Skip to main content
SpringerLink
Log in

Idiotype-specific T cells in multiple myeloma:Targets for an immunotherapeutic intervention?

  • Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

In this paper, the results of some recent studies on idiotype-specific T cells in human multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are discussed. By using differentin vitro measurements such as3H-thymidine incorporation and ELI-SPOT assay, idiotype-specific T cells have been demonstrated in most of MM and MGUS patients. Based on the cytokine-secretion profiles, idiotype-specific T cells were found to comprise both Th1 and Th2 cells. A Thl type immunity was found preferentially in indolent disease and a Th2-like response predominated in advanced MM, suggesting a specific T-cell regulation of the tumor B-cell clone. The mode of T-cell recognition of id determinants on M-components has been studied. We found that idiotype-specific T cells recognized processed id determinants presented by MHC class II (HLA-DR) molecules on APC. B cells were much more efficient APC than monocytes. With the aim to induce or to amplify an idiotype-specific T-cell response, we have immunized MM patients with the autologous M-component precipitated in aluminum. Three out of the five patients showed an induction of specific cellular and humoral immunity. Nevertheless, the role for such immunity in controlling the tumor clone remains to be established.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mellstedt, H., Holm, G. and Björkholm, M. (1984) Multiple myeloma, Waldenström’s macroglobulinemia, and benign monoclonal gammopathy: characteristics of the B cell clone, immunoregulatory cell populations and clinical implications.Adv. Cancer Res. 41, 257–89.

    Article  PubMed  CAS  Google Scholar 

  2. Osgood, E.E. (1960) The survival time of patients with plasmacytic myeloma.Cancer Chemther. Rep. 9, 1–10.

    CAS  Google Scholar 

  3. Alexanian, R., Haut, A., Khan, A.U.et al. (1969) Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens.JAMA 208, 1680–85.

    Article  PubMed  CAS  Google Scholar 

  4. Harousseau, J.-L., Attal, M., Divine, M.et al. (1995) Auto-logous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French registry on autologous transplantation in multiple myeloma.Blood 85, 3077–85.

    PubMed  CAS  Google Scholar 

  5. Gahrton, G., Tura, S., Ljungman, P.et al. (1991) Allogeneic bone marrow transplantation in multiple myeloma.N. Engl. J. Med. 325, 1267–73.

    PubMed  CAS  Google Scholar 

  6. MacKenzie, M.R. and Lewis, J.P. (1985) Cytogenetic evidence that the malignant event in multiple myeloma occurs in a precursor lymphocyte.Cancer Genet. Cytogenet. 17, 13–20.

    Article  PubMed  CAS  Google Scholar 

  7. Berenson, J., Wong, R., Kim, K.et al. (1987) Evidence of peripheral blood B lymphocyte but not T lymphocyte involvement in multiple myeloma.Blood 70, 1550–3.

    PubMed  CAS  Google Scholar 

  8. Billadeau, D., Quam, L., Thomas, W.et al. (1992) Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients.Blood 80, 1818–24.

    PubMed  CAS  Google Scholar 

  9. Österborg, A., Steinitz, M., Lewin, N.et al. (1991) Establishment of idiotype bearing B-lymphocyte clones from a patient with monoclonal gammopathy.Blood 78, 2642–9.

    PubMed  Google Scholar 

  10. Bergui, L., Schena, M., Gaidano, G.et al. (1989) Interleukin 3 and interleukin 6 synergistically promote the proliferation and differentiation of malignant plasma cell precursors in multiple myeloma.J. Exp. Med. 170, 613–8.

    Article  PubMed  CAS  Google Scholar 

  11. Takishita, M, Kosaka, M., Goto, T.et al. (1994) Cellular origin and extent of clonal involvement in multiple myeloma: genetic and phenotypic studies.Br. J. Haematol. 87, 735–42.

