In vivo IL-12 administration induces profound but transient commitment to T helper cell type 1-associated patterns of cytokine and antibody production.
There is much interest in the utility of exogenous IL-12 as a biologic adjuvant in immediate hypersensitivity and infectious or parasitic diseases where the induction of Th1 responses is strongly associated with protective immunity. Using an immediate hypersensitivity model in which C57Bl/6 mice immunized with OVA (alum) normally generate Th2-dominated responses, we examined the ability of rIL-12 to direct and maintain OVA-specific cytokine and Ab responses in a Th1 direction. Exogenous IL-12 administered coincident with OVA immunization stimulated elevated serum IFN-gamma levels, enhanced IFN-gamma synthesis, and inhibited IL-4 synthesis in bulk culture; 80 to 99% inhibited primary Ag-specific serum IgE and IgG1 responses; and 15- to 20-fold enhanced IgG2a synthesis. However, each of these effects was highly transient, as exogenous IL-12, given at levels up to those associated with serious toxicity, failed to have a lasting impact on the OVA-specific T or B cell response. This transience was evident in primary bulk culture cytokine synthesis; in limiting dilution analysis of the frequency of OVA-specific IFN-gamma-, IL-4-, or IL-10-producing CD4 T cells; and, most importantly, in vivo effector responses such as IgE production to secondary and tertiary OVA immunization. The finding that the intense Th1-like phenomena seen following in vivo administration of rIL-12 with this exogenous Ag are highly transient and are not associated with alterations in the allergen-specific CD4 T cell repertoire to Th1-like patterns suggests a need for caution in the enthusiasm for the use of this cytokine as a biologic adjuvant.
Rempel
J D
JD
Department of Immunology, University of Manitoba, Winnipeg, Canada.
Wang
M
M
HayGlass
K T
KT
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D007116:Immunization, Passive; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D018664:Interleukin-12 / Q000008:administration & dosage*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D000939:Epitopes; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin