Cancer Immunology, Immunotherapy

, Volume 21, Issue 2, pp 141–147 | Cite as

The effect of cimetidine on PBL from healthy donors and melanoma patients: Augmentation of T cell responses to TCGF mitogens and alloantigens and of TCGF production

  • Avi Eisenthal
  • Jehudith Monselise
  • Rachel Zinger
  • Aliza Adler
Original Articles

Summary

The effect of cimetidine, an H-2 receptor antagonist, on activation of PBL from both normal individuals and melanoma patients was studied. It has been shown that cimetidine enhanced, though moderately, the production of TCGF from normal PBL after PHA-P stimulation. In addition, cimetidine significantly augmented TCGF-induced proliferation of normal PBL, as well as proliferation induced by allogeneic cells (MLC) by PPD, Con A, and PHA. In PBL samples where coincubation with cimetidine had limited or no effect, preincubation of PBL with cimetidine prior to the addition of IL-2 and other T cell activators showed a significant enhancement effect. This effect mediated by cimetidine was further demonstrated on PBL from melanoma patients whose T cell responses were initially low. The possibilities are discussed that: (a) cimetidine treatment inactivates suppressor cell activity, thus enhancing T cell mediated responses; or (b) cimetidine may act directly at effector cell level.

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References

  1. 1.
    Ades EW, Hinson A, Marder P, Butler LD (1984) Potentiation of Leu 11+ natural cytotoxicity by human Interleukin 2. Clin Immunol Immunopathol 32:119Google Scholar
  2. 2.
    Adler A, Stein JA, Kedar E, Naor D, Weiss DW (1984) Intralesional injection of Interleukin-2-expanded autologous lymphocytes in melanoma and breast cancer patients: a pilot study. J Biol Res Modif 3:491Google Scholar
  3. 3.
    Beer DJ, Rocklin RE (1984) Histamine-induced suppressor-cell activity. J Allergy Clin Immunol 73:439Google Scholar
  4. 4.
    Broder S, Waldman TA (1978) The suppressor-cell network in cancer (Second of two parts) New Engl J Med 299:1335Google Scholar
  5. 5.
    Cheever MA, Greenberg PD, Fefer A, Gillis S (1982) Augmentation of the antitumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin-2. J Exp Med 155:968Google Scholar
  6. 6.
    Cheever MA, Greenberg PD, Irle C, Thompson JA, Urdal DL, et al. (1984) Interleukin 2 administered in vivo induces the growth of cultured T cells. J Immunol 132:2259Google Scholar
  7. 7.
    Farrar JJ, Benjamin WR, Hilfiker ML, Howard M, Farrar WL, Fuller-Farrar J (1982) The biochemistry, biology and role of interleukin 2 in the induction of cytotoxic T cell and antibody-forming B cell responses. Immunol Rev 63:129Google Scholar
  8. 8.
    Flomberg N, Welte K, Mertelsman R, Kernan N, Ciobanu N, Venuta S, Feldman S, Kurger G, Kirkpatrick D, Dupont B, O'Reilly R (1983) Immunologic effects of interleukin 2 in primary immunodeficiency diseases. J Immunol 130:2644Google Scholar
  9. 9.
    Fuller L, Kyriakides G, Flaa C, Esquenazi V, Miller J (1980) In vitro generation of human mixed lymphocyte culture suppressor cells. Transplantation 29:54Google Scholar
  10. 10.
    Gifford RRM, Hatfield SM, Shmidtke JR (1980) Cimetidine-induced augmentation of human lymphocyte blastogenesis by mitogen, bacterial antigen and alloantigen. Transplantation 29:143Google Scholar
  11. 11.
    Gillis S, Smith KA (1977) Long-term culture of tumor specific cytotoxic T cells. Nature 268:154Google Scholar
  12. 12.
    Gillis S, Union NA, Baker PE, Smith KA (1979) The in vitro generation and sustained culture of nude mouse cytolytic T-Lymphocytes. J Exp Med 149:1460Google Scholar
  13. 13.
    Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) The lymphokine activated killer cell phenomenon: lysis of NK-resistant fresh solid tumor cells by IL-2 activated autologous human peripheral blood lymphocytes. J Exp Med 155:1823CrossRefPubMedGoogle Scholar
  14. 14.
    Hellinger SM, Herzig GP (1978) Impaired cell-mediated immunity in Hodgkin's disease mediated by suppressor lymphocytes and monocytes. J Clin Invest 61:1620Google Scholar
  15. 15.
    Knuth A, Danowski B, Oettgen HF, Old LJ (1984) T-cell mediated cytotoxicity against autologous malignant melanoma: analysis with Interleukin-2 dependent T-cell cultures. Proc Natl Acad Sci 81:3511Google Scholar
  16. 16.
    Lefrancois L, Klein JR, Paetkau V, Bevan MJ (1984) Antigen-independent activation of memory cytotoxic T cells by Interleukin 2. J Immunol 132:1845Google Scholar
  17. 17.
