Inhibition of T helper 2‐type responses, IgE production and eosinophilia by synthetic lipopeptides

Abstract

In allergy and asthma, the fine balance between the T helper (Th) 1, Th2 and T regulatory cytokine responses appears to be shifted towards Th2. Here, we report that synthetic lipopeptides which contain the typical lipid part of the lipoprotein of gram-negative bacteria stimulate a distinct regulatory cytokine pattern and inhibit several Th2 cell-related phenomena. The most potent analogue of synthetic lipopeptides, lipopeptide CGP 40774 (LP40) was not active in MyD88-deficient mice and stimulated Toll-like receptor (TLR)-2, but not TLR-4. LP40 potentiated the production of IFN-+ and IL-10, but not IL-4 and IL-5 by human T cells. In addition, triggering of TLR-2 by lipopeptides promoted the in vitro differentiation of naive T cells towards IL-10-and IFN-+ -producing T cells and suppressed IL-4 production by Th2 cells. Accordingly, LP40 inhibited IgE production induced by allergen, anti-IgD antibody, Nippostrongylus brasiliensis or murine acquired immunodeficiency virus. Furthermore, ovalbumin-induced lung eosinophilic inflammation was abolished and Schistosoma mansoni egg-induced granuloma size and eosinophil counts were suppressed in mice by LP40. These results demonstrate that stimulation of TLR-2 by lipopeptides represents a novel way for possible treatment of allergy and asthma by regulating the disrupted cytokine balance.

A synthetic toll-like receptor 2 ligand decreases allergic immune responses in a mouse rhinitis model sensitized to mite allergen

“…Previous studies have evaluated the effect of TLR2 signaling on allergic diseases, but the results are conflicting. In our model, triggering of TLR2 with Pam3CSK4 showed a beneficial antiallergic effect on allergic rhinitis, which is consistent with several pre- vious studies (Akdis et al, 2003;Patel et al, 2005;Revets et al, 2005). The mechanism of its antiallergic effect is still elusive.…”

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

“…TLR9 agonists have also been shown to protect mice from colitis through induction of IFN-a production (Katakura et al, 2005). Furthermore, a synthetic lipopeptide agonist of TLR2 has been shown to stimulate IFN-g and IL-10 production, which had a regulatory role against Th2 type responses ( Akdis et al, 2003).…”

Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes

“…It is probable that use of appropriate adjuvants may increase the efficiency by specifically targeting tolerance-inducing dendritic cell subsets, and enable efficient priming of the memory T cell response before the exposure to native allergen [30,31]. Together the present study demonstrates a novel concept to be used as a preventive vaccine.…”