Leishmania major and Leishmania braziliensis both cause cutaneous leishmaniasis, but the former kills BALB/c mice while the latter is killed by the mice. This killing of L. braziliensis occurred by a gamma interferon-dependent mechanism, potentially made possible by the observed lack of high interleukin-4 production.

The importance of CD40, CD80, and CD86 costimulatory molecules in anti-Leishmania immune responses has been established in murine models. A role for these costimulatory molecules in human anti-Leishmania immune responses was investigated in this study. Autologous macrophages and peripheral blood leukocytes (PBL) were prepared from peripheral blood mononuclear cells of Leishmania-naive donors and cultured with or without Leishmania major in various combinations. After 7 days of culture, high levels of CD40 and CD86 were expressed on macrophages in the presence or absence of L. major. When macrophages were cultured for an additional 7 days with PBL, expression of all three costimulatory molecules was detected. When L. major was present in these cultures, the expression of CD80, and to a lesser extent CD40, on macrophages was enhanced. Blockade of CD80, CD86, or both molecules (in the order of greatest effect) in cultures containing macrophages, PBL, and L. major significantly inhibited the production of gamma interferon, interleukin-5 (IL-5), and IL-12. Blockade of CD40-CD154 interactions also significantly inhibited production of these cytokines in response to L. major. Production of IL-10 was unaltered by the blockade of these costimulatory molecules. Thus, these data suggest that CD40, CD80, and CD86 expression and regulation may significantly impact anti-Leishmania immune responses in humans. The outcome of experimental cutaneous infection withLeishmania major in mice is dependent on the strain of mouse and the predominating T-cell immune response that develops. Resistance is associated with Th1 responses and the appropriate production of interleukin-12 (IL-12) and gamma interferon (IFN-␥), leading to parasite destruction by macrophages (33,34,39,48). Susceptibility is associated with Th2 responses, early IL-4 production, IL-12 insensitivity, and a failure of IFN-␥-induced macrophage activation (7,24,29,30). Because costimulation of T cells by antigen-presenting cells (APCs; e.g., dendritic cells and macrophages) has been shown to influence the activation of T cells (18,20), the influence of costimulatory molecule expression in mice on their resistance to Leishmania infection has been investigated.Appropriate costimulation by CD40 may be essential for resistance in Leishmania-infected mice, but an essential role for B7 costimulation is in dispute. In CD40-or CD154-deficient mice, impaired production of IL-12 and IFN-␥ is observed along with an increased mortality rate following Leishmania infection (6,26,45). In contrast, in CD28-deficient strains of mice, both Leishmania-resistant and Leishmaniasusceptible phenotypes were maintained following infection (3), suggesting that B7-CD28 costimulation played a limited role. However, treatment of L. major-infected mice with CTLA-4Ig caused normally susceptible mice to develop protective Th1 responses (9), suggesting that B7 costimulation is essential for susceptibility. This inference was supported by results in the same study showing that CTLA-4Ig had no effect on t...

Since interleukin-6 (IL-6) may promote Th2 responses, we infected BALB IL-6-deficient (IL-6−/−) mice with Leishmania major. There was not a significant difference between the courses of infection (lesion size and parasite burden) in IL-6−/− and wild-type mice, but IL-6−/−mice expressed lower levels of Th2- and Th1-associated cytokines.

Acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can suppress adaptive immunity. In this study, pre-exposure of Leishmania major-infected mice to TCDD caused a dose-dependent and unexpected decrease in parasite burdens on day 20 after infection. In contrast, TCDD-mediated lymphoid atrophy, suppressed antibody levels, and enhanced interleukin-2 production were observed as expected. These results suggest that TCDD may enhance resistance to L. major in the face of immune suppression.

No abstract