-tonofilament complexes. Oocytes appeared to be devoid of IFs. Corpus luteum cells were rich in vimentin but biochemical analysis also revealed small amounts of cytokeratins Nos. 8 and 18. In contrast, cells of the ovarian stroma and luteinized stromal nodules were positive for vimentin only. A certain type of scattered stromal cells, especially around tertiary follicles and corpora lutea, and also desmin-positive. Pig and rat ovaries differed from human ones in that vimentin was not detected in ovarian mesothelium and cytokeratins were not seen in granulosa cells. The latter, however, contained significant amounts of vimentin. These results indicate that three cell types of human ovary, i.e. surface epithelial, granulosa and rete ovarii cells, can be regarded as true epithelial cells which, however, simultaneously express vimentin, a phenomenon frequently seen in cultured epithelial cells but uncommon in epithelial tissues. The presence of cytokeratins in granulosa cells in all types of human follicles is discussed with regard to the development of these cells. In contrast, granulosa cells of the other two mammalian species only display vimentin IF. Such differences between different mammalian species in IF composition of ovarian components present an example which precludes extrapolation of data from one species to another. The results are discussed in relation to current views of the histogenesis of various ovarian tumors.

Animals↗
PubMed1985

Monoclonal antibodies--therapeutic and diagnostic uses in malignancy.

Murine monoclonal antibodies represent an attractive type of antitumor therapy because of their potential for exquisite specificity, production in large, pure quantities and mediation of in vivo cytotoxic effects. With maturing monoclonal antibody technology has come the use of these antibodies in clinical studies in patients with malignancy. These trials have established that monoclonal antibodies can be safely administered in large doses, that their pharmacokinetics and tissue penetration can be predicted and that in some instances a therapeutic effect can be produced by their infusion. A number of problems have also been identified by these studies, including antigenic heterogeneity of the tumor, the presence of free serum antigen, the immunogenicity of the xenogeneic antibody, modulation of the surface antigen by the antibody and a finite capacity of human effector mechanisms to mediate cytotoxicity directed by murine antibodies. Other workers are concurrently investigating the use of monoclonal antibodies in the ex vivo elimination of cells from bone marrow, as probes for serum tumor marker antigens and as carriers for radioimaging agents or toxins. Although most of these endeavors are at the earliest stages, promising preliminary results presage an important role for native and altered monoclonal antibodies in the diagnosis and treatment of malignant conditions.

Antibodies, Monoclonal↗
PubMed1984

Erythrocyte Lii-Nao countertransport system. Inhibition by N-ethylmaleimide probes for a conformational change of the transport system.

Human erythrocytes were treated by a series of SH-reagents, including maleimides, iodo compounds, mercurials and oxidizing agents. Rates of Li efflux into Na-rich medium, Li leak and Lii-Nao countertransport were then determined. Of the 13 different reagents studied, only N-ethylmaleimide, iodoacetamide and iodoacetate inhibited selectively the countertransport activity. The effect of the various reagents indicates that the sensitive SH-groups of the countertransport system are not externally exposed. N-Ethylmaleimide was used to probe for changes elicited by substrate cations in Lii-Nao countertransport. In Na- and Li-free medium, inhibition of Lii-Nao countertransport by N-ethylmaleimide of 35% was reached within 2 s. In Na or Li medium, maximal inhibition was twice as great, but was attained much more slowly, within 10 min. Kinetic data and Hill plot analysis indicate the involvement of two classes of SH-groups: one expressed in the various media with and without substrate cations, and an additional one, which becomes specifically available to N-ethylmaleimide in the presence of external Na or Li. The affinity of Na to the site promoting inhibition by N-ethylmaleimide (apparent Km = 12 mM) is higher than the affinity of Na to its external countertransport site (apparent Km = 25 mM, as reported by Sarakadi, B., Alifimoff, J.K., Gunn, R.B. and Tosteson, D.C. (1978) J. Gen. Physiol. 72, 249-265). Reactivity of N-ethyl[14C]maleimide was not modified by the media tested. It is concluded that external Na and Li cause a conformational change in the protein(s) of the countertransport system in human erythrocytes.

Biological Transport↗
PubMed1984

Detection of antibodies against Candida albicans ribosomes by the enzyme linked immunosorbent assay.

Enzyme linked immunosorbent assay was found to be a convenient method for the investigation of antibodies in mice immunized with Candida albicans ribosomes. Antibodies against the ribosomal antigen were detected in all the sera of mice (ICR and BALB/c) immunized with ribosomes and incomplete Freund's adjuvant and in some of the sera of mice immunized with ribosomes only; the titer of antibodies varied from 1:320 to 1:10 240. Vaccination of mice with ribosomal protein and IFA resulted in a high titer of antiribosomal antibodies. Treatment of ribosomes with pronase abrogated the capacity of the ribosomes to elicit anti ribosomal humoral responses, suggesting that the antibodies detected were directed against the protein moiety of the ribosomes. The presence of antibodies in sera of immunized mice could not be correlated with the protection afforded by the ribosomal vaccination.

Animals↗