Abstract
Interleukin-12 (IL-12)-deficient mice derived from a strain genetically resistant to infection with Leishmania major were recently shown to be susceptible toward this parasite, developing a strong Th2 response after injection of a large number of parasites. We further investigated the role of IL-12 in L. major infection by studying the responses of mutant mice against smaller numbers of parasites. IL-12-deficient mice infected with only small numbers of parasites showed the progressive lesion development and high parasite burden associated with a polarized Th2 response. Our data show that IL-12 is indispensable for protective immunity against L. major. Even at low inocula, no salvage pathway appears to compensate for the lack of IL-12. However, genetically susceptible BALB/c mice infected with small numbers of parasites were able to resolve lesions and restrict the parasite burden to levels which were 10(5)-fold lower than those in IL-12-deficient mice. In contrast to mutant mice, BALB/c mice mounted a type 1 response against low inocula of L. major. IL-12-deficient BALB/c mice, however, developed a type 2 response. These data emphasize the essential role of IL-12 in resistance against L. major. In addition, this study suggests that in the absence of IL-12, susceptibility to L. major is determined by the inability to induce a Th1 response rather than the development of a Th2 response. Our results are relevant for potential vaccination strategies that use low inocula of infective microorganisms which fail to induce a protective type 1 response at higher inocula.
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- Baniyash M., Eshhar Z. Inhibition of IgE binding to mast cells and basophils by monoclonal antibodies to murine IgE. Eur J Immunol. 1984 Sep;14(9):799–807. doi: 10.1002/eji.1830140907. [DOI] [PubMed] [Google Scholar]
- Bretscher P. A., Ogunremi O., Menon J. N. Distinct immunological states in murine cutaneous leishmaniasis by immunising with different amounts of antigen: the generation of beneficial, potentially harmful, harmful and potentially extremely harmful states. Behring Inst Mitt. 1997 Feb;(98):153–159. [PubMed] [Google Scholar]
- Bretscher P. A., Wei G., Menon J. N., Bielefeldt-Ohmann H. Establishment of stable, cell-mediated immunity that makes "susceptible" mice resistant to Leishmania major. Science. 1992 Jul 24;257(5069):539–542. doi: 10.1126/science.1636090. [DOI] [PubMed] [Google Scholar]
- Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doherty T. M., Coffman R. L. Leishmania major: effect of infectious dose on T cell subset development in BALB/c mice. Exp Parasitol. 1996 Nov;84(2):124–135. doi: 10.1006/expr.1996.0098. [DOI] [PubMed] [Google Scholar]
- Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
- Güler M. L., Gorham J. D., Hsieh C. S., Mackey A. J., Steen R. G., Dietrich W. F., Murphy K. M. Genetic susceptibility to Leishmania: IL-12 responsiveness in TH1 cell development. Science. 1996 Feb 16;271(5251):984–987. doi: 10.1126/science.271.5251.984. [DOI] [PubMed] [Google Scholar]
- HayGlass K. T., Stefura B. P. Anti-interferon gamma treatment blocks the ability of glutaraldehyde-polymerized allergens to inhibit specific IgE responses. J Exp Med. 1991 Feb 1;173(2):279–285. doi: 10.1084/jem.173.2.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinzel F. P., Rerko R. M., Ahmed F., Pearlman E. Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. J Immunol. 1995 Jul 15;155(2):730–739. [PubMed] [Google Scholar]
- Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
- Kolbe L., Heusser C., Kölsch E. Antigen dose-dependent regulation of B epsilon-memory cell expression. Int Arch Allergy Appl Immunol. 1991;95(2-3):202–206. doi: 10.1159/000235430. [DOI] [PubMed] [Google Scholar]
- Kopf M., Brombacher F., Köhler G., Kienzle G., Widmann K. H., Lefrang K., Humborg C., Ledermann B., Solbach W. IL-4-deficient Balb/c mice resist infection with Leishmania major. J Exp Med. 1996 Sep 1;184(3):1127–1136. doi: 10.1084/jem.184.3.1127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Launois P., Ohteki T., Swihart K., MacDonald H. R., Louis J. A. In susceptible mice, Leishmania major induce very rapid interleukin-4 production by CD4+ T cells which are NK1.1-. Eur J Immunol. 1995 Dec;25(12):3298–3307. doi: 10.1002/eji.1830251215. [DOI] [PubMed] [Google Scholar]
