title: Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response.
abstract: Resistance to Leishmania major in mice is associated with the appearance of distinct T helper type 1 (Th1) and Th2 subsets. T cells from lymph nodes draining cutaneous lesions of resistant mice are primarily interferon gamma (IFN-gamma)-producing Th1 cells. In contrast, T cells from susceptible mice are principally Th2 cells that generate interleukin 4 (IL-4). Although existing evidence is supportive of a role for IFN-gamma in the generation of Th1 cells, additional factors may be required for a protective response to be maintained. A potential candidate is IL-12, a heterodimeric cytokine produced by monocytes and B cells that has multiple effects on T and natural killer cell function, including inducing IFN-gamma production. Using an experimental leishmanial model we have observed that daily intraperitoneal administration at the time of parasite challenge of either 0.33 micrograms IL-12 (a consecutive 5 d/wk for 5 wk) or 1.0 micrograms IL-12 per mouse (only a consecutive 5 d) caused a > 75% reduction in parasite burden at the site of infection, in highly susceptible BALB/c mice. Delay of treatment by 1 wk had less of a protective effect. Concomitant with these protective effects was an increase in IFN-gamma and a decrease in IL-4 production, as measured by enzyme-linked immunosorbent assay of supernatants generated from popliteal lymph node cells stimulated with leishmanial antigen in vitro. The reduction in parasite numbers induced by IL-12 therapy was still apparent at 10 wk postinfection. In addition, we observed that the administration of a rabbit anti-recombinant murine IL-12 polyclonal antibody (200 micrograms i.p. every other day for 25 d) at the time of infection to resistant C57Bl/6 mice exacerbated disease. These effects were accompanied by a shift in IFN-gamma production in vitro by antigen-stimulated lymph node cells indicative of a Th2-like response. These findings suggest that IL-12 has an important role in initiating a Th1 response and protective immunity.
authors.affiliation: Department of Preclinical Biology, Genetics Institute, Inc., Cambridge, Massachusetts 02140.
authors.forename: J P
authors.initials: JP
authors.lastname: Sypek
authors.forename: C L
authors.initials: CL
authors.lastname: Chung
authors.forename: S E
authors.initials: SE
authors.lastname: Mayor
authors.forename: J M
authors.initials: JM
authors.lastname: Subramanyam
authors.forename: S J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: D S
authors.initials: DS
authors.lastname: Sieburth
authors.forename: S F
authors.initials: SF
authors.lastname: Wolf
authors.forename: R G
authors.initials: RG
authors.lastname: Schaub
mesh_terms: D000818:Animals; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12; D007378:Interleukins / Q000494:pharmacology*; D007895:Leishmania tropica; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*
chemical_list: D007378:Interleukins; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma