Gene gun-mediated delivery of an interleukin-12 expression plasmid protects against infections with the intracellular protozoan parasites Leishmania major and Trypanosoma cruzi in mice.
An interleukin-12 (IL-12) expression plasmid was transferred, using a gene gun, to mice infected with Leishmania major or Trypanosoma cruzi. Transfer of the IL-12 gene to susceptible BALB/c mice resulted in regression of lesion size and reduced the number of parasites in draining lymph nodes (LN) at the site of L. major infection. Coincident with these protective effects, the T-helper type (Th) response shifted towards Th1, as evaluated by cytokine production in vitro and L. major-specific antibody responses. Protective effects of the IL-12 gene were also observed in T. cruzi infection. Treatment of BALB/c mice infected with T. cruzi enhanced the production of interferon-gamma (IFN-gamma) by spleen cells, while suppressed production of interleukin-10 (IL-10) compared with control mice. Administration of anti-CD4 or anti-CD8 monoclonal antibody (mAb) abolished the protective immunity against T. cruzi infection, and treatment with the IL-12 gene could not restore the resistance in these mice. Mice depleted of natural killer (NK) cells with anti-asialo GM1 also became susceptible to infection, while the resistance was restored when these mice were treated with the IL-12 gene. Thus, target cells for the treatment appear to be CD4+ and CD8+ T cells, which are ordinarily activated by NK cells. These results suggest that the transfer of cytokine genes using a gene gun is an effective method for investigating the roles of cytokines and gene therapy in infectious diseases.
Sakai
T
T
Department of Parasitology and Immunology, University of Tokushima School of Medicine, Tokushima, Japan.
Hisaeda
H
H
Nakano
Y
Y
Ishikawa
H
H
Maekawa
Y
Y
Ishii
K
K
Nitta
Y
Y
Miyazaki
J
J
Himeno
K
K
D000818:Animals; D019470:Biolistics / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics*; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000008:administration & dosage; D018417:Th1 Cells / Q000276:immunology; D014349:Trypanosoma cruzi
D018664:Interleukin-12