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Supernatants (SN) from cloned T cell lines, lymphokine secreting tumour cell lines and mixed lymphocyte culture were analysed for their ability to induce murine peritoneal exudate cell (PEC) macrophages (MO) parasitized with Leishmania tropica to destroy the parasite. The ability of the SN to induce parasite destruction in parasitized PEC Mφ correlated with their content of macrophage activating factor/interferon. Neither granulocyte- macrophage colony stimulating factor. Mφ colony stimulating factor nor interleukin 2 was required for the induction of parasiticidal activity by infected PEC Mφ. Similar results were also obtained using either a different Leislmuinia species, Leishmania enriettii, or a second source of cells: bone marrow derived macrophages. [ABSTRACT FROM AUTHOR]

A Leishmania major–specific primary in vitro system that mimics the immune response of infected mice was used to determine the role that dendritic cells, B cells, and macrophages play in L. major T cell priming. Their relative priming potential (in order) was dendritic cells, B cells, and macrophages. Initiating primary in vitro responses with cell populations depleted of either B or dendritic cells modestly enhanced interferon (IFN)-γ production; deleting both cells markedly enhanced IFN-γ production. Thus, macrophages were the most effective cell for eliciting L. major Thl cells. The effects of exogenously added IFN-γ or neutralizing anti-IFN-γ were also studied. With cells from genetically susceptible BALB/c mice, IFN-γ inhibited proliferation and interleukin- 4 secretion by T cells, whereas with resistant C57BL/6 cells, IFN-γ enhanced IFN-γ secretion. These results could not be explained by differences in IFN-γ receptor expression. [ABSTRACT FROM PUBLISHER]

Bloodfeeding arthropods transmit many of the world's most serious infectious diseases. Leishmania are transmitted to their mammalian hosts when an infected sandfly probes in the skin for a bloodmeal and injects the parasite mixed with its saliva. Arthropod saliva contains molecules that affect blood flow and modulate the immune response of the host. Indeed, sandfly saliva markedly enhances the infectivity of L. major for its host. If the salivary molecule(s) responsible for this phenomenon was identified, it might be possible to vaccinate the host against this molecule and thereby protect the host against infection with Leishmania. Such an approach represents a novel means of controlling arthropod-borne disease transmission. Here, we report that a single molecule, maxadilan, in sandfly saliva can exacerbate infection with L. major to the same degree as whole saliva, and that vaccinating against maxadilan protects mice against infection with L. major.

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.

Levels of expression of costimulatory molecules have been proposed to influence the outcome of antigen-specific T cell priming. We found that Leishmania major selectively modulated the expression of costimulatory molecules on various populations of epidermal cells. B7.2 expression was down-regulated on Thy1.2+ epidermal cells (keratinocytes) from disease-resistant C3H mice, but not from disease-susceptible BALB/c mice. In addition, epidermal cells from BALB/c mice showed a down-regulation of B7.1 expression on NLDC 145+ Langerhans cells. In vitro T cell priming experiments, using syngeneic epidermal cells as antigen-presenting cells (APC), showed that the production of IFN-gamma was inhibited when either B7.1 or B7.2 signaling pathways were blocked. Blockade of B7.2, but not B7.1, significantly inhibited the ability of epidermal cells to induce IL-4 production from CD4+ T cells. In addition, C3H CD4+ T cells, which were unable to secrete detectable levels of IL-4 in cultures with syngeneic APC, were now able to secrete IL-4 following presentation of L. major antigens by congenic BALB/K epidermal cells. Conversely, C3H epidermal cells supported the priming of BALB/K CD4+ T cells for IL-4 production in vitro. Thus, the differential expression of B7 molecules on epidermal cells may not represent the sole factor governing the polarization of L. major-specific CD4+ T cells in vitro.