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C M Hilkens

Publications and source records attributed to C M Hilkens.

24 records · Page 2Linked to original sources
PubMed1996

Production and modulation of T-cell cytokines in atopic allergy.

Atopic allergy is associated with allergen-specific CD4+ T cells showing a bias to production of the type-2 cytokines interleukin (IL)-4 and IL-5. There are indications that this bias is also evident in atopic T-helper (Th) cells with other antigen specificities. The balance between the production of type-1 and type-2 cytokines is influenced by various factors present in the microenvironment of the Th cells during their activation. Factors of special interest are antigen-presenting cell-derived IL-12 and prostaglandin E2, skewing to type-1 and type-2 cytokine production, respectively. The production of IL-12 and prostaglandin E2 is induced by the interaction between CD40 and CD40 ligand expressed by Th cells, and by biologically active agents such as micro-organisms or their products. The IL-12/prostaglandin E2 production ratio depends on the antigen-presenting cell type, the type of stimulus and the presence of certain cytokines. Other Th-cytokine-skewing factors are autocrine or paracrine IFN-gamma and IL-4. In fact, the type-1/type-2 cytokine production balance in Th cells is under the control of various soluble products that act in a complex network of type-1 (e.g. IL-12, IFN-gamma) or type-2 (e.g. IL-4, IL-10 and prostaglandin E2) factors and are produced by Th cells and their accessory antigen-presenting or bystander cells. The levels of these factors may further be determined by gene polymorphisms or aberrant hormone levels. Despite the growing knowledge of the regulation of Th-cell cytokine production, the etiology of biased cytokine production in atopic allergic individuals is still enigmatic.

Animals↗
PubMed1996

Modulation of T-cell cytokine secretion by accessory cell-derived products.

Several major pathological characteristics of atopic disease are causally related to CD4+ allergen-specific type 2 T-helper (Th2) cells with an aberrant cytokine secretion profile, comprising high levels of interleukin (IL)-4 and IL-5 and low levels of interferon (IFN)-gamma. Although the cytokine secretion patterns of CD4+ T-cells may be stable, they can be modulated by physiological factors which may be expected to be present during activation of these T-cells. In this review, we will focus on two secretion products of professional antigen presenting cells (APCs) and accessory cells with opposite modulatory effects on T-cell cytokine profiles, i.e. prostaglandin E2 (PGE2) and IL-12. PGE2 favours Th2-like cytokine secretion profiles by inhibiting the production of the Th1-associated cytokines, IL-2 and IFN-gamma, and in the presence of sufficient levels of IL-2, upregulating the production of the Th2-associated cytokines, IL-4 and IL-5, IL-12, on the other hand, induces and enhances IFN-gamma secretion in activated CD4+ T-cells, thereby promoting the generation of Th1 cells. PGE2 and IL-12 act via independent mechanisms and, therefore, do not mutually interfere with their modulatory effects. These data suggest that the relative contribution of PGE2 and IL-12 to the levels of secreted Th1- and Th2-associated cytokines are determined by their concentration ratio during T-cell activation.

Antigen Presentation↗
PubMed1995

Functional maturation of human naive T helper cells in the absence of accessory cells. Generation of IL-4-producing T helper cells does not require exogenous IL-4.

In the human model, requirements for the primary onset of IFN-gamma and IL-4 production in maturing T helper lymphocytes were compared. Stimulation of freshly isolated CD4+CD45RA+ naive Th cells with immobilized CD3 mAb in the presence of exogenous IL-2 resulted in the proliferative response of this subset, which was equal to or higher than CD4+CD45R0+ memory Th cells. Throughout the first 6 days after this mode of stimulation, naive Th cells did not secrete IL-4 and produced only small amounts of IFN-gamma, whereas high amounts of both lymphokines were secreted by stimulated autologous memory Th cells. Under these conditions, naive Th cells acquired the CD45RA-CD45R0+ memory phenotype. After restimulation, such in vitro-generated CD45R0+ cells produced high amounts of IFN-gamma but, despite the full phenotype conversion, they produced only trace amounts of IL-4. In contrast, when the primary stimulation and the expansion of cells proceeded in the presence of IL-1 beta or CD28 mAb, both IFN-gamma and IL-4 were produced after restimulation, in similar amounts compared with those produced by memory Th cells. The effect of IL-1 beta and CD28 signaling could not be obtained by the administration of exogenous IL-4 nor could the onset of IL-4 production be prevented by the presence of a neutralizing anti-IL-4 Ab in primary cultures. These data show that the development of human IL-4-producing Th cells can proceed in the absence of any pre-existing source of IL-4 and can be driven solely by the APC-related signals.

Antigen-Presenting Cells↗
PubMed1995

Differential modulation of T helper type 1 (Th1) and T helper type 2 (Th2) cytokine secretion by prostaglandin E2 critically depends on interleukin-2.

Prostaglandin E2 (PGE2) favors T helper type 2 (Th2)-like cytokine secretion profiles in murine and human CD4+ T cells by inhibiting the production of the Th1-associated cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and up-regulating the production of the Th2-associated cytokines IL-4 and IL-5 in a dose-dependent way. However, the potent inhibition of IL-2 production by PGE2 seems to be in contrast with the simultaneous up-regulation of IL-4 and IL-5 production, because the induction of these cytokines requires IL-2. We, therefore, investigated to which extent the net modulatory effect of PGE2 is determined by the availability of IL-2. To this aim, we examined the effects of PGE2 on the cytokine secretion profiles of a panel of human Th0 clones upon stimulation via different activation pathways, resulting either in high or low IL-2 production. The differential modulation of Th1 and Th2 cytokines by PGE2 was observed only upon modes of stimulation resulting in high IL-2 production. When IL-2 production was low, PGE2 inhibited the secretion of all four cytokines. These different modulation patterns were directly related to the IL-2 availability, because (i) neutralizing antibody to IL-2 abrogated the up-regulatory effect of PGE2 on IL-4 and IL-5 secretion in experiments with high endogenous IL-2 levels, (ii) lack of differential cytokine modulation by PGE2 in conditions with low levels of endogenous IL-2 could be restored with exogenous IL-2, and (iii) cell viability was comparable in all conditions. These results demonstrate that the net modulatory effect of PGE2 on the cytokine secretion profile of T cells critically depends on the availability of IL-2. Since this parameter varies with the experimental conditions and the T cell population studied, this finding may explain why certain immune responses may be either up- or down-regulated by PGE2 under different conditions.

Animals↗