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ABSTRACT: Type 2 diabetes is associated with microvascular damage that causes frequent infections in the skin and chronic ulcers due to impaired wound healing. To trace pathological changes, we performed a comprehensive analysis of lymphatic vessels in human skin of type 2 diabetic versus non-diabetic patients. The dermis revealed enhanced lymphatic vessel density, and transcriptional profiling of ex vivo isolated lymphatic endothelial cells (LECs) identified 180 genes differentially expressed between type 2 diabetic (dLECs) and non-diabetic (ndLECs) LECs. Bioinformatic analysis of deregulated genes uncovered sets functionally related to inflammation, lymphatic vessel remodelling, lymphangiogenesis and lipid and small molecule transport. Further, we traced CD68+ macrophage accumulation and concomitant upregulation of TNF-α levels in type 2 diabetic skin. TNF-α treatment of LECs and its specific blockade in vitro reproduced differential regulation of a gene set that led to enhanced LEC mobility and macrophage attachment, which was mediated by LEC-derived chemokine CXCL10. Our study identifies lymph vessel gene signatures directly correlated with type 2 diabetes skin manifestations. In addition, we provide evidence for a paracrine crosstalk fostering macrophage recruitment to LECs as one pathophysiological process that might contribute to aberrant lymphangiogenesis and persistent inflammation in the skin.
Diabetes 02/2013; · 8.29 Impact Factor
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Dontscho Kerjaschki,
Zsuzsanna Bago-Horvath,
Margaretha Rudas,
Veronika Sexl,
Christine Schneckenleithner,
Susanne Wolbank,
Gregor Bartel,
Sigurd Krieger,
Romana Kalt, Brigitte Hantusch, [......],
Wolfgang Mikulits,
Michael Gnant,
Satoshi Hirakawa,
Michael Detmar,
Kari Alitalo,
Sebastian Nijman,
Felix Offner,
Thorsten J Maier,
Dieter Steinhilber,
Georg Krupitza
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ABSTRACT: In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.
The Journal of clinical investigation 05/2011; 121(5):2000-12. · 15.39 Impact Factor
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Pamina Pflegerl,
Paul Vesely, Brigitte Hantusch,
Michaela Schlederer,
Rainer Zenz,
Elke Janig,
Günter Steiner,
Arabella Meixner,
Peter Petzelbauer,
Peter Wolf,
Afschin Soleiman,
Gerda Egger,
Richard Moriggl,
Tadamitsu Kishimoto,
Erwin F Wagner,
Lukas Kenner
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ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting various tissues. Involvement of B and T cells as well as increased cytokine levels have been associated with disease manifestation. Recently, we demonstrated that mice with epidermal loss of JunB (JunB(Deltaep)) develop a myeloproliferative syndrome (MPS) due to high levels of G-CSF which are secreted by JunB-deficient keratinocytes. In addition, we show that JunB(Deltaep) mice develop a SLE phenotype linked to increased epidermal interleukin 6 (IL-6) secretion. Intercrosses with IL-6-deficient mice could rescue the SLE phenotype. Furthermore, we show that JunB binds to the IL-6 promoter and transcriptionally suppresses IL-6. Facial skin biopsies of human SLE patients similarly revealed low JunB protein expression and high IL-6, activated Stat3, Socs-1, and Socs-3 levels within lupus lesions. Thus, keratinocyte-induced IL-6 secretion can cause SLE and systemic autoimmunity. Our results support trials to use alpha-IL-6 receptor antibody therapy for treatment of SLE.
Proceedings of the National Academy of Sciences 11/2009; 106(48):20423-8. · 9.68 Impact Factor
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ABSTRACT: Stammzellen verfügen über einige Eigenschaften, die sie als Hoffnungsträger für die molekulare Medizin ausweisen. Sie haben
die Fähigkeit der Selbstregeneration und der Differenzierung in spezialisierte Gewebe. Embryonale Stammzellen (ESZ) haben
eine große Potentialität, bergen aber auch ein hohes Tumorrisiko. Die Verwendung von humanen embryonalen Stammzellen (hESZ)
ist ethisch problematisch, da ihre Gewinnung die Zerstörung menschlicher Embryonen voraussetzt. Neuere Arbeiten bieten die
Möglichkeit einer ethisch unbedenklichen Herstellung von ESZ aus Fibroblasten. Alternativen zu ESZ sind adulte Stammzellen
(AS), wie z. B. Stammzellen aus Knochenmark, Fruchtwasser oder Nabelschnurblut. Der vorliegende Artikel basiert auf der Stellungnahme
von Lukas Kenner für die öffentliche Anhörung des Bildungs- und Forschungsausschusses des Deutschen Bundestages über den Einsatz
von Stammzellen in Forschung, Therapie und Wirkstoffentwicklung. Ethische Aspekte werden gewürdigt.
Stem cells with certain characteristics have become promising tools for molecular medicine. They have the potential to self-regenerate
and to differentiate into specific tissues. Besides their great potential, embryonic stem cells (ESC) run the risk of enhanced
tumorigenesis. The use of human embryonic stem cells (hESC) is ethically problematic because their isolation involves the
destruction of human embryos. Recently developed methods generate are able to pluripotent stem cells from fibroblasts. Alternatives
for ESC are adult stem cells (ASC) derived from bone marrow, cord blood, amniotic fluid and other tissues. The following article
is on the basis of testimony of Lukas Kenner for the German Bundestag about the use of ESC for research, therapy and drug
development. Ethical aspects are taken into consideration.
Wiener Medizinische Wochenschrift 08/2008; 158(17):493-502.