    Article  PubMed  CAS  Google Scholar 

  12. Billadeau, D., Ahmann, G., Greipp, P.et al. (1993) The bone marrow of multiple myeloma patients contains B cell populations at different stages of differentiation that are clonally related to the malignant plasma cell.J. Exp. Med. 178, 1023–31.

    Article  PubMed  CAS  Google Scholar 

  13. Bakkus, M.H., van Riet, I., Camp, B.V.et al. (1994) Evidence that the clonogenic cell in multiple myeloma originates from a pre-switched but somatically mutated B cell.Br. J. Haemtol. 87, 68–74.

    Article  CAS  Google Scholar 

  14. Vescio, R.A., Cao, J., Hong, C.H.et al. (1995) Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but not intraclonal diversity.J. Immunol. 155, 2487–97.

    PubMed  CAS  Google Scholar 

  15. Fearon, E.R. and Vogelstein, B. (1990) A genetic mode for colorectal tumorigenesis.Cell 61, 759–67.

    Article  PubMed  CAS  Google Scholar 

  16. Mellstedt, H., Killander, D. and Pettersson, D. (1977) Bone marrow kinetic studies on three patients with myeloma-tosis: indications for malignant proliferation within both the plasma cell and lymphoid cell compartments.Acta Med. Scand. 202, 413–7.

    PubMed  CAS  Google Scholar 

  17. Chan, C.S., Wormsley, S.B., Pierce, L.E.et al. (1990) B-cell surface phenotypes of proliferating myeloma cells: target antigen for immunotherapy.Am. J. Hematol. 33, 101–9.

    Article  PubMed  CAS  Google Scholar 

  18. Pilarski, L.M. and Belch, A.R. (1994) Circulating monoclonal B cells expressing P glycoprotein may be a reservoir of multidrug-resistant disease in multiple myeloma.Blood 83, 724–36.

    PubMed  CAS  Google Scholar 

  19. Corradini, P., Voena, C., Astolfi, M.et al. (1995) High-dose sequential chemoradiotherapy in multiple myeloma:residual tumor cells are detectable in bone marrow and peripheral blood cell harvests and after autografting.Blood 85, 1596–1602.

    PubMed  CAS  Google Scholar 

  20. Österborg, A., Nilsson, B., Björkholm, M.et al. (1987) Blood clonal B cell excess at diagnosis in multiple myeloma. Relation to prognosis.Eur. J. Haematol. 38, 173–8.

    PubMed  Google Scholar 

  21. Isaksson, E., Björkholm, M., Holm, G.et al. (1996) Blood clonal B-cell excess in patients with monoclonal gammopathy of undetermined significance (MGUS): association with malignant transformation.Br. J. Haematol. 92, 71–6.

    Article  PubMed  CAS  Google Scholar 

  22. Lynch, R.G., Graff, R.J., Sirisinha, S.et al. (1972) Myeloma proteins as tumor-specific transplantation antigens.Proc. Natl. Acad. Sci. USA 69, 1540–4.

    Article  PubMed  CAS  Google Scholar 

  23. Stevenson, F.K., George, A.J.T. and Glennie, M.J. (1990) Anti-idiotypic therapy of leukemias and lymphomas.Chem. Immunol. 48, 126–66.

    Article  PubMed  CAS  Google Scholar 

  24. Jerne, N.K. (1974) Towards a network theory of the immune system.Ann. Immunol (Inst. Pasteur),125C, 373–89.

    CAS  Google Scholar 

  25. Lynch, R.G. (1987) Immunoglobulin-specific suppressor T cells.Adv. Immunol 40, 135–51.

    Article  PubMed  CAS  Google Scholar 

  26. Mahony, J., Bose, A., Cowdrey, D.et al. (1981) A monoclonal antiidiotypic antibody to MOPC 315 IgA inhibits the growth of MOPC 315 myeloma cellsin vitro. J. Immunol 126, 113–7.

