Immunomodulation in human dendritic cells leads to induction of interferon-gamma production by Leishmania donovani derived KMP-11 antigen via activation of NF-[kappa]B in Indian kala-azar patients

Dendritic cells (DCs) and macrophages (M [Phi] s) are well-known antigen presenting cells with an ability to produce IL-12 which indicates that they have potential of directing acquired immunity toward a Th1-biased response. The aim of this study was to examine the effect of Leishmania specific KMP-11 antigen through comparison of immune responses after presentation by DCs and M [Phi] s to T cells in Indian patients with VL. Patients with DCS and M [Phi] s were directed against a purified Leishmania donovani antigen (KMP-11) and phytohaemagglutinin (PHA). The cytokines (IL-12, IL-10, and TGF- [beta] ) producing abilities of the DCs and M [Phi] s against these antigens were determined by flow cytometry. The transcription factor (NF- [kappa] B) and T-cell cytokine support (IFN- [gamma] , IL-10), which could be significant in effector immune function, were also determined. Severe hindrance in the immune protection due to Leishmania parasites, as revealed by decreased expression of IL-12 and upregulation of IL-10 and TGF- [beta] expression in the M [Phi] s compared to DCs, occurred in VL patients. The production of IL-12 in response to L. donovani KMP-11 antigen was increased in DCs which was reduced in M [Phi] s of VL patients. In contrast, the presentation of KMP-11 antigen by DCs to T-lymphocytes in VL patients significantly increased the IFN- [gamma] produced by these immune cells, whereas the levels of IL-10 were significantly elevated after presentation of KMP-11antigen by M [Phi] s. The VL patients were observed with severely dysfunctional M [Phi] s in terms of NF- [kappa] B activity that could be recovered only after stimulation of DCs with L. donovani KMP-11 antigen. Immunologically the better competitiveness of KMP-11 antigen through a dendritic cell delivery system may be used to revert T-cell anergy, and control strategy can be designed accordingly against kala-azar.