Recombinant interleukin 12 cures mice infected with Leishmania major

doi:10.1084/jem.177.5.1505

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Recombinant interleukin 12 cures mice infected with Leishmania major

FP Heinzel, DS Schoenhaut, RM Rerko, LE Rosser and MK Gately
Department of Medicine, Case Western Reserve University, Cleveland, Ohio.

Resistant C57BL/6 mice infected with Leishmania major are self-healing, whereas susceptible BALB/c mice fail to contain cutaneous infection and subsequently undergo fatal visceral dissemination. These disparate outcomes are mediated by dissimilar expansions of T helper type 1 (Th1) and Th2 CD4+ T lymphocyte subsets in vivo during cure and progression of disease. Because interleukin 12 (IL-12) has potent T cell growth and interferon gamma (IFN-gamma) stimulatory effects, we studied its effect on CD4+ T cell differentiation during murine leishmaniasis. Treatment with recombinant murine (rMu)IL-12 during the first week of infection cured 89% of normally susceptible BALB/c mice, as defined by decreased size of infected footpads and 1,000-10,000-fold reduced parasite burdens, and provided durable resistance against reinfection. Cure was associated with markedly depressed production of IL-4 by lymph node cells cultured with antigen or mitogen, but preserved or increased production of IFN-gamma relative to untreated mice. IL-4 and IFN-gamma mRNA associated with CD4+ T lymphocytes isolated from infected lymph nodes showed similar reciprocal changes in response to rMuIL-12 therapy. A single injection of anti-IFN-gamma monoclonal antibody abrogated the protective effect of rMuIL-12 therapy and restored Th2 cytokine responses. We conclude that rMuIL-12 prevents deleterious Th2 T cell responses and promotes curative Th1 responses in an IFN-gamma- dependent fashion during murine leishmaniasis. Since BALB/c leishmaniasis cannot be cured with rMuIFN-gamma alone, additional direct effects of IL-12 during T cell subset selection are suggested. Because rMuIL-12 is uniquely protective in this well-characterized model of chronic parasitism, differences in IL-12 production may underlie heterogenous host responses to L. major and other intracellular pathogens.
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Yao, L., Sgadari, C., Furuke, K., Bloom, E. T., Teruya-Feldstein, J., Tosato, G. (1999). Contribution of Natural Killer Cells to Inhibition of Angiogenesis by Interleukin-12. Blood 93: 1612-1621 [Abstract] [Full Text]
Mohan, K., Sam, H., Stevenson, M. M. (1999). Therapy with a Combination of Low Doses of Interleukin 12�and Chloroquine Completely Cures Blood-Stage Malaria, Prevents Severe Anemia, and Induces Immunity to Reinfection. Infect. Immun. 67: 513-519 [Abstract] [Full Text]
Guler, M. L., Gorham, J. D., Dietrich, W. F., Murphy, T. L., Steen, R. G., Parvin, C. A., Fenoglio, D., Grupe, A., Peltz, G., Murphy, K. M. (1999). Tpm1, a Locus Controlling IL-12 Responsiveness, Acts by a Cell-Autonomous Mechanism. J. Immunol. 162: 1339-1347 [Abstract] [Full Text]
Sam, H., Stevenson, M. M. (1999). In Vivo IL-12 Production and IL-12 Receptors {beta}1 and {beta}2 mRNA Expression in the Spleen Are Differentially Up-Regulated in Resistant B6 and Susceptible A/J Mice During Early Blood-Stage Plasmodium chabaudi AS Malaria. J. Immunol. 162: 1582-1589 [Abstract] [Full Text]
Tarrant, T. K., Silver, P. B., Wahlsten, J. L., Rizzo, L. V., Chan, C.-C., Wiggert, B., Caspi, R. R. (1999). Interleukin 12�Protects from a T Helper Type 1-mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon gamma , Nitric Oxide, and Apoptosis. JEM 189: 219-230 [Abstract] [Full Text]