    CAS  Google Scholar 

  27. Germain, R.N. (1994) MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation.Cell 76, 287–99.

    Article  PubMed  CAS  Google Scholar 

  28. Bogen, B., Malissen, B. and Haas, W. (1986) Idiotype-specific T cell clones that recognize syngeneic immunoglo-bulin fragments in the context of class II molecules.Eur. J. Immunol 16, 1373–8.

    Article  PubMed  CAS  Google Scholar 

  29. Daley, M.J., Gebel, H.M. and Lynch, R.G. (1978) Idiotype-specific transplantation resistance to MOPC-315: abrogation by post-immunization thymectomy.J. Immunol 120, 1620–4.

    PubMed  CAS  Google Scholar 

  30. Flood, P.M., Philipps, C, Taupier, M.A.et al. (1980) Regulation of myeloma growthin vitro by idiotype-specific T lymphocytes.J. Immunol 124, 424–30.

    PubMed  CAS  Google Scholar 

  31. Hornung, R.L., Longo, D.L., Bowersox, O.C.et al. (1995) Tumor antigen-specific immunization of bone marrow transplantation donors as adoptive therapy against established rumor.J. Natl Cancer Inst. 87, 1289–96.

    Article  PubMed  CAS  Google Scholar 

  32. Bergman, L., Mitrou, P.S., Kelker, W.et al. (1985) T-cell subsets in malignant lymphomas and monoclonal gammopathies.Scand. J. Haematol 34, 170–6.

    Google Scholar 

  33. Mellstedt, H., Holm, G., Pettersson, D.et al. (1982) T cells in monoclonal gammopathies.Scand. J. Haematol 29, 57–64.

    PubMed  CAS  Google Scholar 

  34. San Miguel, J.F., Caballero, M.D. and Gonzalez, M. (1985) T-cell subpopulations in patients with monoclonal gammopathies: essential monoclonal gammopathy, multiple myeloma, and Waidenstrom macroglobulinemia.Am. J. Hematol. 20, 267–73.

    Article  PubMed  CAS  Google Scholar 

  35. Shapira, R., Froom, P., Kinarty, A.et al. (1989) Increase in the suppressor-inducer T cell subset in multiple myeloma and monoclonal gammopathy of undetermined significance.Br. J. Haematol. 71, 223–5.

    Article  PubMed  CAS  Google Scholar 

  36. Serra, H.M., Mant, M.J., Ruether, B.A.et al. (1988) Selective loss of CD4+ CD45R+ T cells in peripheral blood of multiple myeloma patients.J. Clin. Immunol 8, 259–65.

    Article  PubMed  CAS  Google Scholar 

  37. Paglieroni, T. and MacKenzie, M.R. (1979)In vitro cytotoxic response to human myeloma plasma cells by peripheral blood leukocytes from patients with multiple myeloma and benign monoclonal gammopathy.Blood 54, 226–37.

    PubMed  CAS  Google Scholar 

  38. Hoover, R.G., Hickman, S., Gebel, H.M.et al. (1981) Expansion of Fc receptor-bearing T lymphocytes in patients with immunoglobulin G and immunoglobulin A myeloma.J. Clin. Invest. 67, 308–11.

    Article  PubMed  CAS  Google Scholar 

  39. Massaia, M., Attisano, C, Peola, S.et al. (1993) Rapid generation of antiplasma cell activity in the bone marrow of myeloma patients by CD3-activated T cells.Blood 82, 1787–97.

    PubMed  CAS  Google Scholar 

  40. Massaia, M., Borrione, P., Attisano, C.et al. (1995) Dysre- gulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients.Blood 85, 3679–87.

    PubMed  CAS  Google Scholar 

  41. Janson, C.K, Grunewald, J., Österborg, A.et al. (1991) Predominant T cell receptor V gene usage in patients with abnormal clones of B cells.Blood 77, 1776–80.

