RESOLUTION OF CUTANEOUS LEISHMANIASIS - INTERLEUKIN-12 INITIATES A PROTECTIVE T-HELPER TYPE-1 IMMUNE-RESPONSE

Resistance to Leishmania major in mice is associated with the appearan ce of distinct T helper type 1 (Th1) and Th2 subsets. T cells from lym ph nodes draining cutaneous lesions of resistant mice are primarily in terferon gamma (IFN-gamma)-producing Th1 cells. In contrast, T cells f rom susceptible mice are principally Th2 cells that generate interleuk in 4 (IL-4). Although existing evidence is supportive of a role for IF N-gamma in the generation of Th1 cells, additional factors may be requ ired 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, inclu ding inducing IFN-gamma production. Using an experimental leishmanial model we have observed that daily intraperitoneal administration at th e time of parasite challenge of either 0.33 mug IL-12 (a consecutive 5 d/wk for 5 wk) or 1.0 mug IL-12 per mouse (only a consecutive 5 d) ca used 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 po pliteal 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 adm inistration of a rabbit anti-recombinant murine IL-12 polyclonal antib ody (200 mug i.p. every other day for 25 d) at the time of infection t o resistant C57Bl/6 mice exacerbated disease. These effects were accom panied by a shift in IFN-gamma production in vitro by antigen-stimulat ed 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.