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.

IL-4-Independent Inhibition of IL-12 Responsiveness DuringLeishmania amazonensisInfection

“…In infected BALB/c mice, we found that IL-12 treatment leads to Th1 cell development and lesion resolution, as previously reported (Fig. 2E) (9,10). In contrast, IL-12 administration had little effect on the course of lesion development in L. amazonensis-infected C3H mice ( Fig.…”

“…This finding is in striking contrast to that in L. major-infected BALB/c mice, where exogenous IL-12 treatment induces the development of a Th1 response and healing (9,10). We linked the inability of L. amazonensis-infected mice to respond to IL-12 with decreased expression of a functional IL-12R, thus providing an explanation for both why IL-12 treatment was unsuccessful and why L. amazonensis induces a nonhealing infection in mice resistant to L. major.…”

“…Whether these factors are similar in L. major infections in BALB/c mice and L. amazonensis infections in C3H or C57BL/6 mice will need to be determined. However, it is quite possible that they differ, because susceptibility to L. major in susceptible BALB/c and BALB/c IL-4 Ϫ/Ϫ mice can be overcome with IL-12 administration, whereas this is not the case with L. amazonensis infection (9,10,37).…”

Genetically Resistant Mice Lacking IL-18 Gene Develop Th1 Response and Control CutaneousLeishmania majorInfection

“…Previous studies have demonstrated that IL-12 plays a critical role in mediating protective immunity against L. major (14,17,18). The protective role of IL-12 in murine L. major infection has been attributed to its ability to activate NK cells and induce IFN-␥ production required to develop a Th1 cell response (19).…”

The debate over the effector function of eosinophils in helminth infection: new evidence from studies on the regulation of vaccine immunity by IL-12

“…Related studies have shown that administration of IL-12 either just before infection or shortly after exposure to a variety of infectious organisms has proven highly effective at eliminating or decreasing infection intensity. Animals infected with Leishmania major (Sypek et al 1993, Heinzel et al 1993, Toxoplasma gondii (Gazzinelli et al 1993, Hunter et al 1995, Listeria monocytogenes (Wagner et al 1994), Cryptococcus neoformans (Clemons et al 1995), Plasmodium yoelii (Sedegah et al 1994), Mycobacterium tuberculosis (Cooper et al 1995), and Histoplasma capsulatum (Zhou et al 1995), have all benefitted from treatment with IL-12 if administered during the initial exposure to the pathogen. In our experiments however, IL-12 had little or no effect on immunity when administered alone.…”