Failure of rIL-12 administration to inhibit established IgE responses in vivo is associated with enhanced IL-4 synthesis by non-B/non-T cells.
Administration of rIL-12 offers a widely successful tactic for preferential induction of type 1 immune responses in vivo. Its use to modulate ongoing cytokine or effector responses has proven to be substantially more difficult. Immediate hypersensitivity is the most common human immunologic disease. Here, rIL-12 was administered to C57Bl/6 and outbred CD1 mice with ongoing ovalbumin (OVA)-specific IgE responses in an attempt to redirect established type 2 cytokine and antibody production. Despite use of a broad range of treatment protocols for >4 months following initial immunization, recall IgE responses were consistently unaffected. rIL-12-treated mice exhibited strong in vivo and in vitro IFN-gamma responses, increased approximately 40-fold relative to controls, but also markedly enhanced (15- to 20-fold) OVA-specific IL-4 production. CD4 T cell function was successfully transformed from a type 2- to a type 1-dominated pattern following long-term IL-12 administration in vivo, as measured by strongly reduced IL-4 and IL-10 responses in antigen-stimulated primary culture, and 5-fold reductions in the frequencies of IL-4- and IL-10-producing OVA-specific CD4 T cells. However, chronically rIL-12-treated mice exhibited increased numbers of non-B/non-T cells that when re-stimulated with specific allergen, produce IL-4 at levels 20-fold higher than did CD4 T cells while IL-13 responses are unaffected. Collectively, the data indicate that even effectively shifting CD4 T cell activation from a type 2- to a type 1-dominated response does not in itself lead to altered effector (IgE) responses upon antigen re-exposure.
Rempel
J D
JD
Department of Immunology, University of Manitoba, 626-730 William Avenue, Winnipeg, Manitoba R3E 0W3, Canada.
Wang
M D
MD
HayGlass
K T
KT
D000818:Animals; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000494:pharmacology*; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology
D007074:Immunoglobulin G; D018793:Interleukin-13; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin