PubMed · 16157737
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2005-09-13. Immunotherapy.. https://pubmed.ncbi.nlm.nih.gov/16157737/
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Cyclophilins constitute a family of proteins involved in many essential cellular functions. They have also been identified as a panallergen family able to elicit IgE-mediated hypersensitivity reactions. Moreover, it has been shown that human cyclophilins are recognized by serum IgE from patients sensitized to environmental cyclophilins. IgE-mediated autoreactivity to self-antigens that have similarity to environmental allergens is often observed in atopic disorders. Therefore comparison of the crystal structure of human proteins with similarity to allergens should allow the identification of structural similarities to rationally explain autoreactivity. A new cyclophilin from Aspergillus fumigatus (Asp f 27) has been cloned, expressed and showed to exhibit cross-reactivity in vitro and in vivo. The three-dimensional structure of cyclophilin from the yeast Malassezia sympodialis (Mala s 6) has been determined at 1.5 A (1 A=0.1 nm) by X-ray diffraction. Crystals belong to space group P4(1)2(1)2 with unit cell dimensions of a=b=71.99 A and c=106.18 A. The structure was solved by molecular replacement using the structure of human cyclophilin A as the search model. The refined structure includes all 162 amino acids of Mala s 6, an active-site-bound Ala-Pro dipeptide and 173 water molecules, with a crystallographic R- and free R-factor of 14.3% and 14.9% respectively. The overall structure consists of an eight-stranded antiparallel beta-barrel and two alpha-helices covering the top and bottom of the barrel, typical for cyclophilins. We identified conserved solvent-exposed residues in the fungal and human structures that are potentially involved in the IgE-mediated cross-reactivity.
Our previous study has shown that the adoptive transfer of dendritic cells (DCs) freshly isolated from Chlamydia-infected mice (iIDCs), unlike those from control naive mice (iNDCs), can inhibit systemic and cutaneous eosinophilia induced by OVA exposure. In the present study, we examined the mechanism by which iIDC inhibits allergen-specific Th2 cell differentiation in vitro and in vivo. The study revealed that iIDCs exhibited higher surface expression of CD8alpha and the ICOS ligand (ICOS-L), as well as higher IL-10 and IL-12 production than iNDCs. In vitro DC:CD4(+) T cell coculture experiments showed that iIDCs could inhibit allergen-specific Th2 cell differentiation and that the inhibitory effect could be abolished by the blockage of IL-10 or IL-12 activity. More interestingly, the coblockade of IL-10 and the ICOS-L showed synergistic effect in enhancing allergen-driven Th2 cytokine production. Furthermore, adoptive transfer of iIDCs, but not iNDCs, to OVA sensitized mice significantly inhibited airway eosinophilia and mucus overproduction following intranasal challenge with OVA. Overall, the data demonstrate a critical role played by ICOS-L-expressing and IL-10-producing DCs from Chlamydia-infected mice in the infection-mediated inhibition of allergic responses.
OBJECTIVE: To investigate the effect of early exposure to allergen (ovalbumin, OVA) on rat asthmatic models. METHODS: Neonate rats were randomly divided into negative control group, asthmatic model group, low dose group and high dose group, with 8 in each. The rats of low dose group and high dose group were injected subcutaneously with 2 g/L OVA 0.1 mL and 10 g/L OVA 0.1 mL separately on the 1st day. OVA was given in asthmatic model group, low dose group and high dose group for allergization 6 weeks later and then asthmatic models were made. The pathologic changes of lung tissue, cell count and differentiation of bronchoalveolar lavage fluid (BALF) and serum interleukin-4 (IL-4), interferon-gamma (IFN-gamma), OVA-specific IgE and OVA-specific IgG were observed. RESULTS: The airway inflammation in both low dose group and high dose group was less severe than that in asthmatic model group. Total cell count of BALF and the ratio of eosinophil and neutrophil of both groups were decreased significantly compared with asthmatic model group. IL-4 and OVA-specific IgE were markedly decreased, while IFN-gamma was significantly increased in both low dose group and high dose group compared with asthmatic model group respectively. There was no significant difference in IL-4, IFN-gamma and OVA-specific IgE between high dose group and control group. The serum OVA-specific IgG was elevated significantly in asthmatic model group, low dose group and high dose group compared with control group, and it was higher in high dose group than in asthmatic model group. CONCLUSION: Early exposure to OVA after birth could inhibit the airway inflammation and OVA-specific IgE increasing induced by OVA in grown-up rats, and the mechanisms might be related to formation of immunology tolerance.