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. 1995 Aug;147(2):445–460.

Local and Systemic Response of Mice to Interferon-α1 -Transfected Friend Leukemia Cells

Lucia Gabriele, Thomas Kaido, David Woodrow, Jill Moss, Maria Ferrantini, Enrico Proletti, Laura Santodonato, Carmela Rozera, Chantal Maury, Ion Gresser
PMCID: PMC1869831  PMID: 7639337

Abstract

DBA/2 mice were injected subcutaneously with an interferon (IFN)-α/-resistant line of Friend erythroleukemia cells (FLC) transfected with the mouse IFN-α1 gene. These tumor cells produced IFN constitutively, and mice had persistently high levels of IFN in the circulation. We examined the IFN-induced host mechanisms responsible for the local inhibition of growth of these IFN-α-transfected FLC and some of the unusual systemic effects of constant interferonemia such as extramedullary hematopoiesis in the liver, an increase in myeloid cells in the spleen, and persistently elevated splenic natural killer (NK) cell activity. In addition, both DBA/2 +/bg and beige mice developed a rapid and specific resistance to intravenous challenge with parental FLC In previous experiments DBA/2 beige mice could not be protected by exogenous IFN-α/β. The differences in the response of mice to the constitutive production of IFN-α by IFN-α-transfected tumor cells and their response to exogenous IFN is discussed in terms of the effects of IFN on the host and of antitumor therapy.