    PubMed  CAS  Google Scholar 

  42. Moss, P.A.H., Gillespie, G., Frodsham, P.et al. (1994) Clonal populations of CD4 and CD8 T cells in patients with paraproteinaemia and myeloma.Blood 84 (suppl. 1), 177a (abstr.).

    Google Scholar 

  43. Farace, F., Orlanducci, F., Dietrich, P-Y.et al. (1994) T cell repertoire in patients with B chronic lymphocytic leukemia.J. Immunol. 153, 4281–90.

    PubMed  CAS  Google Scholar 

  44. Sensi, M.L. and Parmiani, G. (1995) Analyses of TCR usage in human tumors: a new tool for assessing tumor specific immune responses.Immunol. Today 16, 588–95.

    Article  PubMed  CAS  Google Scholar 

  45. Hecht, T.T., Longo, D.L. and Matis, L.A. (1983) The relationship between immune interferon production and proliferation in antigen-specific, MHC-restricted T cell lines and clones.J. Immunol 131, 1049–55.

    PubMed  CAS  Google Scholar 

  46. Czerkinsky, C.C., Andersson, G., Ekre, H.P.et al. (1988) Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells.J. Immunol Meth. 110, 29–36.

    Article  CAS  Google Scholar 

  47. Yi, Q., Bergenbrant, S., Österborg, A.et al. (1993) T-cell stimulation induced by idiotypes on monoclonal immuno-globulins in patients with monoclonal gammopathies.Scand. J. Immunol 38, 529–34.

    Article  PubMed  CAS  Google Scholar 

  48. Österborg, A., Masucci, M., Bergenbrant, S.et al. (1991) Generation of T cell clones binding F(ab′)2 fragments of the idiotypic immunoglobulin in patients with monoclonal gammopathy.Cancer Immunol Immunother. 34, 157–62.

    Article  PubMed  Google Scholar 

  49. Holm, G., Bergenbrant, S., Lefvert, A.K., Yi, Q.et al. (1991) Anti-idiotypic immunity as a potential regulator in myeloma and related diseases.Ann. NY Acad. Sci. 636, 178–83.

    Article  PubMed  CAS  Google Scholar 

  50. Österborg, A., Yi, Q., Bergenbrant, S.et al. (1995) Idiotype- specific T cells in multiple myeloma stage I: an evaluation by four different functional tests.Br.. Haematol 89, 110–6.

    Google Scholar 

  51. Romagnani, S. (1991) Human TH1 and TH2 subsets: doubt no more.Immunol Today 12, 256–7.

    Article  PubMed  CAS  Google Scholar 

  52. Yi, Q., Österborg, A., Bergenbrant, S.et al. (1995) Idiotype- reactive T-cell subsets and tumor load in monoclonal gammopathies.Blood 86, 3043–9.

    PubMed  CAS  Google Scholar 

  53. Lauritzsen, G.F. and Bogen, B. (1991) Idiotype-specific, major histocompatibility complex restricted T cells are of both Thl and Th2 type.Scand. J. Immunol 33, 647–56.

    Article  PubMed  CAS  Google Scholar 

  54. Lauritzsen, G.F., Weiss, S. and Bogen, B. (1993) Anti-tumor activity of idiotype-specific, MHC-restricted Thl and Th2 clonesin vitro andin vivo.Scand. J. Immunol 37, 77–85.

    Article  PubMed  CAS  Google Scholar 

  55. Clark, E. A. and Ledbetter, J. A. (1994) How B and T cells talk to each other.Nature 367, 425–8.

    Article  PubMed  CAS  Google Scholar 

  56. Hilbert, D.M., Shen, M-Y., Rapp, U.R.et al. (1995) T cells induce terminal differentiation of transformed B cells to mature plasma cell tumors.Proc. Natl. Acad. Sci. USA 92, 649–53.

    Article  PubMed  CAS  Google Scholar 

  57. Paglieroni, T., Caggiano, V. and MacKenzie, M. (1992) Abnormalities in immune regulation precede the development of multiple myeloma.Am. J. Hematol. 40, 51–5.

