Clinical & Experimental Metastasis

, Volume 12, Issue 1, pp 37–46 | Cite as

Interleukin-2 therapy of lymphoma-bearing immunosuppressed mice

  • Shantaram S. Joshi
  • Lora J. Messbarger
  • Weimin Hao


In the present study, the immune status of syngeneic Balb/c animals bearing a poorly metastatic RAW117-P lymphoma and the highly malignant liver metastatic variant RAW117-H10 lymphoma were measured and compared to control animals with no known tumor. The immune status was evaluated by performing various analyses of spleen cells for the frequencies of immune cells using flow cytometry,in vitro mitogen response andin vitro NK cell-mediated cytotoxicity assays on days 6, 9 and 12 after tumor transplantation. The results of these studies indicated that from day 9 onwards, some of the immune response of the RAW117 lymphoma-bearing animals appeared to decrease compared to control animals. In order to boost the immune response of the tumor-bearing immunosuppressed animals, recombinant interleukin-2 (rIL-2) was administered to RAW117-H10 lymphoma-bearing animals. The immune status of tumor-bearing animals treated with rIL-2 was evaluated on days 5, 10 and 15 after tumor transplantation using similar analyses of spleen cells as described above. The results of these experiments indicated that IL-2 treatment increased splenic levels of cytotoxic cells, and decreased thein vivo tumorigenicity/metastasis of metastatic RAW117-H10 lymphoma cells. rIL-2 administration resulted in a significant increase in survival of tumor-bearing animals, and histological studies showed significantly lower tumor burdens in treated animals: it appears that rIL-2 has a beneficial therapeutic effect on immunosuppressive metastatic RAW117 lymphoma.


