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At least 19 recordsLinked to original sources
PubMed1995

Isolation of tumor-derived immunoglobulin-idiotype from peripheral blood mononuclear cells in a B-cell lymphoma patient with minimal disease.

Active immunization with autologous idiotypic immunoglobulin, obtained by somatic fusion techniques, has been shown to be a useful alternative treatment in patients with B-cell lymphoma. Nevertheless, the requirement for biopsy specimens to obtain lymphoma cells could be a limitation to this therapeutic strategy. We address the question of whether peripheral blood samples containing small amounts of tumor cells can be used as appropriate fusion partners to rescue tumor-derived idiotypic proteins. In this report, we show that hybrid cells can be obtained from somatic fusions of K6H6/B5 heterohybridoma with lymphoma cells obtained from both lymph node (LN) and peripheral blood mononuclear cells (PBMC) containing only minor amounts of tumor cells. Some hybrid cells obtained from LN or PBMC fusions present an immunoglobulin (Ig) heavy-chain gene rearrangement identical with that of the original tumor and secrete identical Ig protein containing the expected H and L chains.

Female↗
PubMed2005

Toward personalized immunotherapy for non-Hodgkin lymphoma: targeting the idiotypic immunoglobulin.

The idiotypic determinants of B-cell lymphomas, formed by cell-specific rearrangement of the immunoglobulin genes, are unique and are therefore a suitable target against which to direct immunotherapy. Recent advances in our understanding of the fundamental mechanisms behind an effective immune response, coupled with advances in genetic engineering techniques, have led to a renewed interest in immunotherapy. Early clinical studies have confirmed the immunogenicity of the idiotypic antigen in patients with lymphoma. This review discusses the different methods of idiotypic vaccination currently under investigation in the clinic, including protein, genetic, and cellular vaccines. Protein vaccines are the most clinically advanced, with phase III trials of idiotypic protein linked to GM-CSF currently underway. DNA vaccines are easier to produce but to date only appear to be weakly immunogenic in man. Dendritic cell vaccines have shown promise but their use may be limited by the complexity of this approach. This review also highlights other approaches not yet in the clinic but that have shown promise in the laboratory, such as viral vaccines and T-cell therapy.

Animals↗
PubMed2006

[Development of an experimental immunoglobulin test system based on anti-idiotypic immunoglobulins for the determination of specific plague antibodies in serum of patients inoculated with the live plague vaccine EV NIIEG].

A new rapid, inexpensive, strictly specific, highly sensitive, and safe experimental ELISA test system based on rabbit anti-idiotypic immunoglobulins (anti-Id-ab) against Yersinia pestis lipopolysaccharide (LPS) was developed. Its efficiency was demonstrated, by using a panel of xenogenic antisera of biomodels immunized with the LPS extracted according to the Galanos procedure or the live plague vaccine EV NIIEG. In all cases, the similar proportions of positive reactions to the antigen itself or anti-Id-ab to LPS were registered and there was no significant difference in the detectable concentrations of both antigenic substances. The same data were obtained in ELISA with antisera from the human beings immunized with the vaccine irrespective of the time of vaccination or the number of injections. Whether the use of ELISA is promising in the development of a diagnostic immunoglobulin antiplaque test system is discussed.

Animals↗
PubMed2004

Human monoclonal antibodies produced in transgenic BABkappa,lambda mice recognising idiotypic immunoglobulins of human lymphoma cells.

Clonal idiotypic immunoglobulins of follicular lymphomas can be isolated by somatic fusion procedures. Idiotypic IgMs (Id-IgM) were isolated from two patients and used to immunise a strain of mice, deficient in mouse antibody production and engineered with yeast artificial chromosomes (YAC) containing fragments of the human immunoglobulin (Ig) micro/delta heavy chain and kappa/lambda light chain loci. Sequence analysis showed that hybridomas prepared from spleen cells of immunised mice expressed exclusively one of the six VH genes (VH1-2) present in the YAC transgene with different D/J rearrangements, and secrete fully human monoclonal antibodies (mAb) that recognised the tumour-specific IgM proteins. Further studies of the reactivity of the monoclonal anti-human Id-IgM antibodies revealed that they are specific for the individual protein of each patient and probably react with idiotypic determinants. In one case studied, the antibody recognised specifically the lymphoma cell expressing the corresponding idiotypic IgM and lysed those cells in the presence of complement. This is the first example of a human monoclonal antibody with such characteristics and may be of further use in the therapy of patients with B cell malignancies.

