This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kurzawa, H. Articles by Lee, W. M. F. Search for Related Content PubMed PubMed Citation Articles by Kurzawa, H. Articles by Lee, W. M. F.

Recombinant Interleukin 12 Enhances Cellular Immune Responses to Vaccination Only after a Period of Suppression¹

Cell and Molecular Biology Graduate Group [H. K.], Department of Medicine, Cancer Center and Institute for Human Gene Therapy [W. M. F. L.], University of Pennsylvania, and Wistar Institute [M. W., G. T.], Philadelphia, Pennsylvania 19104; and Division of Surgical Oncology, University of Michigan, Ann Arbor, Michigan [E. A., A. E. C.]

Adjuvant use of recombinant murine IL-12 (rmIL-12) was examined in mice vaccinated with irradiated syngeneic tumor or allogeneic cells. rmIL-12 given to A/J mice vaccinated with irradiated SCK tumor cells engineered to secrete granulocyte/macrophage-colony-stimulating factor resulted in significantly better protection from tumor challenges 28 days after vaccination but, unexpectedly, severely compromised host protection 14 days after vaccination. Immune suppression was rmIL-12 dose dependent and manifested as reduced splenic CTL activity, stimulated cytokine release and ability to reject SCK cells. Transient immune suppression was also seen with rmIL-12 given during vaccination of C3H/HeN mice with irradiated K1735 melanoma cells and of C57BL/6 mice with irradiated allogeneic HKB cells. The period of suppression coincided with transiently reduced splenic T-cell mitogenic responses to concanavalin A and IL-2, suggesting that they may be causally related. Suppression appears to be due to impaired immune effector mechanisms rather than impaired host immunization, which is actually enhanced as evidenced by the enhanced reaction to immunogens when hosts are challenged later after rmIL-12 administration. Demonstration that rmIL-12, as it is frequently used, induces a transient period of impaired immune response that can compromise host protection suggests that the unquestioned effectiveness of rmIL-12 against murine tumors is primarily due to activation of mechanisms other than antigen-specific tumor immunity (e.g., antiangiogenic effects) and that use of human IL-12 should be monitored for similar effects.

¹ Supported by funds from Department of the Army Predoctoral Training Grant DAMD17-94-J-4027 (to H. K.), NIH Grant PO1 CA59327 (to A. C.), NIH Grants AI34412, CA10815, CA20833s and CA32898 (to G. T.), and NIH Grant UO1 CA65805 (to W. M. F. L.).

² Present address: Department of Internal Medicine, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277, Japan.

³ To whom requests for reprints should be addressed, at 663 Clinical Research Building, 415 Curie Boulevard, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6140; Fax: (215) 573-7912; E-mail: leemingf@mail.med.upenn.edu.

Received 8/20/97. Accepted 12/ 2/97.

This article has been cited by other articles:

				Y. Peng, F.-c. Lin, P. H. Verardi, L. A. Jones, and T. D. Yilma Lower Levels of Gamma Interferon Expressed by a Pseudotyped Single-Cycle Simian Immunodeficiency Virus Enhance Immunogenicity in Rats J. Virol., February 15, 2009; 83(4): 1592 - 1601. [Abstract] [Full Text] [PDF]

				M. V. Lopez, S. K. Adris, A. I. Bravo, Y. Chernajovsky, and O. L. Podhajcer IL-12 and IL-10 Expression Synergize to Induce the Immune-Mediated Eradication of Established Colon and Mammary Tumors and Lung Metastasis J. Immunol., November 1, 2005; 175(9): 5885 - 5894. [Abstract] [Full Text] [PDF]

				E. Yu. Nikitina, S. A. Desai, X. Zhao, W. Song, A. Z. Luo, R. D. Gangula, K. M. Slawin, and D. M. Spencer Versatile Prostate Cancer Treatment with Inducible Caspase and Interleukin-12 Cancer Res., May 15, 2005; 65(10): 4309 - 4319. [Abstract] [Full Text] [PDF]

				Y. Osorio and H. Ghiasi Recombinant Herpes Simplex Virus Type 1 (HSV-1) Codelivering Interleukin-12p35 as a Molecular Adjuvant Enhances the Protective Immune Response against Ocular HSV-1 Challenge J. Virol., March 15, 2005; 79(6): 3297 - 3308. [Abstract] [Full Text] [PDF]

				X. Peng, S. F. Hussain, and Y. Paterson The Ability of Two Listeria monocytogenes Vaccines Targeting Human Papillomavirus-16 E7 to Induce an Antitumor Response Correlates with Myeloid Dendritic Cell Function J. Immunol., May 15, 2004; 172(10): 6030 - 6038. [Abstract] [Full Text] [PDF]

				D. Nolt and J. L. Flynn Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis Infect. Immun., May 1, 2004; 72(5): 2976 - 2988. [Abstract] [Full Text] [PDF]

				M. L. Salem, A. N. Kadima, Y. Zhou, C. L. Nguyen, M. P. Rubinstein, M. Demcheva, J. N. Vournakis, D. J. Cole, and W. E. Gillanders Paracrine Release of IL-12 Stimulates IFN-{gamma} Production and Dramatically Enhances the Antigen-Specific T Cell Response after Vaccination with a Novel Peptide-Based Cancer Vaccine J. Immunol., May 1, 2004; 172(9): 5159 - 5167. [Abstract] [Full Text] [PDF]

