A recombinant leishmania antigen that stimulates human peripheral blood mononuclear cells to express a th1-type cytokine profile and to produce interleukin 12

Abstract

Leishmania braziliensis causes cutaneous and mucosal leishmaniasis in humans. Most patients with cutaneous leishmaniasis heal spontaneously and may therefore have developed protective immunity. There appears to be a mixed cytokine profile associated with active cutaneous or mucosal disease, and a dominant T helper (Th)l-type response associated with healing. Leishmanial antigens that elicit these potent proliferative and cytokine responses from peripheral blood mononuclear cells (PBMC) are now being identified. Herein, we report on the cloning and expression of a L. braziliensis gene homologous to the eukaryotic ribosomal protein elF4A (LelF) and patient PBMC responses to rLelF. Patients with mucosal and self-healing cutaneous disease had significantly higher proliferative responses than those with cutaneous lesions. Whereas the parasite lysate stimulated patient PBMC to produce a mixed Thl/Th2-type cytokine profile, LelF stimulated the production of interferon ~/(IFN-3'), interleukin 2 (IL-2), and tumor necrosis factor ot but not IL-4 or IL-10. Recombinant 1.elF (rLelF) downregulated both IL-10 mlLNA in the "resting" PBMC of leishmaniasis patients and LPS-induced IL-10 production by patient PBMC. rLelF also stimulated the production of IL-12 in cultured PBMC from both patients and uninfected individuals. The production of IFN-3' by patient PBMC stimulated with either rLelF or parasite lysate was IL-12 dependent, whereas anti-IFN-3, monoclonal antibody only partially blocked the LelF-induced production of IL-12. In vitro production of both IFN-'y and IL-12 was abrogated by exogenous human recombinant IL-10. Therefore, we have identified a recombinant leishmanial antigen that elicits IL-12 production and Thl-type responses in patients as well as IL-12 production in normal human PBMC.