Skip to main content
SpringerLink
Log in

Potentiation of interleukin-2 production and its binding by monoclonal antibodies to the gangliosides GD3 and GD2

  • Original Articles
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Summary

Previous studies have shown that monoclonal antibodies (mAbs) against certain gangliosides, which induced remissions in patients with melanoma, also potentiated the response of lymphocytes to a variety of stimuli, including lectins, interleukin-2 (IL-2) and antigens. The present studies have investigated the mechanism of these effects on lymphocytes. Although the mAbs potentiated phytohemagglutinin (PHA)-induced IL-2 production at high concentrations of mAbs and of PHA, this did not appear to explain their potentiation of the proliferative responses of lymphocytes. Hence, although IL-2 production was minimal or absent from the CD8+ subset the latter showed the highest degree of augmentation. Furthermore, addition of IL-2 to PHA-stimulated cultures did not produce similar augmentation of mitogenic responses to that produced by the mAb to GD3 or GD2. The augmented and normal mitogenic responses were, however, dependent on IL-2, as shown by their inhibition with mAbs against IL-2. The antiganglioside mAbs did not have significant effects on IL-2 receptor expression measured by mAbs to Tac. However, the mAbs appeared to increase the affinity of binding of radiolabelled IL-2 to IL-2 receptor and increased internalization of the latter. These results suggest that the effects of the mAbs on IL-2 production may be distinguished from their effects on the proliferative responses of T cells and that the latter were associated with changes in affinity and internalization of 125I-IL-2. Whether the latter is a direct cause of the increased proliferative response remains unknown. The ability of mAbs to GD2 and GD3 to increase IL-2 production and to “enhance” IL-2-dependent proliferative responses suggests the may have valuable clinical roles as immunopotentiating agents.

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. Behr JP, Lehn JM (1973) The binding of divalent cations by purified gangliosides. FEBS Lett 31:297

    Google Scholar 

  2. Bergelson LD, Bukrinskaya AG, Prokazova NV, Shaposhniknova GI, Kocharov SL, Sherchenko VP, Kornilaeva GV, Fomina G, Ageeva EV (1982) Role of gangliosides in reception of influenza virus. Eur J Biochem 128:467

    Google Scholar 

  3. Besancon F, Ankel H (1974) Binding of interferon to gangliosides. Nature 252:478

    Google Scholar 

  4. Bremer EG, Hakamori S (1982) GM3 ganglioside induces hamster fibroblast growth inhibition in chemically defined medium: ganglioside may regulate growth factor receptor function. Biochem Biophys Res Commun 106:711

    Google Scholar 

  5. Bremer EG, Schlessinger J, Hakomori S (1986) Ganglioside mediated modulation of cell growth. Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor. J Biol Chem 261:2434

    Google Scholar 

  6. Cheresh DA, Harper JR, Schulz G, Reisfeld RA (1984) Localization of the gangliosides GD3 and GD3 in adhesion plaques and on the surface of human melanoma cells. Proc Natl Acad Sci. USA 81:5767

    Google Scholar 

  7. Cheresh DA, Pytela R, Pierschbacher MD, Klier FG, Ruoslahti E, Reisfeld RA (1987) An ARG-GLY-ASP-directed receptor on the surface of human melanona cells exists in a divalent cation-dependent functional complex with the ganglioside GD2. J Cell Biol 105:1163

    Google Scholar 

  8. Churilla AM, Braciale VL (1987) Lack of IL2-dependent proliferation despite significant expression of high affinity IL2 receptor on murine cytolytic lymphocyte clones late after antigenic stimulation. J Immunol 138:1338

    Google Scholar 

  9. Engelman EG, Benike CJ, Grumet FC, Evans RL (1981) Activation of human T lymphocyte subsets: helper and suppressor/cytotoxic T cells recognize and respond to distinct histocompatibility antigens. J Immunol 127:2124

    Google Scholar 

  10. Fishman PH, Brady PO (1976) Biosynthesis and function of gangliosides. Science 194:906

    Google Scholar 

  11. Fujii M, Sugamura K, Sano K, Nakai M, Sugita K, Hinuma Y (1986) High affinity receptor-mediated internalization and degradation of interleukin 2 in human T cells. J Exp Med 163:550

    Google Scholar 

  12. Goldenring JR, Otis LC, Yu RK, DeLorenzo RJ (1985) Calcium ganglioside-dependent protein kinase activity in rat brain membrane. J Neurochem 44:1229

    Google Scholar 

  13. Gonwa TA, Westrick MA, Macher BA (1984) Inhibition of mitogen- and antigen-induced lymphocyte activation by human leukemia cell gangliosides. Cancer Res 44:3467

    Google Scholar 

  14. Hellstrom I, Brankovan V, Hellstrom KE (1985) Strong antitumor activities of IgG3 antibodies to a human melanoma associated ganglioside. Proc Natl Acad Sci USA 82:1499

    Google Scholar 

  15. Hersey P, Jamal O (1988) Expression of the gangliosides GD3 and GD2 on lymphocytes in tissue sections of melanoma. Patholgy (in press)

  16. Hersey P, Bindon C, Edwards A, Murray E, Philipps G, McCarthy WH (1981) Induction of cytotoxic activity in human lymphocytes against autologous and allogeneic melanoma cells in vitro by culture with interleukin 2. Int J Cancer 28:695; Int J Cancer 28:695

    Google Scholar 

  17. Hersey P, Hasic E, MacDonald M, Edwards A, Spurling A, Coates AS, Milton GW, McCarthy WH (1985) Effects of recombinant leukocyte interferon (rIFN-αA) on tumor growth and immune responses in patients with metastatic melanoma. Br J Cancer 51:43

    Google Scholar 

  18. Hersey P, Murray E, Grace J, McCarthy WH (1985) Current research on immunopathology of melanoma: analysis of lymphocyte populations in relation to antigen expression and histological features of melanoma. Pathology 17:385

    Google Scholar 

  19. Hersey P, MacDonald M, Burns C, Cheresh DA (1986) Potentiation of lymphocyte responses by monoclonal antibodies to ganglioside GD3. Cancer Immunol Immunother 15:22

    Google Scholar 

  20. Hersey P, Schibeci S, Townsend SP, Burns C, Cheresh DA (1986) Potentiation of lymphocyte responses by monoclonal antibodies to ganglioside GD3. Cancer Res 46:6083

    Google Scholar 

  21. Hersey P, Jamal O, Henderson C, Zardawi J, D'Alessandro G (1988) Expression of the gangliosides GM3, GD3 and GD2 in tissue sections of normal skin, naevi, primary and metastatic melanoma. Int J Cancer 41:336

    Google Scholar 

  22. Hoffman RA, Kung PC, Hansen WP, Goldstein G (1980) Simple and rapid measurement of human T lymphocytes and their subclasses in peripheral blood. Proc Natl Acad Sci USA 77:4914

    Google Scholar 

  23. Houghton AN, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, Carswell E, Melamed MR, Oettgen HF, Old LJ (1985) Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: a phase I trial in patients with malignant melanoma. Proc Natl Acad Sci USA 82:1242

    Google Scholar 

  24. Irie RF, Morton DL (1986) Regression of cutaneous metastatic melanoma by intralesional injection with human monoclonal antibody to ganglioside GD2. Proc Natl Acad Sci USA 83:8694

    Google Scholar 

  25. Krishnaraj R, Lin J, Kemp RG (1983) Lectin and ionophorestimulated Ca+ + influx in murine lymphocytes: inhibition by disialoganglioside. Cell Immunol 78:152

    Google Scholar 

  26. Kumar A, Moreau JL, Gibert M, Theze J (1987) Internalization of interleukin 2 (IL-2) by high affinity IL-2 receptors is required for growth of IL-2-dependent T cell lines. J Immunol 139:3680

    Google Scholar 

  27. Lacetti P, Tombaccini D, Aloj S, Grollman EF, Kohn LD (1987) Gangliosides, the thyrotropin receptor and autoimmune thyroid disease. Adv Exp Med Biol 174:355

    Google Scholar 

  28. Langone JJ (1982) Applications of immobilized protein A in immunochemical techniques. J Immunol Methods 55:277

    Google Scholar 

  29. Ledbetter JA, Rose LM, Spooner CE, Beatty PG, Martin PJ, Clark EA (1985) Antibodies to common leukocyte antigen P220 influence human T cell proliferation by modifying IL2 receptor expression. J Immunol 135:1819

    Google Scholar 

  30. Ledbetter JA, Martin PJ, Spooner CE, Wofsy D, Tsu TT, Beatty PG, Gladstone P (1986) Antibodies to Tp67 and Tp44 augment and sustain proliferative responses of activated T cells. J Immunol 135:2331

    Google Scholar 

  31. Lengle EE, Krishnaraj R, Kemp RG (1979) Inhibition of the lectin-induced mitogenic response of thymocytes by glycolipids. Cancer Res 39:817

    Google Scholar 

  32. Markwell MAK, Svennerholm L, Paulson JC (1981) Specific gangliosides function as host cell receptors for Sendai virus. Proc Natl Acad Sci USA 78:5406

    Google Scholar 

  33. Martin PJ, Ledbetter JA, Morishita Y, June CH, Beatty PG, Hansen JA (1986) A 44 kilodalton cell surface heterodimer regulates IL2 production by activated human T lymphocytes. J Immunol 136:3282

    Google Scholar 

  34. Merritt WD, Bailey JM, Pluznik DH (1984) Inhibition of interleukin-2-dependent cytotoxic T lymphocyte growth by gangliosides. Cell Immunol 89:1

    Google Scholar 

  35. Nabholz M, Combe MC, Corthesy P, Lowenthal J, Gabathuler R (1987) Interleukin 2 receptor traffic in a murine cytolytic T cell line. Eur J Immunol 17:783

    Google Scholar 

  36. Parker J, Caldini G, Krishnamurti C, Ahrens PB, Ankel H (1984) Binding of interleukin 2 to gangliosides. FEBS Lett 170:391

    Google Scholar 

  37. Pukel CS, Lloyd KO, Travassos LR, Dippold WG, Oettgen HF, Old LJ (1982) GD3, a prominent ganglioside of human melanoma. J Exp Med 155:1133

    Google Scholar 

  38. Rabin H, Hopkins RF, Ruscetti FW, Neubauer RH, Brown RL, Kawakami TG (1981) Spontaneous release of a factor with properties of T cell growth factor from a continous line of primate tumor T cells. J Immunol 127:1852

    Google Scholar 

  39. Reinherz E, Schlossman S (1982) Human T lymphocyte differentiation. Immunol Today 3:239

    Google Scholar 

  40. Robb RJ (1986) The suppressive effect of gangliosides upon IL2-dependent proliferation as a function of inhibition of IL2-receptor association. J Immunol 136:971

    Google Scholar 

  41. Robb RJ, Greene WC, Rusk CM (1984) Low and high affinity cellular receptors for interleukin 2. J Exp Med 160:1126

    Google Scholar 

  42. Smith KA (1984) The interleukin 2 hormone-receptor system. Lymphokine Res 3:75

    Google Scholar 

  43. Smith KA, Favata MF, Oroszlan S (1983) Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol 131:1808

    Google Scholar 

  44. Speigel S, Fishman PH (1987) Gangliosides as a bimodal regulators of cell growth. Proc Natl Acad Sci USA 84:141

    Google Scholar 

  45. Spiegel S, Fishman PH, Weber RJ (1985) Direct evidence that endogenous GM1 can mediate thymocyte proliferation. Science 230:1285

    Google Scholar 

  46. Stanton T, Stevens TL, Ledbetter JA, Wofsky D (1986) Anti-Ly-1 antibody induces interleukin 2 release from T cells. J Immunol 136:1734

    Google Scholar 

  47. Suzuki R, Handa K, Itoh K, Kumagai K (1983) Natural killer cells as a responder to interleukin 2 (IL2). Proliferative response and establishment of cloned cells. J Immunol 130:981

    Google Scholar 

  48. Tamir H, Brunner W, Casper D, Rapport MM (1980) Enhancement by gangliosides of the binding of serotonin to serotonin binding protein. J Neurochem 34:1719

    Google Scholar 

  49. Thurman GB, Maluish AE, Rossio JL, Schlick E, Ondzaki K, Talmadge JE, Procopio AOG, Ortaldo JR, Ruscetti FW, Stevenson HC, Cannon GB, Iyar S, Herberman RB (1986) Comparative evaluation of multiple lymphoid and recombinant human interleukin-2 preparations. J Biol Response Modif 5:85

    Google Scholar 

  50. Uchiyama T, Broder S, Waldmann TA (1981) A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. J Immunol 126:1393

    Google Scholar 

  51. Weissman AM, Harford JD, Svetlik PB, Leonard WL, Depper JM, Waldmann TA, Greene WC, Klausner RO (1986) Only high-affinity receptors for interleukin 2 mediate internalization of ligand. Proc Natl Acad Sci USA 83:1463

    Google Scholar 

  52. Welte K, Andreeff M, Platzer E, Holloway K, Rubin BY, Moore MAS, Mertelsmann R (1984) Interleukin 2 regulates the expression of Tac antigen on peripheral blood T lymphocytes. J Exp Med 160:1390

    Google Scholar 

  53. Welte K, Miller G, Chapman PB, Yuasa H, Natoli E, Kunicka JE, Cordon-Cardo C, Buhrer C, Old LJ, Houghton AN (1987) Stimulation of T lymphocyte proliferation by monoclonal antibodies against GD3 ganglioside. J Immunol 139:1763

    Google Scholar 

  54. Whistler RL, Yates AJ (1980) Regulation of lymphocyte responses by human gangliosides. i. Characteristics of inhibitory effects and the induction of impaired activation. J Immunol 125:2106

    Google Scholar 

  55. Williams LT, Lefkowitz RJ (1978) Theory of ligand-receptor interactions. In: Williams LT, Lefkowitz RJ (eds) Receptor binding studies in adrenergic pharmacology Raven Press, New York, pp 27–43

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Immunology and Oncology Unit, David Maddison Clinical Sciences Building, Royal Newcastle Hospital, Room 443, 2300, Newcastle, N.S.W., Australia

    Stephen Schibeci & Peter Hersey

  2. Immunology Department, Scripps Clinic, La Jolla, California, USA

    David Cheresh

Authors
  1. Stephen Schibeci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Hersey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Cheresh
    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

Schibeci, S., Hersey, P. & Cheresh, D. Potentiation of interleukin-2 production and its binding by monoclonal antibodies to the gangliosides GD3 and GD2. Cancer Immunol Immunother 29, 109–117 (1989). https://doi.org/10.1007/BF00199285

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00199285

Keywords

Search

Navigation