Animals↗
PubMed1989

Induction of surface marker changes and monoclonal idiotypic immunoglobulin secretion in lymphoma/leukemia cells: comparative study with interleukin-1, interleukin-2, interleukin-4, 8-bromo-guanosine, pokeweed mitogen, and tetradecanoyl phorbol-13-acetate.

Induction of differentiation in B lymphoma/leukemia cells with interleukins was compared with differentiation induced by phorbol ester (TPA) and pokeweed mitogen (PWM) or by 8-bromo-guanosine. Both cell surface changes and monoclonal immunoglobulin (Ig) secretion were followed as markers of differentiation. The results indicate great similarity in the differentiation patterns induced by interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-4 (IL-4), with regard to Ig secretion and changes in surface markers. Induction of Ig secretion and surface marker changes by 8-bromo-guanosine was similar to that induced by TPA and PWM; however, for some markers, cell surface changes induced by TPA and PWM or by 8-bromo-guanosine were quite different from those induced by the three interleukins tested. Whereas all three interleukins stimulated the expression of CD5, PWM and TPA and 8-bromo-guanosine substantially decreased CD5 expression on B lymphoma cells. Differences were also observed in the effect on the expression of surface Ig and on the expression of CD19 and CD20. Interestingly, the three interleukins tested and 8-bromo-guanosine induced differentiation and Ig secretion within 24 to 48 hours with no prior activation by B-cell activators, such as anti-surface Ig antibody. These results suggest that leukemic B cells are arrested at a point distal to activation and first cell division. Moreover, the similarity in Ig secretion and surface changes induced by TPA and PWM or 8-bromo-guanosine suggest a similar pathway; however, this pathway is different from the differentiation signal induced by the three interleukins.

Antibodies, Monoclonal↗
PubMed1992

Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors.

BACKGROUND: The idiotypic determinants of the surface immunoglobulin of a B-cell lymphoma can serve as a clonal tumor-specific marker, which may have implications for immunotherapy. We sought to determine whether idiotype-specific immune responses against this autologous antigen could be induced in patients with B-cell lymphoma. METHODS: Nine patients were selected who had minimal residual disease or a complete remission after chemotherapy. Each received a series of subcutaneous injections of the immunoglobulin derived from his or her tumor cells (immunoglobulin-idiotype protein), which had been conjugated to a protein carrier and mixed with an immunologic adjuvant. RESULTS: In seven of the nine patients the injections induced sustained idiotype-specific immunologic responses of the humoral type (two patients), the cell-mediated type (four patients), or both (one patient). The use of an adjuvant was essential for these immune responses. The induced antibodies bound specifically to autologous immunoglobulin idiotype, inhibited the binding of murine monoclonal antiidiotype antibodies, and bound autologous tumor cells. Cell-mediated responses were demonstrated by the specific proliferation of immune peripheral-blood mononuclear cells to the soluble immunoglobulin-idiotype protein in vitro. The tumors of both of the patients with measurable disease regressed completely. Toxicity associated with the vaccine was minimal and consisted only of mild reactions at the site of intramuscular injection. CONCLUSIONS: These results demonstrate that autologous immunoglobulin idiotype can be formulated into an immunogenic, tumor-specific antigen in humans with B-cell lymphoma, and they provide the background for large-scale trials of active specific immunotherapy of this disease.

Adjuvants, Immunologic↗
PubMed2000

Stimulation of cytotoxic T cells against idiotype immunoglobulin of malignant lymphoma with protein-pulsed or idiotype-transduced dendritic cells.