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Selected References

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  1. Affabris E., Jemma C., Rossi G. B. Isolation of interferon-resistant variants of Friend erythroleukemia cells: effects of interferon and ouabain. Virology. 1982 Jul 30;120(2):441–452. doi: 10.1016/0042-6822(82)90044-7. [DOI] [PubMed] [Google Scholar]
  2. Affabris E., Romeo G., Belardelli F., Jemma C., Mechti N., Gresser I., Rossi G. B. 2-5A synthetase activity does not increase in interferon-resistant Friend leukemia cell variants treated with alpha/beta interferon despite the presence of high-affinity interferon receptor sites. Virology. 1983 Mar;125(2):508–512. doi: 10.1016/0042-6822(83)90224-6. [DOI] [PubMed] [Google Scholar]
  3. Amici C., Ferrantini M., Benedetto A., Belardelli F., Gresser I. Biologic and biochemical differences between in vitro and in vivo passaged Friend erythroleukemia cells. II. Changes in cell surface glycoproteins associated with a highly malignant phenotype. Int J Cancer. 1984 Sep 15;34(3):397–402. doi: 10.1002/ijc.2910340317. [DOI] [PubMed] [Google Scholar]
  4. Asher A. L., Mulé J. J., Kasid A., Restifo N. P., Salo J. C., Reichert C. M., Jaffe G., Fendly B., Kriegler M., Rosenberg S. A. Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol. 1991 May 1;146(9):3227–3234. [PMC free article] [PubMed] [Google Scholar]
  5. Belardelli F., Ferrantini M., Maury C., Santurbano L., Gresser I. Biologic and biochemical differences between in vitro and in vivo passaged Friend erythroleukemia cells. I. Tumorigenicity and capacity to metastasize. Int J Cancer. 1984 Sep 15;34(3):389–395. doi: 10.1002/ijc.2910340316. [DOI] [PubMed] [Google Scholar]
  6. Belardelli F., Gessani S., Proietti E., Locardi C., Borghi P., Watanabe Y., Kawade Y., Gresser I. Studies on the expression of spontaneous and induced interferons in mouse peritoneal macrophages by means of monoclonal antibodies to mouse interferons. J Gen Virol. 1987 Aug;68(Pt 8):2203–2212. doi: 10.1099/0022-1317-68-8-2203. [DOI] [PubMed] [Google Scholar]
  7. Belardelli F., Gresser I., Maury C., Duvillard P., Prade M., Maunoury M. T. Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. III. Inhibition of growth and necrosis of tumors implanted subcutaneously. Int J Cancer. 1983 May 15;31(5):649–653. doi: 10.1002/ijc.2910310518. [DOI] [PubMed] [Google Scholar]
  8. Belardelli F., Gresser I., Maury C., Maunoury M. T. Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. I. Int J Cancer. 1982 Dec 15;30(6):813–820. doi: 10.1002/ijc.2910300621. [DOI] [PubMed] [Google Scholar]
  9. Belldegrun A., Tso C. L., Sakata T., Duckett T., Brunda M. J., Barsky S. H., Chai J., Kaboo R., Lavey R. S., McBride W. H. Human renal carcinoma line transfected with interleukin-2 and/or interferon alpha gene(s): implications for live cancer vaccines. J Natl Cancer Inst. 1993 Feb 3;85(3):207–216. doi: 10.1093/jnci/85.3.207. [DOI] [PubMed] [Google Scholar]
  10. Blankenstein T., Qin Z. H., Uberla K., Müller W., Rosen H., Volk H. D., Diamantstein T. Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer. J Exp Med. 1991 May 1;173(5):1047–1052. doi: 10.1084/jem.173.5.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cavallo F., Giovarelli M., Gulino A., Vacca A., Stoppacciaro A., Modesti A., Forni G. Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene. J Immunol. 1992 Dec 1;149(11):3627–3635. [PubMed] [Google Scholar]
  12. Ciolli V., Gabriele L., Sestili P., Varano F., Proietti E., Gresser I., Testa U., Montesoro E., Bulgarini D., Mariani G. Combined interleukin 1/interleukin 2 therapy of mice injected with highly metastatic Friend leukemia cells: host antitumor mechanisms and marked effects on established metastases. J Exp Med. 1991 Feb 1;173(2):313–322. doi: 10.1084/jem.173.2.313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cohen J. J. Apoptosis. Immunol Today. 1993 Mar;14(3):126–130. doi: 10.1016/0167-5699(93)90214-6. [DOI] [PubMed] [Google Scholar]
  14. Colombo M. P., Ferrari G., Stoppacciaro A., Parenza M., Rodolfo M., Mavilio F., Parmiani G. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. J Exp Med. 1991 Apr 1;173(4):889–897. doi: 10.1084/jem.173.4.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Colombo M. P., Forni G. Cytokine gene transfer in tumor inhibition and tumor therapy: where are we now? Immunol Today. 1994 Feb;15(2):48–51. doi: 10.1016/0167-5699(94)90131-7. [DOI] [PubMed] [Google Scholar]
  16. Connor J., Bannerji R., Saito S., Heston W., Fair W., Gilboa E. Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells. J Exp Med. 1993 Apr 1;177(4):1127–1134. doi: 10.1084/jem.177.4.1127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dranoff G., Jaffee E., Lazenby A., Golumbek P., Levitsky H., Brose K., Jackson V., Hamada H., Pardoll D., Mulligan R. C. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539–3543. doi: 10.1073/pnas.90.8.3539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dvorak H. F., Gresser I. Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice. J Natl Cancer Inst. 1989 Apr 5;81(7):497–502. doi: 10.1093/jnci/81.7.497. [DOI] [PubMed] [Google Scholar]
