Zhu, D. et al. A chimeric human-cat fusion protein blocks cat-induced allergy. Nature Med. 11, 446-449

Department of Internal Medicine, Virginia Commonwealth University, Ричмонд, Virginia, United States
Nature Medicine (Impact Factor: 27.36). 05/2005; 11(4):446-9. DOI: 10.1038/nm1219
Source: PubMed


Animal allergens are an important cause of asthma and allergic rhinitis. We designed and tested a chimeric human-cat fusion protein composed of a truncated human IgG Fcgamma1 and the major cat allergen Fel d1, as a proof of concept for a new approach to allergy immunotherapy. This Fcgamma-Fel d1 protein induced dose-dependent inhibition of Fel d1-driven IgE-mediated histamine release from cat-allergic donors' basophils and sensitized human cord blood-derived mast cells. Such inhibition was associated with altered Syk and ERK signaling. The Fcgamma-Fel d1 protein also blocked in vivo reactivity in FcepsilonRIalpha transgenic mice passively sensitized with human IgE antibody to cat and in Balb/c mice actively sensitized against Fel d1. The Fcgamma-Fel d1 protein alone did not induce mediator release. Chimeric human Fcgamma-allergen fusion proteins may provide a new therapeutic platform for the immune-based therapy of allergic disease.

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Available from: Takechiyo Yamada, Oct 13, 2015
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    • "In another approach, the coaggregation of FcϵRI and FcγRII receptors that inhibit FcϵRI signaling and the fusion of allergens to human Fcγ have been reported to inhibit allergen-induced basophil and mast cell degranulation by crosslinking Fcγ and FcϵRI receptors [21,22]. In a different approach, the major cat allergen Fel d 1 was cloned and expressed together with a human immune deficiency virus protein, TAT-derived membrane translocation domain, and a truncated peptide of the invariant chain (modular antigen translocation (MAT)-Fel d 1) [42]. "
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    ABSTRACT: Allergen-specific immunotherapy (SIT) represents the only curative and specific way for the treatment of allergic diseases, which have reached a pandemic dimension in industrial countries affecting up to 20-30% of the population. Although applied for 100 years to cure allergy, SIT still faces several problems related to side effects and limited efficacy. Currently, allergen-SIT is performed with vaccines based on allergen extracts that can cause severe, often life threatening, anaphylactic reactions as well as new IgE sensitization to other allergens present in the extract. Low patient adherence and high costs due to long duration (3 to 5 years) of treatment have been commonly reported. Several strategies have been developed to tackle these issues and it became possible to produce recombinant allergen-SIT vaccines with reduced allergenic activity.
    World Allergy Organization Journal 09/2014; 7(1):23. DOI:10.1186/1939-4551-7-23
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    • "Total lavage cell numbers were evaluated using a hemocytometer. For different cell counts, cytospin preparations were made and stained with Wright-Giemsa, and differentiated into monocytes, eosinophils, lymphocytes, and neutrophils by standard morphology [28]. At least 300 cells of per cytospin preparation were counted at ×400 magnification under a light microscope (Leica, USA) and absolute numbers of every cell type were calculated. "
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    ABSTRACT: Hygiene hypothesis demonstrates that the lack of microbial exposure would promote the development of allergic airway disease (AAD). Therefore, the gut microbiota, including Escherichia coli (E. coli), would probably offer a potential strategy for AAD. To investigate whether E. coli infection is able to suppress the induction of AAD and to elucidate the underlying mechanisms. Nonpathogenic E. coli ATCC 25922 was infected by gavage before AAD phase in three patterns: 10(8) or 10(6) CFU in neonates or 10(8) CFU in adults. Then mice were sensitized and challenged with ovalbumin (OVA) to induce allergic inflammation in both the upper and lower airways. Hallmarks of AAD, in terms of eosinophil infiltration and goblet cell metaplasia in subepithelial mucosa, Th2 skewing of the immune response, and levels of T regulate cells (Tregs), were examined by histological analysis, ELISA, and flow cytometry, respectively. E. coli, especially neonatally infected with an optimal dose, attenuated allergic responses, including a decrease in nasal rubbing and sneezing, a reduction in eosinophil inflammation and goblet cell metaplasia in subepithelial mucosa, decreased serum levels of OVA-specific IgE, and reduced Th2 (IL-4) cytokines. In contrast, this effect came with an increase of Th1 (IFN-r and IL-2) cytokines, and an enhancement of IL-10-secreting Tregs in paratracheal lymph nodes (PTLN). E. coli suppresses allergic responses in mice, probably via a shift from Th1 to Th2 and/or induction of Tregs. Moreover, this infection is age- and dose-dependent, which may open up novel possibilities for new therapeutic interventions.
    PLoS ONE 03/2013; 8(3):e59174. DOI:10.1371/journal.pone.0059174 · 3.23 Impact Factor
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    • "Although this strategy used only T-cell epitope peptides, fusion proteins containing T-cell epitopes have also been used as immunogens for effective hyposensitization therapy of allergy. For example, T-cell epitopes fused with an invariant chain to promote the processing of epitope peptides into the MHC class II loading pathway [16], [17], and an allergen protein fused with an Fc region derived from immunoglobulin [18] for improved stability in the bloodstream, were used for vaccination. In order to produce such complicated artificial proteins containing T-cell epitopes to induce a more effective oral tolerance, the selection of host cells may be important in terms of proper protein folding and post-translation modifications such as glycosylation [19]. "
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    ABSTRACT: Peptide immunotherapy using T-cell epitopes is expected to be an effective treatment for allergic diseases such as Japanese cedar (Cryptomeria japonica; Cj) pollinosis. To develop a treatment for pollen allergy by inducing oral tolerance, we generated genetically manipulated (GM) chickens by retroviral gene transduction, to produce a fusion protein of chicken egg white lysozyme and a peptide derived from seven dominant human T-cell epitopes of Japanese cedar pollen allergens (cLys-7crp). The transgene sequence was detected in all chickens transduced with the retroviral vector. Transduction efficiency in blood cells correlated to transgene expression. Western blot analysis revealed that cLys-7crp was expressed in the egg white of GM hens. Mice induced to develop allergic rhinitis by Cj pollinosis were fed with cLys-7crp-containing egg white produced by GM chickens. Total and Cj allergen (Cry j 1)-specific IgE levels were significantly decreased in allergic mice fed with cLys-7crp-containing egg white compared with allergic mice fed with normal egg white. These results suggest that oral administration of T-cell epitope-containing egg white derived from GM chickens is effective for the induction of immune tolerance as an allergy therapy.
    PLoS ONE 10/2012; 7(10):e48512. DOI:10.1371/journal.pone.0048512 · 3.23 Impact Factor
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