Because of their hypervariable regions and somatic mutations, the antigen receptor molecules of lymphomas (idiotypes) are tumor-specific antigens and attractive targets for antilymphoma immunotherapy. For the optimal induction of human idiotype-specific cytotoxic T cells (CTL), idiotype was presented to CD8(+) peripheral blood mononuclear cells by monocyte-derived autologous dendritic cells (DC) after the endocytosis of idiotype protein or by idiotype-expressing DC. Recombinant idiotype was obtained as a functionally folded Fab fragment by periplasmic expression in Escherichia coli. Idiotype-expressing DC were generated by transduction with recombinant Semliki forest virus vectors encompassing heavy- or light-chain idiotype genes. Autologous lymphoblastoid cell lines stably transfected with Epstein-Barr virus-based idiotype expression vectors were used as target cells to detect idiotype-specific lysis. CTL stimulated with idiotype-loaded DC showed strong specific, CD8-mediated, and major histocompatibility complex (MHC) class I-restricted cytotoxicity against autologous heavy- and light-chain idiotype. In contrast, stimulation with idiotype-transduced DC resulted in only moderate natural killer cell activity. These data confirm the existence of idiotype-specific CTL in patients with lymphoma, define a "good manufacturing practice"-compatible protocol for the generation of these cells without the requirement of viable lymphoma cells, and favor the processing of exogenous antigen over DC transduction for the induction of MHC I-restricted CTL against idiotypes with unknown antigenicity. (Blood. 2000;95:1342-1349)

Adult↗
PubMed1993

Clonal deletion of specific thymocytes by an immunoglobulin idiotype.

We have investigated whether immunoglobulin can induce clonal deletion of thymocytes by employing two strains of transgenic mice. One strain is transgenic for an alpha/beta T cell receptor (TCR) which recognizes a processed idiotypic peptide of the lambda 2(315) light chain variable region, bound to the I-Ed class II major histocompatibility complex molecule. The other mouse strain is transgenic for the lambda 2(315) gene. Double transgenic offspring from a TCR-transgenic female mated with a lambda 2(315) transgenic male exhibit a pronounced clonal deletion of CD4+CD8+ thymocytes. Analysis of neonates from the reciprocal (lambda 2(315)-transgenic female x TCR-transgenic male) cross suggests that the deletion in double transgenic offspring most likely is caused by lambda 2(315) produced within the thymus rather than by maternally derived IgG, lambda 2(315). Nevertheless, IgG, lambda 2(315) can cause deletion of CD4+CD8+ thymocytes when injected in large amounts intraperitoneally into either adult or neonatal TCR-transgenic mice. Deletion is evident 48 and 72 h after injection, but by day 7 the thymus has already regained its normal appearance. A serum concentration of several hundred microgram/ml is required for deletion to be observed. Therefore, the heterogeneous idiotypes of serum Ig are probably each of too low concentration to cause thymocyte deletion in normal animals.

Animals↗
PubMed1992

Immunoglobulin idiotype expression in reactive lymphoid tissues and B-cell lymphomas.

In an investigation of the immunoglobulin idiotypic expression of non-tumour and neoplastic B lymphocytes in situ, fresh-frozen specimens of reactive tonsils, lymph nodes and B-cell malignant lymphomas (B-MLs) from Japanese patients were studied immunohistochemically with 39 different anti-idiotype antibodies. In reactive lymphoid tissues, while idiotype-bearing cells were largely distributed sparsely in follicles and perifollicular areas, some were heavily crowded in particular germinal centres (GCs), suggesting the presence of oligoclonal proliferations of B-cells in GCs. Forty-eight out of 100 B-MLs reacted with anti-idiotype antibodies. This proportion was significantly higher than those reported in Western cases (27-36%), indicating that Japanese B-MLs share public idiotypes much frequently than western cases. The idiotypes demonstrated in these lymphomas, in contrast to those not expressed in any B-ML, were found much commonly in non-tumour lymphocytes, suggesting that such public idiotypes as were common in B-MLs were frequently shared by normal B-lymphocytes.

Antibodies↗
PubMed2006

Cloning of idiotype immunoglobulin genes in B cell lymphomas by anchored PCR and production of individual recombinant idiotype vaccines in Escherichia coli.