  19. Ferrantini M., Giovarelli M., Modesti A., Musiani P., Modica A., Venditti M., Peretti E., Lollini P. L., Nanni P., Forni G. IFN-alpha 1 gene expression into a metastatic murine adenocarcinoma (TS/A) results in CD8+ T cell-mediated tumor rejection and development of antitumor immunity. Comparative studies with IFN-gamma-producing TS/A cells. J Immunol. 1994 Nov 15;153(10):4604–4615. [PubMed] [Google Scholar]
  20. Ferrantini M., Proietti E., Santodonato L., Gabriele L., Peretti M., Plavec I., Meyer F., Kaido T., Gresser I., Belardelli F. Alpha 1-interferon gene transfer into metastatic Friend leukemia cells abrogated tumorigenicity in immunocompetent mice: antitumor therapy by means of interferon-producing cells. Cancer Res. 1993 Mar 1;53(5):1107–1112. [PubMed] [Google Scholar]
  21. Gidlund M., Orn A., Wigzell H., Senik A., Gresser I. Enhanced NK cell activity in mice injected with interferon and interferon inducers. Nature. 1978 Jun 29;273(5665):759–761. doi: 10.1038/273759a0. [DOI] [PubMed] [Google Scholar]
  22. Gresser I., Bandu M. T., Brouty-Boyé D. Interferon and cell division. IX. Interferon-resistant L1210 cells: characteristics and origin. J Natl Cancer Inst. 1974 Feb;52(2):553–559. doi: 10.1093/jnci/52.2.553. [DOI] [PubMed] [Google Scholar]
  23. Gresser I., Belardelli F., Maury C., Tovey M. G., Maunoury M. T. Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant friend leukemia cells. IV. Definition of optimal treatment regimens. Int J Cancer. 1986 Aug 15;38(2):251–257. doi: 10.1002/ijc.2910380216. [DOI] [PubMed] [Google Scholar]
  24. Gresser I., Fontaine D., Coppey J., Falcoff R., Falcoff E. Interferon and murine leukemia. II. Factors related to the inhibitory effect of interferon preparations on development of Friend leukemia in mice. Proc Soc Exp Biol Med. 1967 Jan;124(1):91–94. doi: 10.3181/00379727-124-31673. [DOI] [PubMed] [Google Scholar]
  25. Gresser I., Maury C., Carnaud C., De Maeyer E., Maunoury M. T., Belardelli F. Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases. Int J Cancer. 1990 Sep 15;46(3):468–474. doi: 10.1002/ijc.2910460324. [DOI] [PubMed] [Google Scholar]
  26. Gresser I., Maury C., Tovey M., Morel-Maroger L., Pontillon F. Progressive glomerulonephritis in mice treated with interferon preparations at birth. Nature. 1976 Sep 30;263(5576):420–422. doi: 10.1038/263420a0. [DOI] [PubMed] [Google Scholar]
  27. Gresser I., Maury C., Woodrow D., Moss J., Grütter M. G., Vignaux F., Belardelli F., Maunoury M. T. Interferon treatment markedly inhibits the development of tumor metastases in the liver and spleen and increases survival time of mice after intravenous inoculation of Friend erythroleukemia cells. Int J Cancer. 1988 Jan 15;41(1):135–142. doi: 10.1002/ijc.2910410124. [DOI] [PubMed] [Google Scholar]
  28. Gresser I., Moss J., Woodrow D., Le Bousse C., Maury C., Proietti E., Belardelli F. Influence of the site of tumor growth on the capacity of a low tumorigenic line of Friend erythroleukemia cells to differentiate. Am J Pathol. 1991 May;138(5):1125–1133. [PMC free article] [PubMed] [Google Scholar]
  29. Gresser I., Tovey M. G., Maury C., Chouroulinkov I. Lethality of interferon preparations for newborn mice. Nature. 1975 Nov 6;258(5530):76–78. doi: 10.1038/258076a0. [DOI] [PubMed] [Google Scholar]
  30. Hock H., Dorsch M., Diamantstein T., Blankenstein T. Interleukin 7 induces CD4+ T cell-dependent tumor rejection. J Exp Med. 1991 Dec 1;174(6):1291–1298. doi: 10.1084/jem.174.6.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hock H., Dorsch M., Kunzendorf U., Qin Z., Diamantstein T., Blankenstein T. Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2774–2778. doi: 10.1073/pnas.90.7.2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hooks J. J., Moutsopoulos H. M., Notkins A. L. The role of interferon in immediate hypersensitivity and autoimmune diseases. Ann N Y Acad Sci. 1980;350:21–32. doi: 10.1111/j.1749-6632.1980.tb20603.x. [DOI] [PubMed] [Google Scholar]
  33. Kaido T., Bandu M. T., Maury C., Ferrantini M., Belardelli F., Gresser I. IFN-alpha 1 gene transfection completely abolishes the tumorigenicity of murine B16 melanoma cells in allogeneic DBA/2 mice and decreases their tumorigenicity in syngeneic C57BL/6 mice. Int J Cancer. 1995 Jan 17;60(2):221–229. doi: 10.1002/ijc.2910600216. [DOI] [PubMed] [Google Scholar]
  34. Kaido T., Gresser I., Maury C., Maunoury M. T., Vignaux F., Belardelli F. Sensitized T lymphocytes render DBA/2 beige mice responsive to IFN alpha/beta therapy of Friend erythroleukemia visceral metastases. Int J Cancer. 1993 May 28;54(3):475–481. doi: 10.1002/ijc.2910540320. [DOI] [PubMed] [Google Scholar]
  35. Karp S. E., Farber A., Salo J. C., Hwu P., Jaffe G., Asher A. L., Shiloni E., Restifo N. P., Mulé J. J., Rosenberg S. A. Cytokine secretion by genetically modified nonimmunogenic murine fibrosarcoma. Tumor inhibition by IL-2 but not tumor necrosis factor. J Immunol. 1993 Feb 1;150(3):896–908. [PMC free article] [PubMed] [Google Scholar]
