title: Immunomodulation in human dendritic cells leads to induction of interferon-gamma production by Leishmania donovani derived KMP-11 antigen via activation of NF-κB in Indian kala-azar patients.
abstract: Dendritic cells (DCs) and macrophages (MΦs) 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 MΦs to T cells in Indian patients with VL. Patients with DCS and MΦs were directed against a purified Leishmania donovani antigen (KMP-11) and phytohaemagglutinin (PHA). The cytokines (IL-12, IL-10, and TGF-β) producing abilities of the DCs and MΦs against these antigens were determined by flow cytometry. The transcription factor (NF-κB) and T-cell cytokine support (IFN-γ, 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-β expression in the MΦs 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 MΦs of VL patients. In contrast, the presentation of KMP-11 antigen by DCs to T-lymphocytes in VL patients significantly increased the IFN-γ produced by these immune cells, whereas the levels of IL-10 were significantly elevated after presentation of KMP-11 antigen by MΦs. The VL patients were observed with severely dysfunctional MΦs in terms of NF-κB 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.
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chaudhary
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Amit
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Vikash
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Narayan
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Vidyanand
authors.initials: V
authors.lastname: Rabidas
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: K
authors.initials: K
authors.lastname: Pandey
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
authors.affiliation: Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India ; Division of Immunology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar 800007, India.
authors.forename: Sanjiva
authors.initials: S
authors.lastname: Bimal
mesh_terms: D000293:Adolescent; D000328:Adult; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D007893:Leishmania donovani / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000235:genetics* / Q000276:immunology / Q000469:parasitology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D015800:Protozoan Proteins; C090009:kinetoplastid membrane protein 11, Leishmania donovani; D007371:Interferon-gamma