Li, J., Hunter, C. A., Farrell, J. P. (1999). Anti-TGF-{beta} Treatment Promotes Rapid Healing of Leishmania major Infection in Mice by Enhancing In Vivo Nitric Oxide Production. J. Immunol. 162: 974-979 [Abstract] [Full Text]
Alexander, J, Satoskar, A., Russell, D. (1999). Leishmania species: models of intracellular parasitism. J. Cell Sci. 112: 2993-3002 [Abstract]
Alexander, J., Coombs, G. H., Mottram, J. C. (1998). Leishmania mexicana Cysteine Proteinase-Deficient Mutants Have Attenuated Virulence for Mice and Potentiate a Th1 Response. J. Immunol. 161: 6794-6801 [Abstract] [Full Text]
Wilson, M. E., Young, B. M., Davidson, B. L., Mente, K. A., McGowan, S. E. (1998). The Importance of TGF-{beta} in Murine Visceral Leishmaniasis. J. Immunol. 161: 6148-6155 [Abstract] [Full Text]
Himmelrich, H., Parra-Lopez, C., Tacchini-Cottier, F., Louis, J. A., Launois, P. (1998). The IL-4 Rapidly Produced in BALB/c Mice After Infection with Leishmania major Down-Regulates IL-12 Receptor {beta}2-Chain Expression on CD4+ T Cells Resulting in a State of Unresponsiveness to IL-12. J. Immunol. 161: 6156-6163 [Abstract] [Full Text]
Skeiky, Y. A. W., Kennedy, M., Kaufman, D., Borges, M. M., Guderian, J. A., Scholler, J. K., Ovendale, P. J., Picha, K. S., Morrissey, P. J., Grabstein, K. H., Campos-Neto, A., Reed, S. G. (1998). LeIF: A Recombinant Leishmania Protein That Induces an IL-12-Mediated Th1 Cytokine Profile. J. Immunol. 161: 6171-6179 [Abstract] [Full Text]
Stamm, L. M., Raisanen-Sokolowski, A., Okano, M., Russell, M. E., David, J. R., Satoskar, A. R. (1998). Mice with STAT6-Targeted Gene Disruption Develop a Th1 Response and Control Cutaneous Leishmaniasis. J. Immunol. 161: 6180-6188 [Abstract] [Full Text]
Silva, R. A., Pais, T. F., Appelberg, R. (1998). Evaluation of IL-12 in Immunotherapy and Vaccine Design in Experimental Mycobacterium avium Infections. J. Immunol. 161: 5578-5585 [Abstract] [Full Text]
Hoffmann, K. F., Caspar, P., Cheever, A. W., Wynn, T. A. (1998). IFN-{gamma}, IL-12, and TNF-{alpha} Are Required to Maintain Reduced Liver Pathology in Mice Vaccinated with Schistosoma mansoni Eggs and IL-12. J. Immunol. 161: 4201-4210 [Abstract] [Full Text]
Decken, K., Kohler, G., Palmer-Lehmann, K., Wunderlin, A., Mattner, F., Magram, J., Gately, M. K., Alber, G. (1998). Interleukin-12 Is Essential for a Protective Th1 Response in Mice Infected with Cryptococcus neoformans. Infect. Immun. 66: 4994-5000 [Abstract] [Full Text]
Assenmacher, M., Lohning, M., Scheffold, A., Richter, A., Miltenyi, S., Schmitz, J., Radbruch, A. (1998). Commitment of Individual Th1-Like Lymphocytes to Expression of IFN-{gamma} Versus IL-4 and IL-10: Selective Induction of IL-10 by Sequential Stimulation of Naive Th Cells with IL-12 and IL-4. J. Immunol. 161: 2825-2832 [Abstract] [Full Text]
Maekawa, Y., Himeno, K., Ishikawa, H., Hisaeda, H., Sakai, T., Dainichi, T., Asao, T., Good, R. A, Katunuma, N. (1998). Switch of CD4+ T Cell Differentiation from Th2 to Th1 by Treatment with Cathepsin B Inhibitor in Experimental Leishmaniasis. J. Immunol. 161: 2120-2127 [Abstract] [Full Text]
Hensler, T., Heidecke, C.-D., Hecker, H., Heeg, K., Bartels, H., Zantl, N., Wagner, H., Siewert, J.-R., Holzmann, B. (1998). Increased Susceptibility to Postoperative Sepsis in Patients with Impaired Monocyte IL-12 Production. J. Immunol. 161: 2655-2659 [Abstract] [Full Text]