Prevention of Allergen-Specific, Th2-Biased Immune Responses In Vivo: Role of Increased IL-12 and IL-18 Responsiveness

Abstract

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-γ results in markedly reduced induction of IgG2c responses following OA-POL treatment, but only IFN-γ−/− mice demonstrate reduced capacity to prevent IgE induction. This indicates that while both IL-12 and IFN-γ are critical promoters of type 1 immunity, only IFN-γ 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-12Rβ2, IL-18Rα, and IL-18Rβ mRNA levels, as well as increased IFN-γ 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.

Water-soluble polysaccharide obtained from Acorus calamus L. classically activates macrophages and stimulates Th1 response

“…Our data showing the suppression of the production of IgE and IgG1 by pectic polysaccharide PS may comply with the nowadays view that factors stimulating Th1 response inhibit, at least partially, Th2. Thus, it is known that IL-12 possesses to inhibit Th2 [66][67][68] and does not influence on IL-10 production [69,70]. Besides, during in vivo experiments, we discovered that PS reduces the production of IgE and IgG1, which indirectly signifies the reduction of the content of IL-4 [71], one of the most essential cytokines Th2.…”

Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function

“…The results showed that pulmonary DCs from OVA-sensitized and -challenged mice treated with MSCs showed reduced expression of CD40, CD80 and CD86 compared with those in the PBS-treated asthma group. It was recently shown that CD80/CD86 co-stimulation on DCs is necessary for differentiation of Th2 cells from naive T cells and for re-stimulation of effector Th2 cells in the lung (40,46,47). Thus, in the present study, MSC transplantation hampered DC maturation, leading to the reduced capacity of priming the naive T-cell response with concomitant reduced airway inflammation.…”

Lessons from ten years of genome‐wide association studies of asthma

“…The first five are located in the same asthma risk locus, and were first suspected to contribute to asthma pathophysiology because of GWAS findings. Of the remaining eight genes, for five it can be argued that functional studies provided the first suggestion of a key role in asthma/allergies, namely IL6R , 71 CHIT1 , 72 FCER1G , 73 IL18RAP 74 and NDFIP1 75 . But that is unlikely to be the case for the other three genes, SLC22A5 (organic cation transporter involved in pulmonary absorption of asthma-related drugs 76 , 77 ), WDR36 (nucleolar protein involved in processing of 18S rRNA 78 ) and HLA-DQA2 (HLA class II molecule expressed in epidermal Langerhans cells 79 ).…”