    Article  PubMed  CAS  Google Scholar 

  58. Dianzani, U., Pileri, A., Boccadoro, M.et al. (1988) Activated idiotype-reactive cells in suppressor/cytotoxic sub-populations of monoclonal gammopathies: correlation with diagnosis and disease status.Blood 72, 1064–8.

    PubMed  CAS  Google Scholar 

  59. Bottomly, K. and Mosier, D.E. (1981) Antigen-specific helper T cells required for dominant idiotype expression are not H-2 restricted.J. Exp. Med. 154, 411–21.

    Article  PubMed  CAS  Google Scholar 

  60. Parra, C.C., Lima, M.S., Gazzinelli, G.et al. (1988) Immune responses during human Schistosomiasis Mansoni. XV. Anti-idiotypic T cells can recognize and respond to anti-SEA idiotypes directly.J. Immunol. 140, 2401–5.

    PubMed  CAS  Google Scholar 

  61. Yamamoto, H., Araki, K., Bitoh, S.et al. (1987) Cytotoxic T lymphocyte clone recognizing self idiotype: its regulatory role in antibody production.Eur. J. Immunol. 17, 719–22.

    Article  PubMed  CAS  Google Scholar 

  62. Yi, Q., Holm, G. and Lefvert, A.K. (1996) Idiotype-induced T cell stimulation requires antigen presentation in association with HLA-DR molecules.Clin. Exp. Immunol. 104, 359–650.

    Article  PubMed  CAS  Google Scholar 

  63. George, A.J.T., Folkard, S.G., Hamblin, T.et al. (1988) Idiotypic vaccination as a treatment for a B cell lymphoma.J. Immunol 141, 2168–74.

    PubMed  CAS  Google Scholar 

  64. Kwak, L.W., Campbell, M. and Levy, R. (1991) Idiotype vaccination post-bone marrow transplantation for B-cell lymphoma: initial studies in a murine model.Cancer Detec. Prev. 15, 323–5.

    PubMed  CAS  Google Scholar 

  65. Kwak, L.W., Campbell, M., Czerwinski, D.K.et al. (1992) Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors.N. Engl. J. Med. 327, 1209–15.

    PubMed  CAS  Google Scholar 

  66. Raffeld, M., Necker, L., Longo, D.L.et al. (1985) Spontaneous alteration of idiotype in a monoclonal B-cell lymphoma: Escape from detection by anti-idiotype.N. Engl J. Med. 312, 1653–8.

    PubMed  CAS  Google Scholar 

  67. Maloney, D.G., Brown, S., Czerwinski, D.K.et al. (1992) 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 80, 1502–10.

    PubMed  CAS  Google Scholar 

  68. Bakkus, M.H.C., Heirman,C, van Riet, I.et al. (1992) Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation.Blood 80, 2326–35.

    PubMed  CAS  Google Scholar 

  69. Bergenbrant, S., Yi, Q., Österborg, A.et al. (1996) Modulation of anti-idiotypic immune response by immunization with the autologous M-component protein in multiple myeloma patients.Br. J. Haematol. 92, 840–6.

    Article  PubMed  CAS  Google Scholar 

  70. Kwak, L.W., Taub, D.D., Duffey, P.L.et al. (1995) Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor.Lancet 345, 1016–20.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Immunological Research Laboratory and Department of Medicine, Karolinska Hospital, S-17176, Stockholm, Sweden

    Qing Yi

  2. Department of Oncology, Karolinska Hospital, S-17176, Stockholm, Sweden

    Anders Österborg

Authors
  1. Qing Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anders Österborg
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yi, Q., Österborg, A. Idiotype-specific T cells in multiple myeloma:Targets for an immunotherapeutic intervention?. Med Oncol 13, 1–7 (1996). https://doi.org/10.1007/BF02988835

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02988835

Keywords

Search

Navigation