OBJECTIVES: Individual immunoglobulins expressed by B-cell lymphomas represent tumor-specific antigens ('idiotypes'). Immunization with idiotype in follicular lymphoma patients may induce specific immune responses, sustained progression-free survival, and disappearance of minimal residual disease. Manufacturing of idiotype vaccines has mostly relied on heterohybridomas established from viable lymphoma cells. This paper describes the feasibility of production of GMP-grade idiotype vaccines as recombinant Fab fragments in Escherichia coli. METHODS: IgH and IgL transcripts were analyzed by anchored PCR from 106 lymphoma and nine control biopsies. Lymphoma-derived V segments were inserted into prokaryotic expression plasmids. Recombinant idiotype Fab fragments were expressed in E. coli in a fermentation system. RESULTS: Idiotype IgH and IgL transcripts were identified in 95% of 106 lymphoma biopsies according to stringent clonality criteria. Large-scale idiotype expression was successful in 69 of 78 cases (89%) and yielded a median of 17 mg (range: 1.2-250 mg) recombinant Fab protein. After affinity chromatography, median vaccine purity was 99% heterodimeric Fab protein (range: 72-100%). Bacterial protein contamination was detectable in one vaccine only. Fab proteins with IgL lambda chains had a tendency for inferior yield and lesser purity than kappa-type Fabs. Among other structural idiotype features (isotype, V family usage, somatic hypermutation pattern, novel glycosylation sites, CDR III net charge), no consistent influences on Fab yield or purity were detected. CONCLUSIONS: Anchored PCR cloning and subsequent protein expression in E. coli provides a reliable technological basis for clinical idiotype vaccination trials.

Cancer Vaccines↗
PubMed1988

Idiotypic immunoglobulin secretion by human B cell non-Hodgkin's lymphomas is related to the expression of the interleukin-2 receptor.

Tumor cells from 5 human B cell non-Hodgkin's lymphoma (B-NHL) patients were investigated for proliferative activity and idiotypic (Id+) immunoglobulin (Ig) secretion in serum-free medium without deliberate addition of B cell growth or differentiation factors (BCDF). These data were compared with cell surface marker expression, notably of activation antigens such as 4F2 and interleukin-2 (IL-2) receptor. Cells from all patients became 4F2 positive at the end of the 6-day culture period. Freshly drawn cells from 3 out of 5 patients expressed the IL-2 receptor (CD25; Tac antigen) or acquired this marker during culture in vitro and secreted relatively high levels of Id+ Ig in vitro. This correlated with elevated serum Id levels (greater than or equal to 0.5 micrograms/ml in vitro versus greater than or equal to 20 micrograms/ml in vivo). In the 2 CD25 (Tac)- B-NHL patients serum Id levels were below the detection limit and the amount of Id+ Ig secreted in vitro did not surpass 50 ng/ml. Only the B-NHL cells from a single patient were initially CD25 (Tac) positive and only these cells proliferated in serum-free culture. To test whether IL-2 receptor expression in the 3 CD25 (Tac)+ patients was functional, recombinant IL-2 (rIL-2) either alone or in conjunction with BCDF and recombinant IL-4 (rIL-4) was added to the cultures. In 2 out of 3 CD25 (Tac)+ patients rIL-2 was capable of enhancing proliferation or Ig secretion. In addition rIL-2 was found to enhance BCDF-mediated but not rIL-4 mediated responses. The third CD25 (Tac)+ B-NHL population was resistant to any of these lymphokines. Thus, this serum-free culture system may accurately reflect patient serum Id levels. IL-2 appears to regulate not only the in vitro but also the in vivo Ig secretion by neoplastic B cells.

Antigens, Surface↗
PubMed1992

Induction of syngeneic cytotoxic T lymphocytes against a B cell tumor. I. Role of idiotypic immunoglobulin.

