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Ralph E Schrohenloher - One of the best experts on this subject based on the ideXlab platform.
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expression of rheumatoid factor Idiotypes 17 109 6b6 6 and 4c9 in the sera of pima indians
Autoimmunity, 1994Co-Authors: Anne Davidson, Ralph E Schrohenloher, Harold Keiser, Antonio Del Puente, Peter H Bennett, William J KoopmanAbstract:This study was undertaken to determine whether the expression of 17.109, 6B6.6 and 4C9 rhematoid factor (RF) Idiotypes is predictive of the development of rheumatoid arthritis (RA) and whether the RF response is idiotypically restricted in an inbred population of Pima Indians who have a genetic predisposition for the disease.Serial sera were obtained from 25 subjects who developed RA and 25 RF-positive subjects who did not develop RA over the course of a longitudinal community health survey. RF titers and titers of the RF-associated Idiotypes 17.109, 6B6.6 and 4C9 were determined by ELISA, and the relationship between 6B6.6 and 4C9 was analyzed by cross-absorption studies.Expression of the three RF-associated Idiotypes was found in both the subjects who developed RA and those who did not. The amount of Idiotype expressed was variable, but a few subjects in both groups had high levels indicative of an oligoclonal RF response. Reactivity with 6B6.6 and 4C9 antiIdiotypes overlapped, with 4C9 appearing to mar...
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shared Idiotypes in mesangial deposits in iga nephropathy are not disease specific
Kidney International, 1993Co-Authors: Warmold A L Van Den Wall Bake, Jan A Bruijn, Mary Ann Accavitti, Peggy A Crowleynowick, Ralph E SchrohenloherAbstract:Shared Idiotypes in mesangial deposits in IgA nephropathy are not disease-specific. The antigenic specificity of the mesangial IgA in IgA nephropathy (IgAN) remains unknown. Because shared antigenic specificities may be reflected in the usage of shared Idiotypes, we prepared five monoclonal anti-idiotypic antibodies (MoAbs) specific for the mesangial IgA eluted from the kidney of an IgAN patient. All five MoAbs reacted with the same Idiotype, which proved to be of a public nature. Although the Idiotype could be identified in the mesangial deposits of the majority of IgAN patients studied, it was not specific for the disease because it was also found in the glomerular deposits of other types of glomerulonephritis. The Idiotype was also expressed in polyethylene glycol precipitates of sera and in pokeweed mitogen-induced plasma cells from both IgAN patients and healthy controls. The conclusion that no disease-specific Idiotypes are present in the renal eluate was further supported by the failure to produce polyclonal anti-idiotypic antibodies by immunizing a rabbit with the eluted mesangial IgA. Our results support the concept that mesangial IgA deposits in IgAN are of a polyclonal nature.
Ronald Levy - One of the best experts on this subject based on the ideXlab platform.
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Idiotype vaccines for non hodgkin s lymphoma induce polyclonal immune responses that cover mutated tumor Idiotypes comparison of different vaccine formulations
Blood, 1997Co-Authors: Clemens B Caspar, Shoshana Levy, Ronald LevyAbstract:The Idiotype (Id) of the Ig expressed on the surface of non-Hodgkin's lymphoma cells is a suitable target for immunotherapy. Indeed, treatment with monoclonal anti-Id antibodies (Abs) can induce long-lasting clinical remissions. However, some of the treated patients relapse with a tumor expressing Ig with point mutations in the idiotope recognized by the particular monoclonal antibody (MoAb). The alternative approach of active immunization with tumor Id can cure the disease in mice with established tumors and is now being studied in clinical trials. Here, we tested the hypothesis that active immunization with the Idiotype would evoke a polyclonal immune response that would cover mutated tumor variants. As a test system, we chose the tumor from a patient who had achieved a complete remission after therapy with anti-Id Ab but subsequently relapsed with a mutated tumor variant no longer binding the treatment Ab. Mice were immunized with proteins and genetic vaccines derived from the original tumor, including (1) Id-keyhole limpet hemocyanin protein, (2) Id single-chain variable fragment (scFv) granulocyte-macrophage colony-stimulating factor (GM-CSF) protein, (3) DNA encoding the Id, and (4) an adenovirus encoding the Id. All immunized mice developed a specific immune response detecting tumor-derived Id proteins from the original tumor and from all tumor variants. We conclude that active immunization with tumor Id can induce a polyclonal immune response and therefore may prevent the escape of mutated tumor variants.
