In the absence of CD154, administration of interleukin-12 restores Th1 responses but not protective immunity to Schistosoma mansoni.
The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154(-/-) mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154(-/-) mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154(-/-) mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154(-/-) mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154(-/-) mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c(+) cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154(-/-) mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.
Hewitson
James P
JP
Department of Biology (Area 5), University of York, York, United Kingdom.
Hamblin
Paul A
PA
Mountford
Adrian P
AP
D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood; D023201:CD40 Ligand / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D012550:Schistosoma mansoni / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity / Q000528:radiation effects; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage* / Q000276:immunology / Q000528:radiation effects
D000909:Antibodies, Helminth; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated; D023201:CD40 Ligand; D018664:Interleukin-12