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\ud Not IL-4 or IL-13

摘要

There is an acute dearth of therapeutic interventions against visceral leishmaniasis that is required to\udrestore an established defective cell-mediated immune response. Hence, formulation of effective immunotherapy\udrequires the use of dominant antigen(s) targeted to elicit a specific antiparasitic cellular immune response.\udWe implemented hybrid cell vaccination therapy in Leishmania donovani-infected BALB/c mice by electrofusing\uddominant Leishmania antigen kinetoplastid membrane protein 11 (KMP-11)-transfected bone marrow-derived\udmacrophages from BALB/c mice with allogeneic bone marrow-derived dendritic cells from C57BL/6 mice.\udHybrid cell vaccine (HCV) cleared the splenic and hepatic parasite burden, eliciting KMP-11-specific major\udhistocompatibility complex class I-restricted CD8� cytotoxic T-lymphocyte (CTL) responses. Moreover, splenic\udlymphocytes of HCV-treated mice not only showed the enhancement of gamma interferon but also marked an\udelevated expression of the Th2 cytokines interleukin-4 (IL-4) and IL-13 at both transcriptional and translational\udlevels. On the other hand, IL-10 production from splenic T cells was markedly suppressed as a result\udof HCV therapy. CD8� T-cell depletion completely abrogated HCV-mediated immunity and the anti-KMP-11\udCTL response. Interestingly, CD8� T-cell depletion completely abrogated HCV-induced immunity, resulting in\uda marked increase of IL-10 but not of IL-4 and IL-13. The present study reports the first implementation of\udHCV immunotherapy in an infectious disease model, establishing strong antigen-specific CTL generation as a\udcorrelate of HCV-mediated antileishmanial immunity that is reversed by in vivo CD8� T-cell depletion of\udHCV-treated mice. Our findings might be extended to drug-nonresponsive visceral leishmaniasis patients, as\udwell as against multiple infectious diseases with pathogen-specific immunodominant antigens.