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tumor specific Idiotype vaccines in the treatment of patients with b cell lymphoma long term results of a clinical trial
Blood, 1997Co-Authors: Frank J Hsu, Debra K Czerwinski, Clemens B Caspar, Larry W Kwak, Tina Marie Liles, Athanasia Syrengelas, Behnaz Taidilaskowski, Ronald LevyAbstract:The surface Ig on each B-cell lymphoma has unique portions (Idiotypes), which can be recognized by the immune system. In this study, we immunized patients against the Ig expressed by their tumor and observed their clinical outcomes. After standard chemotherapy, 41 patients with non-Hodgkin's B-cell lymphoma received a series of injections with a vaccine consisting of tumor Ig protein coupled to keyhole limpet hemocyanin and emulsified in an immunologic adjuvant. Subjects were observed for toxicity, immune responses, and tumor status. The median duration of follow-up of all patients is 7.3 years from diagnosis and 5.3 years from the last chemotherapy given before vaccine treatment. Twenty patients (49%) generated specific immune responses against the Idiotypes of their tumor Ig. Two patients who had residual disease experienced complete tumor regression in association with the development of these immune responses. The median duration of freedom from disease progression and overall survival of all 20 patients mounting an anti-Idiotype immune response are significantly prolonged compared to the patients who did not mount an immune response. Thirty-two patients were in their first remission and nine were in subsequent remissions before beginning vaccine treatments. Analysis of the 32 first remission patients also shows an improved clinical outcome for those patients who mounted a specific immune response compared to those who did not (freedom from progression, 7.9 years v 1.3 years P = .0001; median survival from time of last chemotherapy not yet reached v 7 years, P = .04). This study confirms an earlier report that patients with B-cell lymphoma can be induced to make a specific immune response against the Ig expressed by their own tumor. It further shows that the ability to make such an immune response is correlated with a more favorable clinical outcome. Prospective controlled trials will be needed to prove a causal relationship between anti-Idiotype immunity and improved clinical outcome.
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Idiotype granulocyte macrophage colony stimulating factor fusion protein as a vaccine for b cell lymphoma
Nature, 1993Co-Authors: Mihua Tao, Ronald LevyAbstract:To produce a vaccine against cancer, antigens must be found that are preferentially expressed by tumour cells and can induce an immune response against the tumour. The variable regions of the immunoglobulin molecules expressed on malignant B cells (Idiotypes) are tumour-specific, but are weak immunogens. To induce an immune response in animals or humans, the idiotypic protein has therefore to be chemically coupled to a strongly immunogenic protein and mixed with an adjuvant. The resulting response can protect animals from subsequent tumour challenge, and cure animals with established tumours in combination with chemotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) augments antigen presentation in a variety of cells. Here we show that by fusing a tumour-derived Idiotype to GM-CSF, it can be converted into a strong immunogen capable of inducing Idiotype-specific antibodies without other carrier proteins or adjuvants and of protecting recipient animals from challenge with an otherwise lethal dose of tumour cells. This approach may be applicable to the design of vaccines for a variety of other diseases.
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monoclonal anti Idiotype antibody therapy of b cell lymphoma the addition of a short course of chemotherapy does not interfere with the antitumor effect nor prevent the emergence of Idiotype negative variant cells
Blood, 1992Co-Authors: David G Maloney, Sarah Hart, Richard A Miller, S Brown, Debra K Czerwinski, T M Liles, Ronald LevyAbstract:The Ig Idiotype of B-cell lymphoma can be used as a tumor-specific target. Prior trials with monoclonal anti-Idiotype antibodies alone and combined with alpha-interferon have shown significant antitumor activity. In some patients, Idiotype-negative tumors emerged after treatment. In this trial, patients with relapsed non-Hodgkin's lymphoma were treated with two identical courses of monoclonal anti-Idiotype anti-body therapy. Concurrent with the second course, at a time when Idiotype-negative cells were suspected to be proliferating, a pulse dose of chlorambucil was administered. Tumor biopsies obtained before the first and second courses of treatment and at relapse were analyzed for Idiotype expression and proliferation. Thirteen patients received 24 courses of antibody with minimal toxicity. Eleven had tumor regression, with 1 complete remission, 8 partial remissions, and 2 minor remissions, with freedom from progression lasting a median of 7 months in responding patients. Idiotype-negative tumor cells appeared in some relapse specimens despite the use of chlorambucil. In retrospect, this was not surprising because there was no increase in the proliferative rate of these tumors at the time the drug was used. Anti-Idiotype antibodies continue to demonstrate antitumor activity against B-cell lymphoma with minimal toxicity. The mechanism of the effect is presumed to involve both direct antiproliferative effects of the antibody on the tumor cells as well as indirect, more long-lasting effects on the host. The addition of a mild chemotherapeutic agent in the dose and schedule used here to the second cycle of antibody therapy did not interfere with the antitumor effect, nor did it decrease the emergence of Idiotype-negative cells.