- Locksley R. M., Louis J. A. Immunology of leishmaniasis. Curr Opin Immunol. 1992 Aug;4(4):413–418. doi: 10.1016/s0952-7915(06)80032-4. [DOI] [PubMed] [Google Scholar]
- Magram J., Connaughton S. E., Warrier R. R., Carvajal D. M., Wu C. Y., Ferrante J., Stewart C., Sarmiento U., Faherty D. A., Gately M. K. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996 May;4(5):471–481. doi: 10.1016/s1074-7613(00)80413-6. [DOI] [PubMed] [Google Scholar]
- Mattner F., Magram J., Ferrante J., Launois P., Di Padova K., Behin R., Gately M. K., Louis J. A., Alber G. Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response. Eur J Immunol. 1996 Jul;26(7):1553–1559. doi: 10.1002/eji.1830260722. [DOI] [PubMed] [Google Scholar]
- Menon J. N., Bretscher P. A. Characterization of the immunological memory state generated in mice susceptible to Leishmania major following exposure to low doses of L. major and resulting in resistance to a normally pathogenic challenge. Eur J Immunol. 1996 Jan;26(1):243–249. doi: 10.1002/eji.1830260138. [DOI] [PubMed] [Google Scholar]
- Moll H., Flohé S., Röllinghoff M. Dendritic cells in Leishmania major-immune mice harbor persistent parasites and mediate an antigen-specific T cell immune response. Eur J Immunol. 1995 Mar;25(3):693–699. doi: 10.1002/eji.1830250310. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
- Müller I., Louis J. A. Immunity to experimental infection with Leishmania major: generation of protective L3T4+ T cell clones recognizing antigen(s) associated with live parasites. Eur J Immunol. 1989 May;19(5):865–871. doi: 10.1002/eji.1830190513. [DOI] [PubMed] [Google Scholar]
- Noben-Trauth N., Kropf P., Müller I. Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Science. 1996 Feb 16;271(5251):987–990. doi: 10.1126/science.271.5251.987. [DOI] [PubMed] [Google Scholar]
- Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
- Okamura H., Tsutsi H., Komatsu T., Yutsudo M., Hakura A., Tanimoto T., Torigoe K., Okura T., Nukada Y., Hattori K. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995 Nov 2;378(6552):88–91. doi: 10.1038/378088a0. [DOI] [PubMed] [Google Scholar]
- Prat M., Gribaudo G., Comoglio P. M., Cavallo G., Landolfo S. Monoclonal antibodies against murine gamma interferon. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4515–4519. doi: 10.1073/pnas.81.14.4515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Preston P. M., Dumonde D. C. Experimental cutaneous leishmaniasis. V. Protective immunity in subclinical and self-healing infection in the mouse. Clin Exp Immunol. 1976 Jan;23(1):126–138. [PMC free article] [PubMed] [Google Scholar]
- Reiner S. L., Locksley R. M. The regulation of immunity to Leishmania major. Annu Rev Immunol. 1995;13:151–177. doi: 10.1146/annurev.iy.13.040195.001055. [DOI] [PubMed] [Google Scholar]
- Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug;12(8):256–257. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
- Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scharton-Kersten T., Afonso L. C., Wysocka M., Trinchieri G., Scott P. IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis. J Immunol. 1995 May 15;154(10):5320–5330. [PubMed] [Google Scholar]
- Schmitt E., Hoehn P., Germann T., Rüde E. Differential effects of interleukin-12 on the development of naive mouse CD4+ T cells. Eur J Immunol. 1994 Feb;24(2):343–347. doi: 10.1002/eji.1830240211. [DOI] [PubMed] [Google Scholar]
- Scott P. The role of TH1 and TH2 cells in experimental cutaneous leishmaniasis. Exp Parasitol. 1989 Apr;68(3):369–372. doi: 10.1016/0014-4894(89)90120-3. [DOI] [PubMed] [Google Scholar]
- Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
- Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Titus R. G., Ceredig R., Cerottini J. C., Louis J. A. Therapeutic effect of anti-L3T4 monoclonal antibody GK1.5 on cutaneous leishmaniasis in genetically-susceptible BALB/c mice. J Immunol. 1985 Sep;135(3):2108–2114. [PubMed] [Google Scholar]
- Titus R. G., Marchand M., Boon T., Louis J. A. A limiting dilution assay for quantifying Leishmania major in tissues of infected mice. Parasite Immunol. 1985 Sep;7(5):545–555. doi: 10.1111/j.1365-3024.1985.tb00098.x. [DOI] [PubMed] [Google Scholar]
- Zurawski G., de Vries J. E. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994 Jan;15(1):19–26. doi: 10.1016/0167-5699(94)90021-3. [DOI] [PubMed] [Google Scholar]