    Mazumer A, Rosenberg SA (1984) Successful immunotherapy of natural killer resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by Interleukin 2. J Exp Med 159:495Google Scholar
  18. 18.
    Osband ME, Shen YJ, Schlesinger M, et al. (1981) Successful tumor immunotherapy with cimetidine in mice. Lancet I:636Google Scholar
  19. 19.
    Palacios R, Moller G (1981) T cell growth factor abrogates concanavalin A-induced suppressor cell function. J Exp Med 153:1360Google Scholar
  20. 20.
    Palacios R, Guy K, Van Heyningen V (1983) Monoclonal antibodies against HLA-DR antigens acting on stimulator cells prevent OKT8+ T Lymphocytes from acquiring sensitivity to Interleukin 2 and expressing suppressor function. Eur J Immunol 13:64Google Scholar
  21. 21.
    Pinto M, Herzberg H (1981) Cimetidine prevents the induction of unresponsiveness by feeding T-dependent antigens. Experimentia 37:511Google Scholar
  22. 22.
    Primack WA (1978) Cimetidine and renal-allograft rejection. Lancet I:924Google Scholar
  23. 23.
    Rocklin Re, Greineder D, Littman BH, Melmon KL (1978) Modulation of cellular immune function in vitro by histamine receptor-bearing lymphocytes: mechanism of action. Cell Immunol 37:162Google Scholar
  24. 24.
    Rosenberg SA (1984) Immunotherapy of cancer by systemic administration of lymphoid cells plus Interleukin-2. J Biol Res Modif 3:475Google Scholar
  25. 25.
    Rosenberg SA (1984) Adoptive immunotherapy of cancer: accomplishments and prospects. Cancer Treat Rep 68:233Google Scholar
  26. 26.
    Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL (1985) Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high dose recombinant Interleukin 2. J Exp Med 161:1169Google Scholar
  27. 27.
    Rosenstein M, Rosenberg SA (1984) Generation of lytic and proliferative lymphoid clones to syngeneic tumor: in vitro and in vivo studies. J Natl Cancer Inst 72:1161Google Scholar
  28. 28.
    Rosenstein M, Eberlein T, Kemeny PH, Sugarbaker PH, Rosenberg SA (1981) In vitro growth of murine T cells. VI. Accelerated skin graft rejection caused by adoptive transferred cells expanded in T cell growth factor. J Immunol 127:566Google Scholar
  29. 29.
    Rosenstein M, Yron I, Kaufmann Y, Rosenberg SA (1984) Lymphokine-activated killer cells: lysis of fresh syngeneic natural killer-resistant murine tumor cells by lymphocytes cultured in Interleukin 2. Cancer Res 44:1946Google Scholar
  30. 30.
    Schechter B, Segal S, Feldman M (1977) Enhancing lymphocytes in spleens of tumor-bearing mice: affinity chromathography on insolubilized histamine. Int J Cancer 20:239Google Scholar
  31. 31.
    Stotter HE, Rude E, Wagner H (1980) T cell factor (interleukin-2) allows in vivo induction of T helper cells against heterologous eryhtrocytes in a thymic (nu/nv) mice. Eur J Immunol 10:719–722Google Scholar
  32. 32.
    Susskind BM, Merluzzi VJ, Faanes RB, Polladino MA, Choi YS (1983) Regulatory mechanisms in cytotoxic T lymphocyte development. I. A suppressor T cell subset that regulates the proliferative stage of CTL development. J Immunol 130:527Google Scholar
  33. 33.
    Thoman ML, Weigle WO (1984) Interleukin 2 induction of antigen-nonspecific suppressor cells. Cell Immunol 85:215Google Scholar
  34. 34.
    Ting S, Yang SS, Hargrove ME (1984) Induction of suppressor T cells by Interleukin 2. J Immunol 133:261Google Scholar
  35. 35.
    Wagner H, Hardt C, Heeg K, Rollinghoff M, Pfizermaier K (1981) T-cell derived helper factor allows in vivo induction of cytotoxic T cells in nu/nv mice. Nature 284:278–280Google Scholar
  36. 36.
    Wang SR, Zweiman B (1978) Histamine suppression of human lymphocytes to mitogens. Cell Immunol 36:28Google Scholar
  37. 37.
    Yamasaki T, Handa H, Yamashita J, Watanbe Y, Namba Y, et al. (1984) Specific adoptive immunotherapy with tumor-specific T-Lymphocyte clone for murine malignant gliomas. Cancer Res 44:1776Google Scholar
  38. 38.
    Yu A, Watts H, Jaffee W, Parkman R (1977) Concomitant presence of tumor-specific cytotoxic and inhibitor lymphocytes in patients with osteogeneic sarcoma. New Engl J Med 297:121Google Scholar
  39. 39.
    Zarling JM, Berman C, Raich PC (1980) Depressed cytotoxic T-cell responses in previously treated Hodgkin's and non-Hodgkin's lymphoma patients. Evidence for histamine receptor-bearing suppressor cells. Cancer Immunol Immunother 7:243Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • Avi Eisenthal
    • 1
  • Jehudith Monselise
    • 1
  • Rachel Zinger
    • 1
  • Aliza Adler
    • 1
  1. 1.Tumor Immunology Section, Institute of OncologyBeilinson Medical CenterPetah-TiqvaIsrael

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