Emerging principles for the design of promiscuous HLA-DR-restricted peptides: an example from the major bee venom allergen

Texier, Catherine; Pouvelle‐Moratille, Sandra; Buhot, Cécile; Castelli, Florence; Pecquet, C.; Ménèz, Andre; Leynadier, F.; Maillère, Bernard

doi:10.1002/1521-4141(200212)32:12<3699::aid-immu3699>3.0.co;2-v

Cited by 11 publications

(12 citation statements)

References 41 publications

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“…Its recombinant form produced in Escherichia coli was found as allergenic as the wild-type molecule (Forster et al 1995) in contrast to the denatured protein or internal fragments Texier et al 2002). Therefore, IgE epitopes appear to be contained mainly in the polypeptide side chains (and not in the glycosylated moieties) and to be conformational .…”

Section: Discussionmentioning

confidence: 98%

“…As the B cell epitopes of Api m 1 were essentially of the conformational type Texier et al 2002), we investigated the secondary and tertiary structure of the molecules by CD and fluorescence spectroscopy. We observed that Api wt and Api mut shared a similar content of secondary structure (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies on allergic patients have shown that the two main stimulating regions are concentrated in the Cterminal half of this allergen (Carballido et al 1993;Kammerer et al 1997;Texier et al 2002) and correspond to regions rich in HLA-DR binding sequences: 76-106 and 111-134 (Texier et al 2000(Texier et al , 2001. Based on all the binding data, mutations were introduced outside the 76-106 and 116-134 regions.…”

Section: Discussionmentioning

confidence: 99%

“…Api mut shares with Api wt a common repertoire of specific T cells in BALB/c mice. In particular, these cells reacted with the peptide 81-98, which is a T cell epitope in humans (Carballido et al 1993;Kammerer et al 1997;Texier et al 2002).…”

Section: T Cell Reactivity Of Api Mutmentioning

confidence: 99%

“…Recognition by these antibodies is mainly dependent on the conformation of the allergen . A number of T cell epitopes from Api m 1 have been already delineated by proliferative cellular assays performed with PBMC from allergic patients (Carballido et al 1993;Kammerer et al 1997;Texier et al 2002). They appear to be localized mainly in the central and C-terminal parts of the molecule.…”

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confidence: 99%

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Alteration of the tertiary structure of the major bee venom allergen Api m 1 by multiple mutations is concomitant with low IgE reactivity

Buhot¹,

Chenal²,

Sanson³

et al. 2004

Protein Science

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We have engineered a recombinant form of the major bee venom allergen (Api m 1) with the final goal of reducing its IgE reactivity. This molecule (Api mut) contains 24 mutations and one deletion of 10 amino acids. The successive introduction of these sequence modifications led to a progressive loss of specific IgE and IgG reactivity and did not reveal any immunodominant epitopes. However, Api mut exhibited a clear loss of reactivity for Api m 1-specific IgE and IgG. Injection of Api mut into mice induced specific antibody production. This humoral response was as high as that induced by the Api m 1 but the cross-reactivity of the antibodies was weak. As inferred by far UV circular dichroism, this mutant was correctly folded. However, near UV circular dichroism and denaturation curves of Api mut showed that it exhibits a dynamic tertiary structure and that it is a highly flexible molecule. Finally, as all the sequence modifications have been introduced outside the human and murine T cell epitope regions, we investigated its T cell properties in mice. We showed that Api mut-specific T lymphocytes induced in vivo were stimulated in vitro by both proteins. These data provide new insights in the design of hypoallergenic molecules.Keywords: IgE; protein engineering; allergy; immunotherapy Specific immunotherapy is the only curative treatment of IgE mediated allergy. It is based on repeated injections of increasing doses of crude allergen extracts and exhibits variable efficacy. Crude allergen extracts have the major drawback of being highly allergenic. They present the risk of inducing severe anaphylactic side effects upon injection. Thus, there is a need for new molecules derived from allergens to perform safer immunotherapy. Recent advances in the understanding of immunotherapy have underlined the major role played by the allergen-specific CD4 + T lymphocytes in the control of the allergic response and the induction of tolerance (Akdis and Blaser 1999). These cells recognize the allergens as 13 to 25 amino acid peptides, called T cell epitopes. These peptides are produced by the degradation of the allergen in the antigen presenting cells and are presented by HLA Class II molecules to CD4 + T cells. Their injection in mice in saline buffer and by different routes (Briner et al. 1993;Burkhart et al. 1999;Sundstedt et al. 2003) leads to T cell tolerance as a result of IL-10 secretion by antigen-specific CD4 + T lymphocytes (Burkhart et al. 1999;Sundstedt et al. 2003).IL-10 is an immunosuppressive cytokine, which diminishes the T cell activation and IgE secretion by B lympho- Article published online ahead of print. Article and publication date are at

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: T Cell Reactivity Of Api Mutmentioning

confidence: 99%

mentioning

confidence: 99%

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Alteration of the tertiary structure of the major bee venom allergen Api m 1 by multiple mutations is concomitant with low IgE reactivity

Buhot¹,

Chenal²,

Sanson³

et al. 2004

Protein Science

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Selective identification of HLA-DP4 binding T cell epitopes encoded by the MAGE-A gene family

Wang

Cohen

Castelli

et al. 2006

Cancer Immunol Immunother

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Because of the high frequency of HLA-DP4 in the Caucasian population, we have selectively delineated HLA-DP4 restricted T cell epitopes in the MAGE-A tumor antigens. We identified 12 good binders to HLA-DP4 and investigated the capacity of the seven best binders to induce in vitro specific CD4+ T cell lines from HLA-DP4 healthy donors. We found that the MAGE-A1 90-104 peptide exhibited a high and constant frequency of CD4+ T cell precursors in all the six tested donors. The MAGE-A1 268-282 peptide was found immunogenic in only two donors but with a high precursor frequency. The MAGE-A12 127-141 peptide was T cell stimulating in six different donors and induced fewer T cell lines. The peptide-specific T cell lines were stimulated by DC loaded with the lysates of cells transfected with MAGE-A1 or MAGE-A12, or loaded with the recombinant protein. We also show that the immunoreactivity of CD4+ T cell epitopes restricted to the same HLA II molecule may vary from one individual to another, as a result of inter-individual variations in the CD4+ T cell repertoire.

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Immunotherapy of Allergic Disease

Valenta¹,

Ball²,

Focke³

et al. 2004

Advances in Immunology

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Emerging principles for the design of promiscuous HLA-DR-restricted peptides: an example from the major bee venom allergen

Cited by 11 publications

References 41 publications

Alteration of the tertiary structure of the major bee venom allergen Api m 1 by multiple mutations is concomitant with low IgE reactivity

Alteration of the tertiary structure of the major bee venom allergen Api m 1 by multiple mutations is concomitant with low IgE reactivity

Selective identification of HLA-DP4 binding T cell epitopes encoded by the MAGE-A gene family

Immunotherapy of Allergic Disease

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