The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/6/2101/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 12, June 16, 1997 2101-2110

Articles

Altered Immune Responses in Interleukin 10 Transgenic Mice

Amy Hagenbaugh*,{ddagger}, Sherven Sharma, Steven M. Dubinett, Sherry H.-Y. Wei§§, Richard Aranda§, Hilde Cheroutre{ddagger}, Deborah J. Fowell**, Scott Binder{dagger}{dagger}, Betty Tsao||, Richard M. Locksley**, Kevin W. Moore§§, and Mitchell Kronenberg*,{ddagger},§

From the * Molecular Biology Institute, {ddagger} Department of Microbiology & Immunology, § Division of Digestive Diseases, and || Division of Rheumatology, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095; Pulmonary Immunology Laboratory, Division of Pulmonary and Critical Care Medicine, West Los Angeles Veteran's Administration Medical Center, Los Angeles, California 90073, and University of California at Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, California 90095; ** Department of Medicine and Department of Microbiology & Immunology, University of California at San Francisco, San Francisco, California 94143, {dagger}{dagger} Midway Hospital Medical Center, Los Angeles, California 90019; and §§ Department of Molecular Biology, DNAX Research Institute, Palo Alto, California 94304

Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigenspecific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-{gamma} than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4+ CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4+ CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.

Address correspondence to Dr. Mitchell Kronenberg, La Jolla Institute for Allergy & Immunology, 10355 Science Center Dr., San Diego, CA 92121.

1Abbreviation used in this paper: NSCLC, nonsmall cell lung carcinoma.


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