  36. Katsanis E., Orchard P. J., Bausero M. A., Gorden K. B., McIvor R. S., Blazar B. R. Interleukin-2 gene transfer into murine neuroblastoma decreases tumorigenicity and enhances systemic immunity causing regression of preestablished retroperitoneal tumors. J Immunother Emphasis Tumor Immunol. 1994 Feb;15(2):81–90. doi: 10.1097/00002371-199402000-00001. [DOI] [PubMed] [Google Scholar]
  37. Krüger-Krasagakes S., Li W., Richter G., Diamantstein T., Blankenstein T. Eosinophils infiltrating interleukin-5 gene-transfected tumors do not suppress tumor growth. Eur J Immunol. 1993 Apr;23(4):992–995. doi: 10.1002/eji.1830230438. [DOI] [PubMed] [Google Scholar]
  38. Lee S. B., Esteban M. The interferon-induced double-stranded RNA-activated protein kinase induces apoptosis. Virology. 1994 Mar;199(2):491–496. doi: 10.1006/viro.1994.1151. [DOI] [PubMed] [Google Scholar]
  39. Locardi C., Belardelli F., Federico M., Romeo G., Affabris E., Gresser I. Effect of mouse interferon alpha/beta on the expression of H-2 (class I) antigens and on the levels of 2'-5' oligoadenylate synthetase activity in interferon-sensitive and interferon-resistant Friend leukemia cell tumors in mice. J Biol Regul Homeost Agents. 1987 Oct-Dec;1(4):189–194. [PubMed] [Google Scholar]
  40. Lollini P. L., Bosco M. C., Cavallo F., De Giovanni C., Giovarelli M., Landuzzi L., Musiani P., Modesti A., Nicoletti G., Palmieri G. Inhibition of tumor growth and enhancement of metastasis after transfection of the gamma-interferon gene. Int J Cancer. 1993 Sep 9;55(2):320–329. doi: 10.1002/ijc.2910550224. [DOI] [PubMed] [Google Scholar]
  41. Miller A. R., McBride W. H., Dubinett S. M., Dougherty G. J., Thacker J. D., Shau H., Kohn D. B., Moen R. C., Walker M. J., Chiu R. Transduction of human melanoma cell lines with the human interleukin-7 gene using retroviral-mediated gene transfer: comparison of immunologic properties with interleukin-2. Blood. 1993 Dec 15;82(12):3686–3694. [PubMed] [Google Scholar]
  42. Moss J., Woodrow D. F., Sloper J. C., Rivière Y., Guillon J. C., Gresser I. Interferon as a cause of endoplasmic reticulum abnormalities within hepatocytes in newborn mice. Br J Exp Pathol. 1982 Feb;63(1):43–49. [PMC free article] [PubMed] [Google Scholar]
  43. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  44. Puddu P., Locardi C., Sestili P., Varano F., Petrini C., Modesti A., Masuelli L., Gresser I., Belardelli F. Human immunodeficiency virus (HIV)-infected tumor xenografts as an in vivo model for antiviral therapy: role of alpha/beta interferon in restriction of tumor growth in nude mice injected with HIV-infected U937 tumor cells. J Virol. 1991 May;65(5):2245–2253. doi: 10.1128/jvi.65.5.2245-2253.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Roth C., Mir L. M., Cressent M., Quintin-Colonna F., Ley V., Fradelizi D., Kourilsky P. Inhibition of tumor growth by histoincompatible cells expressing interleukin-2. Int Immunol. 1992 Dec;4(12):1429–1436. doi: 10.1093/intimm/4.12.1429. [DOI] [PubMed] [Google Scholar]
  46. Sarraf C. E., Bowen I. D. Kinetic studies on a murine sarcoma and an analysis of apoptosis. Br J Cancer. 1986 Dec;54(6):989–998. doi: 10.1038/bjc.1986.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sorenson C. M., Barry M. A., Eastman A. Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. J Natl Cancer Inst. 1990 May 2;82(9):749–755. doi: 10.1093/jnci/82.9.749. [DOI] [PubMed] [Google Scholar]
  48. Stoppacciaro A., Melani C., Parenza M., Mastracchio A., Bassi C., Baroni C., Parmiani G., Colombo M. P. Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma. J Exp Med. 1993 Jul 1;178(1):151–161. doi: 10.1084/jem.178.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Strander H. Interferon treatment of human neoplasia. Adv Cancer Res. 1986;46:1–265. [PubMed] [Google Scholar]
  50. Teng M. N., Park B. H., Koeppen H. K., Tracey K. J., Fendly B. M., Schreiber H. Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3535–3539. doi: 10.1073/pnas.88.9.3535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tepper R. I., Mulé J. J. Experimental and clinical studies of cytokine gene-modified tumor cells. Hum Gene Ther. 1994 Feb;5(2):153–164. doi: 10.1089/hum.1994.5.2-153. [DOI] [PubMed] [Google Scholar]
  52. Tepper R. I., Pattengale P. K., Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell. 1989 May 5;57(3):503–512. doi: 10.1016/0092-8674(89)90925-2. [DOI] [PubMed] [Google Scholar]
  53. Watanabe Y., Kuribayashi K., Miyatake S., Nishihara K., Nakayama E., Taniyama T., Sakata T. Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9456–9460. doi: 10.1073/pnas.86.23.9456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Woodrow D., Moss J., Gresser I. Interferon induces pulmonary cysts in A2G mice. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7937–7940. doi: 10.1073/pnas.81.24.7937. [DOI] [PMC free article] [PubMed] [Google Scholar]

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