host immunosuppression immunotherapy interleukin-2 lymphoma metastasis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cole D, van Epps DE and Williams RC Jr, 1986, Defective T-lymphocyte chemotactic factor productions in patients with established malignancy.Clinical Immunology and Immunopathology,38, 209–221.PubMedGoogle Scholar
  2. 2.
    Killburn SA, 1974, Suppression of T lymphocyte responses in mice with progressively growing tumors.European Journal of Immunology,4, 784–788.Google Scholar
  3. 3.
    Unger SW, Bernhard MI, Pace RC and Wancebo HJ, 1983, Monocyte dysfunction in human cancer.Cancer,51, 669–674.PubMedGoogle Scholar
  4. 4.
    Baumann MA, Milwan TJ, Patrick CW, Libnoch JA and Keller RH, 1987, Correlation of circulating natural killer cell count with prognosis in large cell lymphoma.Cancer,57, 2309–2312.Google Scholar
  5. 5.
    Brunson KW and Goldfarb RH. Immunosuppression by metastatic tumors. In: Herberman RB, ed.Influence of the Host on Tumor Development, pp. 133–138. Dordrecht: Kluwer, 1989.Google Scholar
  6. 6.
    Lovett EJ III, Dickinson RW and Varani J. Metastatic variants from a methylacholanthrane induced syngeneic murine fibrosarcoma produce immunosuppression proportional to the metastatic potential of the variant In: Lapis K, Jenny A, Price MR, eds.Tumor Progression and Markers, pp. 145–153. Amsterdam: Kugler Publishing, 1982.Google Scholar
  7. 7.
    Gharpure HM, Joshi SS and Brunson KW, 1982, Effect of metastatic variant lymphosarcoma cell line on host immune response.Immunobiology,163, 159.Google Scholar
  8. 8.
    Joshi SS, O'Connor SJ, Weisenburger DD, Sharp JG, Gharpure HM and Brunson KW, 1991, Enhanced antiproliferative activity by metastatic lymphoma cells.Clinical and Experimental Metastasis,9, 27–37.PubMedGoogle Scholar
  9. 9.
    Hao W, Lundquist DL, McDonald TL and Joshi SS, 1989, Purification of an immunoregulatory molecule from metastatic lymphoma cells.Proceedings of the American Association for Cancer Research,30, 321.Google Scholar
  10. 10.
    Hao W and Joshi SS, 1990, Suppression of bone marrow colony formation and lymphokine activated killer (LAK) cell mediated cytotoxicity by a lymphoma-associated glycoprotein.Proceedings of the American Association for Cancer Research,31, 235.Google Scholar
  11. 11.
    Joshi SS and Brunson KW, 1990, Differential cell surface antigen expression on metastatic variant lymphoma cell lines.Oncology,47, 339–343.PubMedGoogle Scholar
  12. 12.
    Higuchi CM, Thompson JA, Peterson FB, Buckner CD and Fefer A, 1991, Toxicity and immunomodulatory effects of interleukin-2 after autologous bone marrow transplantation for hematologic malignancies.Blood,77, 2561–2568.PubMedGoogle Scholar
  13. 13.
    Ackerstein A, Kedar E and Slavin S, 1991, Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematological disorders.Blood,78, 1212–1215.PubMedGoogle Scholar
  14. 14.
    Hunter N, Nakayama T, Ito H, Woo S and Milas L, 1992, Combination of interleukin-2 and irradiation in therapy of murine tumors.Clinical and Experimental Metastasis,10, 431–436.PubMedGoogle Scholar
  15. 15.
    Raschke WC, Ralph P, Watson J, Sklar M and Coon H, 1975, Oncogenic transformation of murine lymphoid cells byin vitro infection with Abelson leukemia virus.Journal of the National Cancer Institute,54, 1249–1253.PubMedGoogle Scholar
  16. 16.
    Brunson KW and Nicolson GL, 1978, Selection and biologic properties of malignant variants of a murine lymphosarcoma.Journal of the National Cancer Institute,61, 1499–1503.PubMedGoogle Scholar
  17. 17.
    Brunson KW and Joshi SS, 1982, Properties of malignant lymphosarcoma variant cell lines associated with enhanced liver metastasis. In: Lapis K, ed.Tumor Progression and Markers. Amsterdam: Kugler Publishing, pp. 137–143.Google Scholar
  18. 18.
    Nicolson GL, Birdwell CR and Brunson KW. Blood-borne tumor metastasis: Some properties of selected tumor cell variants of differing malignancies. In: Crispen RG, ed.Tumor Progression, pp. 31–48, 1980.Google Scholar
  19. 19.
    Joshi SS and Brunson KW, 1981, Hypoploidy and cell density of malignant lymphosarcoma cell lines grownin vitro.In Vitro,17, 227.Google Scholar
  20. 20.
    Reading CL, Belloni PN and Nicolson GL, 1980, Selection andin vivo properties of lectin-attachment variants of malignant murine lymphosarcoma cell lines.Journal of the National Cancer Institute,64, 1241–1249.PubMedGoogle Scholar
  21. 21.
