Bibliothek

Notizen: Interleukin (IL)-10, an immunomodulatory cytokine predominantly produced by monocytes/macrophages and T cells, inhibits several functions of dendritic cells (DC), monocytes and T cells including their cytokine production, but it stimulates B cell immunoglobulin (Ig) production and cytotoxic T lymphocyte (CTL) generation. A precise knowledge of the mechanisms that control the IL-10 production is therefore highly important for understanding the immunoregulation. The IL-10 production was studied in cultures of freshly isolated human T cells. A rise in intracellular calcium as well as the common γ-chain containing cytokine receptor triggering or CD28 triggering were found to be important signals for IL-10 induction. CD80, CD58, rIL-12 and rIFN-α all had efficacious and independent costimulatory activities on the IL-10 production, while PGE2 was inhibitory. Dependence on autocrine IL-2 signalling was shown by the effects of anti-IL-2 and anti-IL-2R monoclonal antibodies (MoAb), but the IL-10 production proceeded partly IL-2-independent when CD80 provided costimulation. Sensitivity to inhibition by CsA was not removed by CD80 or CD58 costimulation and/or by addition of rIL-12 or rIFN-α, pointing to the absolute requirement for calcineurin activity. These data reveal important differences in the regulatory pathways between IL-10 (a cytokine-inhibitory interleukin) and IL-2 (a cytokine-inducing interleukin), which can potentially be exploited therapeutically. The fact that CsA blocks the production of IL-10, which itself has important immunosuppressive properties, should be taken into account in defining immunosuppressive treatment schedules which include the use of CsA.

Notizen: Interaction of the CD40L (CD154) molecule on activated T cells with its receptor, CD40, on macrophages and dendritic cells (DC) provides a strong signal for interleukin (IL)-12 production. As IL-12 is the most important factor in driving Th precursor (Thp) cells into T(h)elper 1 cells, CD40–CD40L interactions strongly promote Th1 differentiation. Th2 cytokines (IL-4, IL-13, IL-10) on the other hand, are known to inhibit Th1 differentiation, and to promote either directly or indirectly, Th2 differentiation. Inhibition of lipopolysaccharide (LPS)-induced IL-12 production by IL-4, IL-13 and IL-10 is supposed to be one such mechanism. However, we here report that IL-4 and IL-13 enhance p70 IL-12 production and p40 mRNA transcription by human monocytes when the latter are stimulated trough triggering of CD40. This effect on IL-12 induction is most clear in the presence of interferon (IFN)-γ, which upregulates CD40 expression. IL-10 potently inhibits IL-12 production. The increased IL-12 production in the presence of IL-4 and IL-13 is however, not the indirect result of a reduction in IL-10 production, but is most likely owing to a direct effect of IL-4 and IL-13. We conclude that IL-4 and IL-13 enhance rather than decrease the IL-12 production by human monocytes during interaction with T cells. This effect can potentially contribute in vivo to switching of an ongoing Th2 response towards a Th1 response and the findings also support the dominant effect of CD40/CD40L interaction on Th1 development, even in the presence of Th2 cytokines.

Notizen: Background T-helper type 2 (Th2) cells play an important role in the pathogenesis of allergic diseases. Recent studies have demonstrated that allergen-specific T cells can also be found in the blood of healthy individuals. Both IL-10 and IFN-γ might modulate the induction and maintenance of allergen-specific tolerance.Aim To study the phenotype and functional characteristics of allergen-specific T cells in healthy non-atopic children.Methods Peripheral blood mononuclear cells (PBMC) from 13 symptomatic house dust mite (HDM)-allergic children and from nine matched healthy control children were stimulated with recombinant (r)Der p 2, a major allergen from HDMs.Results Stimulation with rDer p 2 resulted in Th2 cytokine production in cultures of PBMC from allergic but not from healthy children. In contrast, IL-10 and IFN-γ were induced in PBMC cultures from both healthy and HDM-allergic children. Intracellular staining revealed that IL-10 and IFN-γ are largely produced by the same T cells. Stimulation of T cells from healthy children with rDer p 2 also induced expression of inducible costimulator (ICOS) on a small T cell subset.Conclusion Allergen-specific memory T cells from healthy non-atopic children produce IL-10 and IFN-γ (but not Th2 cytokines) and express ICOS upon stimulation. These cells might be responsible for a normal immune balance after allergen encounter in non-atopics.

Notizen: Background T helper (Th)2 cells play an important role in the development of IgE-mediated diseases, with local overproduction of Th2 cytokines (IL-4, IL-5 and IL-13) at the site of allergic inflammation. Furthermore, IL-10 has been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in human atopic diseases.Aim We studied whether circulating allergen-specific Th2 cells persist outside the season of exposure in patients mono-sensitized to birch pollen and whether healthy control individuals also have allergen-specific Th2 cells. We also studied whether IL-10-producing allergen-specific T cells can be found in circulation either in healthy controls or in allergic patients.Methods Blood was drawn outside the birch-pollen season from 15 birch-pollen-allergic patients, with seasonal respiratory symptoms and with (n=12) or without (n=3) oral allergy syndrome, and from 10 matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with recombinant Bet v 1 allergen, control antigen tetanus toxoid (TT) and anti-CD3/CD80. In part of the cultures, rIL-4 was added in order to reinforce the allergen-specific Th2 cell responses.Results In the presence of rBet v 1, T cells from allergic patients, but not from healthy controls, produced IL-4, IL-5 and IL-13. IL-5 production by patients' T cells was further enhanced by adding more IL-4. In contrast, rBet v 1 together with IL-4-induced significant IL-10 production in control subjects but not in patients. Both Th1 and Th2 cytokines were equally induced by polyclonal stimulation in allergic patients and controls, but in the presence of IL-4, polyclonally induced IL-10 production was lower in the patient group.Conclusion rBet v 1-specific Th2 cells circulate outside the season of exposure in the blood of birch-pollen-allergic subjects but not in healthy controls. Allergen-specific T cells were also demonstrated in controls but these cells produce IL-10 when stimulated with rBet v 1 in the presence of IL-4. Our data reveal a different allergen-induced cytokine profile in birch-pollen-allergic patients vs. controls, and suggest that a regulatory mechanism involving IL-4-induced allergen-specific IL-10 production might be defective in allergic subjects.