				Y. Nishioka, H. Wen, K. Mitani, P. D. Robbins, M. T. Lotze, S. Sone, and H. Tahara Differential effects of IL-12 on the generation of alloreactive CTL mediated by murine and human dendritic cells: a critical role for nitric oxide J. Leukoc. Biol., May 1, 2003; 73(5): 621 - 629. [Abstract] [Full Text] [PDF]

				K. Peter, M. J. Brunda, and G. Corradin IL-12 Administration Leads to a Transient Depletion of T Cells, B Cells, and APCs and Concomitant Abrogation of the HLA-A2.1-Restricted CTL Response in Transgenic Mice J. Immunol., July 1, 2002; 169(1): 63 - 67. [Abstract] [Full Text] [PDF]

				J. C. Lee, D. C. Kim, M. S. Gee, H. M. Saunders, C. M. Sehgal, M. D. Feldman, S. R. Ross, and W. M. F. Lee Interleukin-12 Inhibits Angiogenesis and Growth of Transplanted but not in Situ Mouse Mammary Tumor Virus-induced Mammary Carcinomas Cancer Res., February 1, 2002; 62(3): 747 - 755. [Abstract] [Full Text] [PDF]

				H.-W. Chen, C.-H. Pan, H.-W. Huan, M.-Y. Liau, J.-R. Chiang, and M.-H. Tao Suppression of Immune Response and Protective Immunity to a Japanese Encephalitis Virus DNA Vaccine by Coadministration of an IL-12-Expressing Plasmid J. Immunol., June 15, 2001; 166(12): 7419 - 7426. [Abstract] [Full Text] [PDF]

				L. Cifaldi, E. Quaglino, E. Di Carlo, P. Musiani, M. Spadaro, P. L. Lollini, S. Wolf, K. Boggio, G. Forni, and F. Cavallo A Light, Nontoxic Interleukin 12 Protocol Inhibits HER-2/neu Mammary Carcinogenesis in BALB/c Transgenic Mice with Established Hyperplasia Cancer Res., April 1, 2001; 61(7): 2809 - 2812. [Abstract] [Full Text]

				M. M. Gherardi, J. C. Ramírez, and M. Esteban Interleukin-12 (IL-12) Enhancement of the Cellular Immune Response against Human Immunodeficiency Virus Type 1 Env Antigen in a DNA Prime/Vaccinia Virus Boost Vaccine Regimen Is Time and Dose Dependent: Suppressive Effects of IL-12 Boost Are Mediated by Nitric Oxide J. Virol., July 15, 2000; 74(14): 6278 - 6286. [Abstract] [Full Text]

				L. Sfondrini, M. Rodolfo, M. Singh, M. P. Colombo, M. I. Colnaghi, S. Ménard, and A. Balsari Cooperative Effects of Mycobacterium tuberculosis Ag38 Gene Transduction and Interleukin 12 in Vaccination against Spontaneous Tumor Development in Proto-neu Transgenic Mice Cancer Res., July 1, 2000; 60(14): 3777 - 3781. [Abstract] [Full Text]

				N. K. Egilmez, Y. S. Jong, M. S. Sabel, J. S. Jacob, E. Mathiowitz, and R. B. Bankert In Situ Tumor Vaccination with Interleukin-12-encapsulated Biodegradable Microspheres: Induction of Tumor Regression and Potent Antitumor Immunity Cancer Res., July 1, 2000; 60(14): 3832 - 3837. [Abstract] [Full Text]

				J. A. Gollob, J. W. Mier, K. Veenstra, D. F. McDermott, D. Clancy, M. Clancy, and M. B. Atkins Phase I Trial of Twice-Weekly Intravenous Interleukin 12 in Patients with Metastatic Renal Cell Cancer or Malignant Melanoma: Ability to Maintain IFN-{{gamma}} Induction Is Associated with Clinical Response Clin. Cancer Res., May 1, 2000; 6(5): 1678 - 1692. [Abstract] [Full Text] [PDF]

				M. S. Gee, C. J. Koch, S. M. Evans, W. T. Jenkins, C. H. Pletcher Jr., J. S. Moore, H. K. Koblish, J. Lee, E. M. Lord, G. Trinchieri, et al. Hypoxia-mediated Apoptosis from Angiogenesis Inhibition Underlies Tumor Control by Recombinant Interleukin 12 Cancer Res., October 1, 1999; 59(19): 4882 - 4889. [Abstract] [Full Text] [PDF]

				I. Okamoto, K. Kohno, T. Tanimoto, H. Ikegami, and M. Kurimoto Development of CD8+ Effector T Cells Is Differentially Regulated by IL-18 and IL-12 J. Immunol., March 15, 1999; 162(6): 3202 - 3211. [Abstract] [Full Text] [PDF]

				F. Cavallo, E. D. Carlo, M. Butera, R. Verrua, M. P. Colombo, P. Musiani, and G. Forni Immune Events Associated with the Cure of Established Tumors and Spontaneous Metastases by Local and Systemic Interleukin 12 Cancer Res., January 1, 1999; 59(2): 414 - 421. [Abstract] [Full Text] [PDF]

				H. K. Koblish, C. A. Hunter, M. Wysocka, G. Trinchieri, and W. M.F. Lee Immune Suppression by Recombinant Interleukin (rIL)-12 Involves Interferon {gamma} Induction of Nitric Oxide Synthase 2 (iNOS) Activity: Inhibitors of NO Generation Reveal the Extent of rIL-12 Vaccine Adjuvant Effect J. Exp. Med., November 2, 1998; 188(9): 1603 - 1610. [Abstract] [Full Text] [PDF]