title: 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.
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.
authors.affiliation: Department of Immunology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Calcutta 700032, India.
authors.forename: Rajatava
authors.initials: R
authors.lastname: Basu
authors.forename: Suniti
authors.initials: S
authors.lastname: Bhaumik
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Haldar
authors.forename: Kshudiram
authors.initials: K
authors.lastname: Naskar
authors.forename: Tripti
authors.initials: T
authors.lastname: De
authors.forename: Syamal Kumar
authors.initials: SK
authors.lastname: Dana
authors.forename: Peter
authors.initials: P
authors.lastname: Walden
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
mesh_terms: D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D006822:Hybrid Cells / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology*; D054332:Leishmaniasis Vaccines / Q000276:immunology* / Q000627:therapeutic use; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D008099:Liver / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015800:Protozoan Proteins / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000469:parasitology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D007378:Interleukins; D054332:Leishmaniasis Vaccines; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; C090009:kinetoplastid membrane protein 11, Leishmania donovani