Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis.

Abstract

SummaryWhen administered at or near the initiation of experimental intracellular infection caused by Leishmania major, Toxoplasma gondii, or Cryptococcus neoformans, treatment with the immunoregulatory cytokine interleukin 12 (IL-12), induces protective antimicrobial activity. In contrast, once infections are established, IL-12 exerts considerably less or no effect in the face of a suppressive Th2 cell-associated response (L. major) or rapidly progressive fatal infection (T. gondii). To test the efficacy of IL-12 in an established intracellular protozoal infection but under quite different immunologic conditions (Thl cell response, acquired resistance), L. donovani-infected BALB/c mice were treated starting 2 wk after challenge coincident with the onset of the Thl cell response. In this environment, 7 d of IL-12 treatment reduced liver parasite burdens by 47%, an effect comparable to that induced by exogenous interferon (IFN) % The in vivo mechanism responsive to IL-12 was complex, and required both CD4 + and CD8 + T cells as well as natural killer cells and the action of multiple endogenous antileishmanial cytokines (IFN-% IL-2, tumor necrosis factor oe). Early treatment with IL-12 before the expression of the Thl cell response was also effective and induced an accelerated, near-cure response via an IFN-'lr-dependent mechanism. These results extend the antimicrobial-inducing capacity of IL-12 beyond prophylaxis by indicating that IL-12 can exert clear-cut therapeutic activity in an established intracellular infection.N 'umerous recent reports have identified the pleiotropic cytokine, IL-12, as a critical component of the early events that initiate successful cell-mediated antimicrobial defense (1-3). The role and/or effect of IL-12 has thus far been tested in four models of intraceUular infection caused by Le/shmania major (4,5), Toxoplasma gondii (6-8), Listeria monocytogenes (9), and Cyptococcus neoformans (10). Results from these models suggest that the role of endogenous IL-12 and the treatment effect of exogenous IL-12 are both most prominent at or near the time infection is first introduced (4, 5, 7). Indeed, when tested after the initial stage of host-parasite interaction in two of these models, IL-12 in exogenous form exerted considerably less activity in L. major infection (4, 5) and no effect in acute toxoplasmosis (7). These latter results have prompted the impression that while IL-12 appears to be of clear-cut immunoregulatory importance (1-3) and effective early on or as prophylaxis (4-7, 10), there may nevertheless be a narrow therapeutic window for IL-12 in such infections.Specific features of the preceding models of uncontrolled progressive infection (4, 5, 7), however, likely influenced the efficacy of delayed IL-12 treatment: (a) the rapid establishment of an overwhelming and uniformly fatal infection in the acute T gondii model (7), and (b) the prompt emergence of a particularly suppressive Th2 cell-assodated response which characterizes and propagates L. major infection in BALB/c mice (4...

RecombinantLeishmania majorSecreting Biologically Active Granulocyte-Macrophage Colony-Stimulating Factor Survives Poorly in Macrophages In Vitro and Delays Disease Development in Mice

“…It has also been shown that macrophages preincubated in vitro with cytokines prior to infection with Leishmania acquire the capacity to kill the intracellular parasites (21,29). Moreover, cytokines such as IFN-␥, tumor necrosis factor alpha (TNF-␣), IL-12 and granulocytemacrophage colony-stimulating factor (GM-CSF) have been used as antileishmanial therapy in experimental model systems (20,25,29,30,49,52). The role of proinflammatory cytokines in cell-mediated immunity in leishmaniasis has not been fully defined.…”

Induction of cell-mediated immunity during early stages of infection with intracellular protozoa

“…In addition, it is also known that treatment of resistant mice with neutralizing mA bs against either IL-12 or IFN-γ enhances animal susceptibility to infection with different Leishmania species (21,22,47,61,62).…”

Association study between polymorphism of interleukin 12B 1188A/C and hepatitis B virus infection in a Chinese Han population

“…A weak or absent hepatitis B core antigen (HBcAg)-specific IFN-γ production will lead to a disturbed secretory function of Th1 cells, which plays a significant role in immunopathogenesis of HBV infection. At the same time, IL-12 stands for an acknowledged inducer of IFN-γ secretion by Th1 cells [13,14]. Interleukin 12 is an effective immunostimulatory cytokine which was produced by antigen-presenting cells that not only can generate normal Th1 response, but also have the ability to induce IFN-γ secretion by T and natural killer cells) [15,16].…”