Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt fur Sera und Impfstoffe) zu Frankfurt a.M最新文献

I discuss herein our efforts to identify biological markers of efficacy in support of the development of sublingual allergy vaccines. Biomarkers are of major interest to facilitate clinical development, for example by predicting safety and efficacy of candidate vaccines or their components (e.g. adjuvants and formulations) on the basis of immunogenicity evaluated in humans. They will be mandatory in the future to evaluate customized recombinant allergy vaccines designed upon component-resolved diagnosis. In this regard, they must ideally be both qualitative and quantitative. Such markers would also be useful to confirm foreseen mechanisms of action potentially associated with successful immunotherapy (e.g. the Treg hypothesis). The recent availability of sophisticated technologies (referred here as the technology push) to assess in details both humoral and cellular arms of the immune system provides new opportunities to identify such markers. In this regard, documenting natural immune responses, most particularly allergen-specific T cell responses in healthy persons, is critical to identify immunological correlates of protection, and thus to design optimal allergy vaccines.

Purpose of review: This review summarizes current knowledge regarding the control of human mast cell and basophil signaling and recent developments using a new therapeutic platform consisting of a human bifunctional gamma and epsilon heavy chain (Fcgamma-Fcepsilon) protein to inhibit allergic reactivity.

Recent findings: Crosslinking of FcgammaRIIb to FcepsilonRI on human mast cells and basophils by a genetically engineered Fcgamma-Fcepsilon protein (GE2) leads to the inhibition of mediator release upon FcepsilonRI challenge. GE2 protein was shown to inhibit cord blood-derived mast cell and peripheral blood basophil mediator release in vitro in a dose dependent fashion including inhibition of human IgE reactivity to cat. In addition, IgE-mediated release from lung tissue was inhibited through GE2. The mechanism of inhibition in mast cells included alterations in IgE-mediated Ca2+ mobilization, Syk phosphorylation and the formation of Dok-Grb2-SHIP complex. Proallergic effects of Langerhans-like dendritic cells and B cell IgE switching were also inhibited by GE2. In vivo, GE2 was shown to block passive cutaneous anaphylaxis (PCA) driven by human IgE in mice expressing the human FcepsilonRI and inhibit skin test reactivity to dust mite antigen in a dose dependent manner in rhesus monkeys. The balance between positive and negative signaling controls mast cell and basophil reactivity that is critical in the expression of human allergic diseases. This approach using a human Fcgamma-Fcepsilon fusion protein to co-aggregate FcepsilonRI with the FcgammaRII holds promise as a new therapeutic platform for the immunomodulation of allergic diseases and potentially other mast cell/basophil-dependent disease states.

The standardization of animal epithelia is warranted for an accurate diagnosis and safe and efficacious treatment of allergic respiratory diseases induced by the inhalation of mammalian aeroallergens. We have compared several sources of raw materials of cat, hamster, goat and rabbit hair and epithelia to establish differences between the protein and allergenic composition of these extracts. The main differences in these raw materials was that "epithelia" were supplied as a mixture of hair and epithelia previously treated with acetone, and that the hair was supplied and used untreated. A possible influence of the age of rabbits on the composition of rabbit hair extracts was also evaluated. Overall, important differences were detected in the composition of epithelia versus hair extracts. Epithelia extracts contained more irrelevant proteins and, in most cases, less amounts of major allergens. Important differences were also detected in the composition of the extracts prepared with hair of young versus adult animals. In general, the extracts derived from young animals contained less major allergen and more albumin than those derived from older animals. A greater effort should be made to identify the ideal sources of animal skin derived allergen extracts to provide the allergologists with better extracts for the diagnosis and treatment of allergic respiratory diseases. There is also a need for a consensus on the terminology applied to animal skin derived extracts. The use of the term dander extracts seems to be more appropriate. These extracts contain more relevant allergens and fewer albumins.

Since allergenicity and antigenicity (potency) are no longer equivalent, one must scientifically justify modifications and demonstrate (a) loss of allergenicity by standard methods, (b) potency with animal and clinical studies, as well as surrogate markers for clinical efficacy, and (c) biochemical and biologic stability.