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. 1987 Jul;84(14):5053–5057. doi: 10.1073/pnas.84.14.5053

Retention of an idiotypic determinant in a human B-cell lymphoma undergoing immunoglobulin variable-region mutation.

S Kon, S Levy, R Levy
PMCID: PMC305245  PMID: 3496601

Abstract

Tumor cells from a patient with B-cell lymphoma were fused with a mouse myeloma cell line. A set of heterohybridomas was thus derived, each of which represented a separate clonal derivative from the tumor cell population. The immunoglobulins secreted by these cell lines reacted variably with a panel of anti-idiotypic antibodies, indicating that the tumor was heterogeneous; however, one antibody, 4D6, reacted strongly with the product of all the heterohybridomas. cDNA for the immunoglobulin heavy chain variable-region genes expressed in these heterohybridomas was cloned and sequenced. Comparison of these sequences indicated that the cells expressing them were clonally related but that they had undergone considerable mutation. Despite mutation, the cells in this tumor population continued to express a functional immunoglobulin molecule and to retain, over a span of 3 years, the idiotypic determinant defined by the 4D6 monoclonal antibody. Thus a selective force existed within the host to retain tumor cells bearing an immunoglobulin molecule with a particular idiotypic structure.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berek C., Griffiths G. M., Milstein C. Molecular events during maturation of the immune response to oxazolone. Nature. 1985 Aug 1;316(6027):412–418. doi: 10.1038/316412a0. [DOI] [PubMed] [Google Scholar]
  2. Brown S., Dilley J., Levy R. Immunoglobulin secretion by mouse X human hybridomas: an approach for the production of anti-idiotype reagents useful in monitoring patients with B cell lymphoma. J Immunol. 1980 Sep;125(3):1037–1043. [PubMed] [Google Scholar]
  3. Clarke S. H., Huppi K., Ruezinsky D., Staudt L., Gerhard W., Weigert M. Inter- and intraclonal diversity in the antibody response to influenza hemagglutinin. J Exp Med. 1985 Apr 1;161(4):687–704. doi: 10.1084/jem.161.4.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cleary M. L., Meeker T. C., Levy S., Lee E., Trela M., Sklar J., Levy R. Clustering of extensive somatic mutations in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma. Cell. 1986 Jan 17;44(1):97–106. doi: 10.1016/0092-8674(86)90488-5. [DOI] [PubMed] [Google Scholar]
  5. Cumano A., Rajewsky K. Clonal recruitment and somatic mutation in the generation of immunological memory to the hapten NP. EMBO J. 1986 Oct;5(10):2459–2468. doi: 10.1002/j.1460-2075.1986.tb04522.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Even J., Griffiths G. M., Berek C., Milstein C. Light chain germ-line genes and the immune response to 2-phenyloxazolone. EMBO J. 1985 Dec 16;4(13A):3439–3445. doi: 10.1002/j.1460-2075.1985.tb04102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Griffiths G. M., Berek C., Kaartinen M., Milstein C. Somatic mutation and the maturation of immune response to 2-phenyl oxazolone. Nature. 1984 Nov 15;312(5991):271–275. doi: 10.1038/312271a0. [DOI] [PubMed] [Google Scholar]
  8. Hartman A. B., Rudikoff S. VH genes encoding the immune response to beta-(1,6)-galactan: somatic mutation in IgM molecules. EMBO J. 1984 Dec 1;3(12):3023–3030. doi: 10.1002/j.1460-2075.1984.tb02249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Köhler G., Howe S. C., Milstein C. Fusion between immunoglobulin-secreting and nonsecreting myeloma cell lines. Eur J Immunol. 1976 Apr;6(4):292–295. doi: 10.1002/eji.1830060411. [DOI] [PubMed] [Google Scholar]
  10. Levy R., Dilley J. Rescue of immunoglobulin secretion from human neoplastic lymphoid cells by somatic cell hybridization. Proc Natl Acad Sci U S A. 1978 May;75(5):2411–2415. doi: 10.1073/pnas.75.5.2411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McKean D., Huppi K., Bell M., Staudt L., Gerhard W., Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 1984 May;81(10):3180–3184. doi: 10.1073/pnas.81.10.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Meeker T., Lowder J., Cleary M. L., Stewart S., Warnke R., Sklar J., Levy R. Emergence of idiotype variants during treatment of B-cell lymphoma with anti-idiotype antibodies. N Engl J Med. 1985 Jun 27;312(26):1658–1665. doi: 10.1056/NEJM198506273122602. [DOI] [PubMed] [Google Scholar]
  13. Merlini G., Farhangi M., Osserman E. F. Monoclonal immunoglobulins with antibody activity in myeloma, macroglobulinemia and related plasma cell dyscrasias. Semin Oncol. 1986 Sep;13(3):350–365. [PubMed] [Google Scholar]
  14. Miller R. A., Maloney D. G., Warnke R., Levy R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med. 1982 Mar 4;306(9):517–522. doi: 10.1056/NEJM198203043060906. [DOI] [PubMed] [Google Scholar]
  15. Norrander J., Kempe T., Messing J. Construction of improved M13 vectors using oligodeoxynucleotide-directed mutagenesis. Gene. 1983 Dec;26(1):101–106. doi: 10.1016/0378-1119(83)90040-9. [DOI] [PubMed] [Google Scholar]
  16. Pettersson U., Sambrook J. Amount of viral DNA in the genome of cells transformed by adenovirus type 2. J Mol Biol. 1973 Jan;73(1):125–130. doi: 10.1016/0022-2836(73)90164-2. [DOI] [PubMed] [Google Scholar]
  17. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  19. Thielemans K., Maloney D. G., Meeker T., Fujimoto J., Doss C., Warnke R. A., Bindl J., Gralow J., Miller R. A., Levy R. Strategies for production of monoclonal anti-idiotype antibodies against human B cell lymphomas. J Immunol. 1984 Jul;133(1):495–501. [PubMed] [Google Scholar]
  20. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  21. Wysocki L., Manser T., Gefter M. L. Somatic evolution of variable region structures during an immune response. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1847–1851. doi: 10.1073/pnas.83.6.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]

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