In previous studies we showed that idiotypic determinants of a B cell hybrid, 2C3, was involved in the generation of idiotype (Id)-specific noncytolytic CD4+ effector T cells that suppressed the Ig expression of wild type 2C3 tumor. In the present investigation we report that Id+ Ig associated with 2C3 was also capable of eliciting syngeneic cytotoxic T lymphocytes (CTL) when mice were hyperimmunized with irradiated 2C3 cells. These effector cells were predominantly Thy 1.2+, CD8+, and CD4- and highly cytotoxic to 2C3 as shown by in vitro and in vivo assays. The unique idiotypic determinants (private Id) of 2C3 Ig was important in the induction of CTL since these effector cells were generated in mice only after immunization with Id+ 2C3 cells. In contrast, immunization of mice with 6B2, an Ig-loss variant of 2C3, and 1BF7, an unrelated syngeneic B cell hybrid which expresses Ig of the same isotype as that of 2C3 but of different Id, failed to elicit any cytotoxic response. Furthermore, incorporation of anti-idiotypic monoclonal and polyclonal antibodies into culture medium abrogated the activation of CTL during in vitro stimulation of the primed splenocytes. Induction of CTL was also inhibited by anti-MHC class I and anti-CD3 monoclonal antibodies, indicating that CD3-TcR complex of the effector T cells were involved in the recognition of Id+ Ig in the context of MHC class I antigens. These results, together with our previous observation, suggest that the anti-2C3 immune response is mediated by two kinds of effector cells, namely, CD4+ noncytolytic and CD8+ cytotoxic T cells. Moreover, the unique private Id associated with 2C3 plays a pivotal role in the induction of both of these effector cells.

Animals↗
PubMed1983

Immunoglobulin idiotype and anti-anti-idiotype utilize the same variable region genes irrespective of antigen specificity.

Idiotypic determinants characterizing certain antibody specificities have been proven valuable structural and genetic markers in studies of antibody diversity and regulation. The heritable predominant idiotype associated with the response to p-azophenylarsonate in A/J mice consists of a set of highly homologous (greater than 95%) heavy and light chain variable region amino acid sequences probably arising by somatic mutation from one or a few V region genes. We examined a peculiar set of monoclonal antibodies that have been defined as CRI by serologic analysis, but that have no affinity for the hapten Ars. These antibodies were elicited by immunization with anti-CRI rather than by the conventional immunization with antigen. The amino acid sequences of the amino terminal half of the V regions of these anti-(anti-CRI) antibodies are indistinguishable from those of conventional Ars-binding CRI antibodies. Thus, Ars-binding CRI and Ars-nonbinding anti-(anti-CRI) are derived from similar or identical VH and VL genes.

Amino Acid Sequence↗
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↗
PubMed1987

Analysis of the interaction of antibodies with immunoglobulin idiotypes on neoplastic B lymphocytes: implications for immunotherapy.

We have examined the reactions of a panel of nine monoclonal anti-idiotype antibodies with the surface immunoglobulin in situ on guinea pig L2C leukemic lymphocytes. Equilibrium binding constants were shown to range between 10(7) and 10(8) M-1 for univalent Fab' gamma fragments and between 10(8) and 10(9) M-1 for intact IgG. Saturation of the cell surface binding sites was achieved with 2.9 X 10(5) Fab' gamma molecules/cell and 1.2 X 10(5) IgG molecules/cell for each antibody, a result that is consistent with a bivalent mode of interaction for the IgG. Despite these overall similarities in binding characteristics antibodies showed striking differences in their ability to clear Ig from the cell surface by antigenic modulation in vitro. This suggested differences in the readiness with which the antibodies cross-linked neighboring surface Ig molecules. Such an interpretation was supported by differences in the times required to achieve bivalent binding at 0 degree C, and in the rates at which labeled antibody dissociated from the cell surface in the presence or absence of an excess of unlabeled antibody. The data are consistent with there being two functionally distinct types of anti-idiotype antibody: those that form predominantly intra-Ig bridges, with each antibody Fab being linked to an Fab on one target molecule ("monogamous" binding) and not favoring modulation; and those that form predominantly inter-Ig bridges ("bigamous" binding) and favor modulation. The nature of interaction is presumably dictated by the orientation of the particular idiotope concerned. This distinction could be of great importance in the therapeutic use of anti-idiotype to ablate 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↗