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Infection and Immunity, December 2007, p. 5956-5966, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00944-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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 ^,

Rajatava Basu,^1, Suniti Bhaumik,^1, Arun Kumar Haldar,¹ Kshudiram Naskar,¹ Tripti De,¹ Syamal Kumar Dana,³ Peter Walden,² and Syamal Roy^1*

Department of Immunology, Indian Institute of Chemical Biology, Jadavpur, Calcutta, WB, India,¹ Department of Dermatology and Allergy, Charite-Universitätsmedizin Berlin, Humboldt University, D-10098 Berlin, Germany,² Central Instrumentation Division, Indian Institute of Chemical Biology, Jadavpur, Calcutta, WB, India³

Received 11 July 2007/ Returned for modification 30 August 2007/ Accepted 20 September 2007

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.

Published ahead of print on 1 October 2007.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: W. A. Petri, Jr.

R.B. and S.B. contributed equally to this study.