    Reading CL, Brunson KW, Torrianni M and Nicolson GL, 1980, Malignancies of metastatic murine lymphosarcoma cell lines and clones correlate with decreased cell surface display of RNA tumor virus envelope glycoprotein gp70.Proceedings of the National Academy of Sciences, USA,77, 5943–5947.Google Scholar
  22. 22.
    Joshi SS, Jackson JD, Sharp JG and Brunson KW, 1987, Cell surface properties associated with malignancy of metastatic large cell lymphoma.Cancer Research,47, 3551–3557.PubMedGoogle Scholar
  23. 23.
    Joshi SS, Sharp JG, Gharpure HM and Brunson KW, 1987, Characterization of metastasis associated antigens on metastatic variant RAW117 lymphosarcoma cell lines.Clinical and Experimental Metastasis,5, 89–104.PubMedGoogle Scholar
  24. 24.
    Joshi SS, Sharp JG and Brunson KW, 1987, Differential growth characteristics of low and high metastatic RAW117 murine lymphosarcoma cells.Oncology,44, 180–185.PubMedGoogle Scholar
  25. 25.
    Miner KM and Nicolson GL, 1983, Differences in sensitivity of murine metastatic lymphoma/lymphosarcoma variants to macrophage mediated cytolysis and/or cytostasis.Cancer Research,43, 2063–2067.PubMedGoogle Scholar
  26. 26.
    Joshi SS, Mathews NB, Sinangil F, Jackson JD, Volsky DJ, Brunson KW and Sharp JG, 1988, Effects of differentiation inducing chemicals on metastatic RAW117 lympho cell lines.Cancer Detection and Prevention,11, 405–417.PubMedGoogle Scholar
  27. 27.
    Joshi SS and McDonald TL, 1988, Immunoregulation by metastatic lymphoma cells and their cell surface molecules.Experimental Hematology,16, 534.Google Scholar
  28. 28.
    Hao W, McDonald TL, Brunson KW and Joshi SS, 1993, Enhanced immunosuppressive activity associated with metastatic lymphoma cells.Cancer Research,53, 1921–1928.PubMedGoogle Scholar
  29. 29.
    Wiltrout RH, Mathieson BJ, Talmadge JE, Reynolds CW, Zhang SR, Herberman RB and Ortaldo R, 1984, Augmentation of organ-associated NK activity by biological response modifiers: Isolation and characterization of large granular lymphocytes from the liver.Journal of Experimental Medicine,160, 1431–1442.PubMedGoogle Scholar
  30. 30.
    Molineux G, Pojda Z and Dexter TM, 1990, A comparison of hematopoiesis in normal and splenectomized mice treated with granulocyte colony stimulating factor.Blood,75, 563–569.PubMedGoogle Scholar
  31. 31.
    Saarloos MN, Khoo NKS and Lala PK, 1990, Effects of tumor therapy with indomethacin and IL-2 on hemopoietic stem cells.Proceedings of the American Association of Cancer Research,31, 278.Google Scholar
  32. 32.
    Rosenberg SA, Lotze MT and Mule JJ, 1988, New approaches to the immunotherapy of cancer using interleukin-2.Annals of Internal Medicine,108, 853–864.PubMedGoogle Scholar
  33. 33.
    Maas RA, Dullens HF, De Jong WH and Den Otter W, 1989, Immunotherapy of mice with a large burden of disseminated lymphoma with low-dose interleukin-2.Cancer Research,49, 7037–7040.PubMedGoogle Scholar
  34. 34.
    Belardelli F, Ciolli V, Testa U, Montesora E, Bulgarini D, Proietti E, Borghi P, Sestili P, Locardi C and Peschle C, 1989, Anti-tumor effects of interleukin-2 and interleukin-1 in mice transplanted with different syngeneic tumors.International Journal of Cancer,44, 1108–1116.Google Scholar
  35. 35.
    Charak BS, Choudhasy M and Mazumder A, 1992, Interleukin-2 in bone marrow transplantation: Preclinical studies.Bone Marrow Transplantation,10, 103–111.PubMedGoogle Scholar
  36. 36.
    Vourka-Karussis U, Levi-Schaffer F and Slavin S, 1992, Investigations on the role of inflammatory and anti-inflammatory agents on the treatment of murine B cell leukemia by recombinant human interleukin-2.Experimental Hematology,21, 93–97.Google Scholar
  37. 37.
    Gottlieb DJ, Prentice HG, Heslop HE, Bello-Fernandez C, Bianchi AC, Galazka AR and Brenner MK, 1989, Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemoradiotherapy for hematological malignancy.Blood,74, 2335–2342.PubMedGoogle Scholar
  38. 38.
    Urba WJ, Steis RG, Longo DL, Kopp WC, Maluish AE, Marcon L, Nelson DL, Stevenson HC and Clark JW, 1990, Immunomodulatory properties and toxicity of interleukin-2 in patients with cancer.Cancer Research,50, 185–192.PubMedGoogle Scholar

Copyright information

© Rapid Communications of Oxford Ltd 1994

Authors and Affiliations

  • Shantaram S. Joshi
    • 1
  • Lora J. Messbarger
    • 1
  • Weimin Hao
    • 1
  1. 1.Tumor Cell Biology Laboratory, Department of Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations