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Hybrid Cell Vaccination Resolves Leishmania donovani Infection by Eliciting a Strong CD8⁺ Cytotoxic T-Lymphocyte Response with Concomitant Suppression of Interleukin-10 (IL-10) but Not IL-4 or IL-13

Author:
Basu, Rajatava, Bhaumik, Suniti, Haldar, Arun Kumar, Naskar, Kshudiram, De, Tripti, Dana, Syamal Kumar, Walden, Peter, Roy, Syamal
Source:
Infection and immunity 2007 v.75 no.12 pp. 5956-5966
ISSN:
0019-9567
Subject:
Leishmania donovani, antigens, antiparasitic agents, cell-mediated immunity, cytotoxic T-lymphocytes, dendritic cells, disease models, hybrids, infectious diseases, interferon-gamma, interleukin-10, interleukin-13, interleukin-4, macrophages, major histocompatibility complex, membrane proteins, mice, parasites, patients, transcription (genetics), vaccination, visceral leishmaniasis
Abstract:
There is an acute dearth of therapeutic interventions against visceral leishmaniasis that is required to restore an established defective cell-mediated immune response. Hence, formulation of effective immunotherapy requires the use of dominant antigen(s) targeted to elicit a specific antiparasitic cellular immune response. We implemented hybrid cell vaccination therapy in Leishmania donovani-infected BALB/c mice by electrofusing dominant Leishmania antigen kinetoplastid membrane protein 11 (KMP-11)-transfected bone marrow-derived macrophages from BALB/c mice with allogeneic bone marrow-derived dendritic cells from C57BL/6 mice. Hybrid cell vaccine (HCV) cleared the splenic and hepatic parasite burden, eliciting KMP-11-specific major histocompatibility complex class I-restricted CD8⁺ cytotoxic T-lymphocyte (CTL) responses. Moreover, splenic lymphocytes of HCV-treated mice not only showed the enhancement of gamma interferon but also marked an elevated expression of the Th2 cytokines interleukin-4 (IL-4) and IL-13 at both transcriptional and translational levels. On the other hand, IL-10 production from splenic T cells was markedly suppressed as a result of HCV therapy. CD8⁺ T-cell depletion completely abrogated HCV-mediated immunity and the anti-KMP-11 CTL response. Interestingly, CD8⁺ T-cell depletion completely abrogated HCV-induced immunity, resulting in a marked increase of IL-10 but not of IL-4 and IL-13. The present study reports the first implementation of HCV immunotherapy in an infectious disease model, establishing strong antigen-specific CTL generation as a correlate of HCV-mediated antileishmanial immunity that is reversed by in vivo CD8⁺ T-cell depletion of HCV-treated mice. Our findings might be extended to drug-nonresponsive visceral leishmaniasis patients, as well as against multiple infectious diseases with pathogen-specific immunodominant antigens.
Agid:
273261