title: Modulation of antiviral immune responses by exogenous cytokines: effects of tumour necrosis factor-alpha, interleukin-1 alpha, interleukin-2 and interferon-gamma on the immunogenicity of an inactivated rabies vaccine.
abstract: In vivo administration of exogenous cytokines may influence elicited immune responses, and hence may change the efficacy of a vaccine. We investigated the effects of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) on the immune response elicited by inactivated rabies virus vaccine in a mouse model. Each of the cytokines increased virus-specific IgG responses after primary and after secondary immunization. A single dose of 1.3 ng TNF-alpha or IL-1 alpha, when injected shortly before vaccination, only marginally stimulated resistance to challenge infection (four- and seven-fold, respectively) without enhancing virus neutralizing antibody (VNAb) responses. In contrast, a single injection of 10(3) units of IFN-gamma or five daily injections of 1.6 micrograms IL-2 increased vaccine dilutions protecting 50% of mice (PD50 values) 77- to 50-fold, respectively, with a concomitant enhancement of VNAb. At a 1:10,000 dilution of a standard inactivated rabies vaccine preparation both IFN-gamma and IL-2 increased protective immunity without enhancing VNAb responses; in non-vaccinated animals this treatment had no effect on resistance to challenge. Combined administration of IFN-gamma and IL-2 synergistically enhanced VNAb responses. In contrast to the other cytokines tested, IFN-gamma preferentially stimulated virus-specific IgG2a production. It also augmented the vaccine-induced priming of rabies virus-specific splenocyte proliferation. These results document that certain cytokines alone or in combination are potent immunological adjuvants which may direct and modulate immunization-induced antiviral immune responses.
authors.affiliation: Department of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, The Netherlands.
authors.forename: V E
authors.initials: VE
authors.lastname: Schijns
authors.forename: I J
authors.initials: IJ
authors.lastname: Claassen
authors.forename: A A
authors.initials: AA
authors.lastname: Vermeulen
authors.forename: M C
authors.initials: MC
authors.lastname: Horzinek
authors.forename: A D
authors.initials: AD
authors.lastname: Osterhaus
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D011819:Rabies Vaccines / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D007074:Immunoglobulin G; D007375:Interleukin-1; D007376:Interleukin-2; D011819:Rabies Vaccines; D014409:Tumor Necrosis Factor-alpha; D015164:Vaccines, Inactivated; D007371:Interferon-gamma