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-Mediated Susceptibility in Kala-azar and Post-kala-azar Dermal Leishmaniasis: The Significance of Amphotericin B in the Control of Leishmania donovani Infection in India1
* Infectious Disease and Immunology Division, Indian Institute of Chemical Biology, and
Department of Tropical Medicine, School of Tropical Medicine, Kolkata, India
Visceral leishmaniasis (VL) or kala-azar is known to be associated with a mixed Th1-Th2 response, and effective host defense requires the induction of IFN-
and IL-12. We address the role of the differential decline of IL-10 and TGF-
in response to sodium antimony gluconate (SAG) and amphotericin B (AmB), the therapeutic success of SAG and AmB in Indian VL, and the significance of IL-10 and TGF- in the development and progression of post-kazla-azar dermal leishmaniasis (PKDL). In the active disease, PBMC from VL patients showed suppressed Ag-specific lymphoproliferation, IFN- and IL-12 production, and elevation of IL-10 and TGF-. Cure corresponded with an elevation in IFN- and IL-12 production and down-regulation of IL-10 and TGF-. Both CD4+ and CD8+ T cells were involved in IFN- and IL-10 production. Interestingly, the retention and maintenance of residual IL-10 and TGF- in some SAG-treated individuals and the elevation of IL-10 and TGF- in PKDL, a sequel to kala-azar, probably reflects the role of these cytokines in reactivation of the disease in the form of PKDL. Contrastingly, AmB treatment of VL resulted in negligible TGF- levels and absolute elimination of IL-10, reflecting the better therapeutic activity of AmB and its probable role in the recent decline in PKDL occurrences in India. Moreover, elucidation of immune responses in Indian PKDL patients revealed a spectral pattern of disease progression where disease severity could be correlated inversely with lymphoproliferation and directly with TGF-, IL-10, and Ab production. In addition, the enhancement of CD4+CD25+ T cells in active VL, their decline at cure, and reactivation in PKDL suggest their probable immunosuppressive role in these disease forms.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Council for Scientific and Industrial Research, Department of Science and Technology, and University Grants Commission (UGC) grants. S.S. is a research fellow supported by UGC.
2 Current address of Rajesh Ravindran: Department of Medicine, Gastrointestinal (GI) Division and Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, McGuire Translational Research Facility, TRF DC 2873, 2001 Sixth Street Southeast, Minneapolis, MN 55455.
3 Address correspondence and reprint requests to Dr. Nahid Ali, Indian Institute of Chemical Biology, 4 Raja. Subodh Chandra Mullick Road, Kolkata, India. E-mail: nali{at}iicb.res.in
4 Abbreviations used in this paper: VL, visceral leishmaniasis; AmB, amphotericin B; CMI, cell-mediated immunity; DTH, delayed-type hypersensitivity; LAg, leishmanial membrane antigen; PKDL, post-kala-azar dermal leishmaniasis; SAG, sodium antimony gluconate; SI, stimulation index; Treg, regulatory T cell; wcSLA, whole cell soluble leishmanial Ag.
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