Prevention of allergen-specific, Th2-biased immune responses in vivo: role of increased IL-12 and IL-18 responsiveness.
The factors that control development of adaptive responses to exogenous Ag remain incompletely understood. An ability to selectively direct immunity toward a specific phenotype would be of clinical benefit in numerous immunological disorders. Administration of chemically modified allergen glutaraldehyde-polymerized OVA (OA-POL) leads to >90% reductions in murine IgE and >500-fold increases in IgG2c responses that develop upon subsequent immunization with native Ag. In the present study, we examine the mechanisms underlying this reorientation of the type 2 dominant response that would normally develop. Lack of endogenous IL-12 or IFN-gamma results in markedly reduced induction of IgG2c responses following OA-POL treatment, but only IFN-gamma(-/-) mice demonstrate reduced capacity to prevent IgE induction. This indicates that while both IL-12 and IFN-gamma are critical promoters of type 1 immunity, only IFN-gamma is required to maximally inhibit development of type 2 immune responses. Compared with OVA-immunized mice, CD69(+) T cells from OA-POL-immunized mice demonstrate elevated IL-12Rbeta(2), IL-18Ralpha, and IL-18Rbeta mRNA levels, as well as increased IFN-gamma production in response to rIL-12 or rIL-18 stimulation. Collectively, these data indicate that preventing induction of type 2 immune responses is critically dependent on altered T cell responsiveness to these cytokines. The finding that targeted, Ag-specific manipulation of IL-12 and IL-18 responsiveness can be used to shape the phenotype of the dominant immune response that develops suggests that specifically targeting IL-12 and IL-18 receptor expression may offer clinical options for clinical prophylaxis or intervention.
Lewkowich
Ian P
IP
Department of Immunology, Canadian Institutes for Health Research National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada.
Rempel
Julia D
JD
HayGlass
Kent T
KT
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D007110:Immunity, Active / Q000235:genetics; D007111:Immunity, Cellular / Q000235:genetics; D007073:Immunoglobulin E / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000485:Allergens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D020382:Interleukin-18; D018664:Interleukin-12; D007073:Immunoglobulin E; D010047:Ovalbumin