John H Vaughan - One of the best experts on this subject based on the ideXlab platform.
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occurrence of two germline related rheumatoid factor Idiotypes in rheumatoid arthritis and in non rheumatoid seropositive individuals
Clinical and Experimental Immunology, 2008Co-Authors: T Kouri, J Crowley, K Aho, T Palosuo, H Isomaki, R Essen, M Heliovaara, Dennis A Carson, John H VaughanAbstract:Human rheumatoid factor (RF) paraproteins express two distinct light chain cross-reactive Idiotypes defined by the monoclonal antibodies 17.109 and 6B6.6. These germline gene-related cross-reactive Idiotypes are both carried on VK3 light chains and are each present on about one-third of IgM RF paraproteins. We assessed the degree to which these Idiotypes are represented in polyclonal RFs. We used rheumatoid arthritis (RA) and non-RA RF-positive sera selected from a large cross-sectional population study (the Mini-Finland Health Survey), and sera from a community-based follow-up study of recent-onset RA patients from Heinola, Finland. In the Mini-Finland Health Survey, elevated levels of the 17.109 RF Idiotype were seen in sera of 13% of the RA and 19% of the non-RA group; 6B6.6 RF was seen in 26% of the RA and 28% of the non-RA group. In sera of the Heinola follow-up study, 17.109 RF was seen in 12% initially, but in only 3% at 8 years. Similarly, 6B6.6 RF was detected in 25% initially, but in only 7% at 8 years. Ten sera positive for RF prior to the onset of clinical RA were identified from individuals of a second large population study from Finland (North Karelia project); two of these sera exhibited the 6B6.6 Idiotype; none exhibited the 17.109 Idiotype. The data are consistent with the concept that these germline gene-related cross-reactive RF Idiotypes occur frequently in the polyclonal RF of non-RA as well as RA sera, and that in RA the Idiotypes may sometimes be reduced or lost as a consequence of somatic diversification of the RF through somatic mutation, usage of new germline genes, or both.
Dennis A Carson - One of the best experts on this subject based on the ideXlab platform.
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CHARACTERIZATION OF AN EPIBODY An AntiIdiotype That Reacts With Both the Idiotype of Rheumatoid Factors (RF) and the Antigen Recognized by RF
2013Co-Authors: Dennis A CarsonAbstract:Since the original discovery of Idiotypes (1-3), their structural basis and biological significance have been a central interest in immunology. Recently, Bona et ai. (4) described a peculiar antiidiotypic antibody that reacted not only with an Idiotype on a monoclonal, human anti-IgG autoantibody (rheumatoid factor, RF), 1 but also with the Fc fragment of human IgG (4). They called this doubly reactive antiIdiotype an epibody, i.e., an antibody recognizing both an idiotope and an epitope on the original antigen. Very recently, we prepared and characterized three different types of antiidiotypic antibodies against human rheumatoid factors: (a) a monoclonal antiIdiotype (mAb 17.109), that reacts with 30 % of human monoclonai RF (5); (b) antiIdiotype that bears the "internal image " of human IgG, and thus binds to most human RF (6); and (c) antiIdiotypes induced by synthetic peptides corresponding to distinct, complementarity-determining regions (CDR) on RF heavy and light chains (7, 8). The latter, CDR peptide-induced antibodies identify preselected Idiotypes, with amino acid sequences homologous to the immunizin
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Brief Definitive Report SYNTHETIC PEPTIDES CORRESPONDING TO THIRD HYPERVARIABLE REGION OF HUMAN MONOCLONAL IgM RHEUMATOID FACTOR HEAVY CHAINS DEFINE AN IMMUNODOMINANT Idiotype
2013Co-Authors: Dennis A CarsonAbstract:The structural basis ofidiotypic antigens has been studied intensively in murine model systems (1), but less thoroughly in humans. Analyses of Idiotype-antiIdiotype reactions may be important in understanding the pathogenesis of human immunologic diseases, and in developing new approaches to treatment. Kunkel and coworkers (2), and subsequently Powell and Agnello (3), showed that IgM anti-IgG autoantibodies (rheumatoid factors [RF]) from unrelated individuals may display crossreactive Idiotypes. The heavy and light chain variable region sequences of several IgM-RF have been reported (4-6). However, genetic studies and hybridoma techniques are difficult to apply in an outbred human population. Therefore, we have taken a different approach toward defining relationships between Idiotype and structure on these human Ig. Rabbit antisera were generated against synthetic peptides with sequences corresponding to the hypervariable regions (complementarity determining regions [CDR]), of human IgM-RF. The antipeptide antibodies enabled us to clarify the structural basis for a private (7) and a crossreactive (8) Idiotype on the anti-IgG autoantibodies. Recent results in mice (9, 10), and our own preliminary data in humans (1 1), have focused attention on the third CDR of the heavy chain as a site of dominant Idiotype formation. We now report that antisera raised against synthetic peptides corresponding to the third heavy chain CDR consistently recognize Idiotypes expressed by intact IgM-RF autoantibodies. In contrast, high-titer antibodies against synthetic peptides representing the first and second heavy chain CDR infrequently bind to the IgM-RF molecule. These results suggest a distinctive role of the D (diversity-generating) region in the generation of idiotypic determinants, and have implications concerning the manipulation of Idiotype-antiIdiotype reactions in patients
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occurrence of two germline related rheumatoid factor Idiotypes in rheumatoid arthritis and in non rheumatoid seropositive individuals
Clinical and Experimental Immunology, 2008Co-Authors: T Kouri, J Crowley, K Aho, T Palosuo, H Isomaki, R Essen, M Heliovaara, Dennis A Carson, John H VaughanAbstract:Human rheumatoid factor (RF) paraproteins express two distinct light chain cross-reactive Idiotypes defined by the monoclonal antibodies 17.109 and 6B6.6. These germline gene-related cross-reactive Idiotypes are both carried on VK3 light chains and are each present on about one-third of IgM RF paraproteins. We assessed the degree to which these Idiotypes are represented in polyclonal RFs. We used rheumatoid arthritis (RA) and non-RA RF-positive sera selected from a large cross-sectional population study (the Mini-Finland Health Survey), and sera from a community-based follow-up study of recent-onset RA patients from Heinola, Finland. In the Mini-Finland Health Survey, elevated levels of the 17.109 RF Idiotype were seen in sera of 13% of the RA and 19% of the non-RA group; 6B6.6 RF was seen in 26% of the RA and 28% of the non-RA group. In sera of the Heinola follow-up study, 17.109 RF was seen in 12% initially, but in only 3% at 8 years. Similarly, 6B6.6 RF was detected in 25% initially, but in only 7% at 8 years. Ten sera positive for RF prior to the onset of clinical RA were identified from individuals of a second large population study from Finland (North Karelia project); two of these sera exhibited the 6B6.6 Idiotype; none exhibited the 17.109 Idiotype. The data are consistent with the concept that these germline gene-related cross-reactive RF Idiotypes occur frequently in the polyclonal RF of non-RA as well as RA sera, and that in RA the Idiotypes may sometimes be reduced or lost as a consequence of somatic diversification of the RF through somatic mutation, usage of new germline genes, or both.
William J Koopman - One of the best experts on this subject based on the ideXlab platform.
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expression of rheumatoid factor Idiotypes 17 109 6b6 6 and 4c9 in the sera of pima indians
Autoimmunity, 1994Co-Authors: Anne Davidson, Ralph E Schrohenloher, Harold Keiser, Antonio Del Puente, Peter H Bennett, William J KoopmanAbstract:This study was undertaken to determine whether the expression of 17.109, 6B6.6 and 4C9 rhematoid factor (RF) Idiotypes is predictive of the development of rheumatoid arthritis (RA) and whether the RF response is idiotypically restricted in an inbred population of Pima Indians who have a genetic predisposition for the disease.Serial sera were obtained from 25 subjects who developed RA and 25 RF-positive subjects who did not develop RA over the course of a longitudinal community health survey. RF titers and titers of the RF-associated Idiotypes 17.109, 6B6.6 and 4C9 were determined by ELISA, and the relationship between 6B6.6 and 4C9 was analyzed by cross-absorption studies.Expression of the three RF-associated Idiotypes was found in both the subjects who developed RA and those who did not. The amount of Idiotype expressed was variable, but a few subjects in both groups had high levels indicative of an oligoclonal RF response. Reactivity with 6B6.6 and 4C9 antiIdiotypes overlapped, with 4C9 appearing to mar...