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ABSTRACT: Stem cells with certain characteristics have become promising tools for molecular medicine. They have the potential to self-regenerate and to differentiate into specific tissues. Besides their great potential, embryonic stem cells (ESC) run the risk of enhanced tumorigenesis. The use of human embryonic stem cells (hESC) is ethically problematic because their isolation involves the destruction of human embryos. Recently developed methods generate are able to pluripotent stem cells from fibroblasts. Alternatives for ESC are adult stem cells (ASC) derived from bone marrow, cord blood, amniotic fluid and other tissues. The following article is on the basis of testimony of Lukas Kenner for the German Bundestag about the use of ESC for research, therapy and drug development. Ethical aspects are taken into consideration.
Wiener Medizinische Wochenschrift 02/2008; 158(17-18):493-502.
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ABSTRACT: Cross-linking of IgE antibodies through allergens is a basic event in type I allergy and leads to the immediate release of mediators like histamine, responsible for allergic symptoms like rhino-conjunctivitis or asthma. Critical for the binding of allergens to IgE are the IgE-epitopes, which represent a congregation of several amino acid residues often derived from different regions of the allergen. By means of the mimotope-technology, we isolated peptides from phage libraries, which were able to structurally mimic IgE-epitopes of the plant allergens Bet v 1 (birch) and Phl p 5a (timothy grass). Hence, these are candidates for an epitope-specific immunotherapy. In this mode of immunotherapy, it is the aim to induce IgG antibodies directed exclusively against the IgE-epitopes of allergens without induction of anaphylactogenic IgG species, and without the risk of anaphylaxis through cross-linking of IgE. Immunizing mice, we applied the mimotopes displayed on bacteriophages as well as on alternative carrier systems to enhance their antigenicity. With these systems it was possible to elicit an allergen-specific immune response, which was also accompanied by the appropriate T-cell help. Mimotopes resemble a promising concept for an epitope-tailored immunotherapy of allergic patients.
Wiener Medizinische Wochenschrift 02/2008; 158(1-2):13-8.
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ABSTRACT: Cross-reactive carbohydrate determinants (CCDs) are probably the most widely occurring IgE epitopes. Approximately one fifth of patients with allergy develop IgE antibodies against such glycans. However, they appear to be of low clinical significance.
We wanted to elucidate the reasons for this lack of clinical symptoms on contact with CCD allergens by determination of the binding affinities of patients' IgE and IgG antibodies.
IgE and IgG against CCDs were affinity-purified from sera of selected patients. The binding affinity to defined glyco-epitopes was measured by surface plasmon resonance.
From a pool of CCD-positive sera, we isolated 0.1 and 25 microg CCD-specific IgE and IgG, respectively. The binding affinity of purified IgE antibodies to core alpha1,3-fucosylated glycans was in the 10(-10) mol/L range. The affinity was highest when both fucose and xylose were present, whereas xylosylation alone did not cause IgE binding. CCD-specific IgG exhibited a dissociation constant of approximately 10(-8) mol/L. IgG(4) amounted to only 20% of the CCD-specific IgG (as well as total IgG).
Low binding affinity of anti-CCD IgE cannot be the reason for the observed clinical insignificance of IgE against plant/insect glycan epitopes. Notably, the affinity of IgG to CCDs is higher than that to protein allergens, and it may therefore function as blocking antibody.
The Journal of allergy and clinical immunology 02/2008; 121(1):185-190.e2. · 9.17 Impact Factor
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ABSTRACT: Podoplanin is a membrane mucin that, among a series of tissues, is expressed on late osteoblasts and osteocytes. Since recent findings have focussed on podoplanin's potential role as a tumour progression factor, we aimed at identifying regulatory elements conferring PDPN promoter activity. Here, we characterized the molecular mechanism controlling basal PDPN transcription in human osteoblast-like MG63 versus Saos-2 cells.
We cloned and sequenced 2056 nucleotides from the 5'-flanking region of the PDPN gene and a computational search revealed that the TATA and CAAT box-lacking promoter possesses features of a growth-related gene, such as a GC-rich 5' region and the presence of multiple putative Sp1, AP-4 and NF-1 sites. Reporter gene assays demonstrated a functional promoter in MG63 cells exhibiting 30-fold more activity than in Saos-2 cells. In vitro DNase I footprinting revealed eight protected regions flanked by DNaseI hypersensitive sites within the region bp -728 to -39 present in MG63, but not in Saos-2 cells. Among these regions, mutation and supershift electrophoretic mobility shift assays (EMSA) identified four Sp1/Sp3 binding sites and two binding sites for yet unknown transcription factors. Deletion studies demonstrated the functional importance of two Sp1/Sp3 sites for PDPN promoter activity. Overexpression of Sp1 and Sp3 independently increased the stimulatory effect of the promoter and podoplanin mRNA levels in MG63 and Saos-2 cells. In SL2 cells, Sp3 functioned as a repressor, while Sp1 and Sp3 acted positively synergistic. Weak PDPN promoter activity of Saos-2 cells correlated with low Sp1/Sp3 nuclear levels, which was confirmed by Sp1/Sp3 chromatin immunoprecipitations in vivo. Moreover, methylation-sensitive Southern blot analyses and bisulfite sequencing detected strong methylation of CpG sites upstream of bp -464 in MG63 cells, but hypomethylation of these sites in Saos-2 cells. Concomitantly, treatment with the DNA methyltransferase inhibitor 5-azaCdR in combination with trichostatin A (TSA) downregulated podoplanin mRNA levels in MG63 cells, and region-specific in vitro methylation of the distal promoter suggested that DNA methylation rather enhanced than hindered PDPN transcription in both cell types.
These data establish that in human osteoblast-like MG63 cells, Sp1 and Sp3 stimulate basal PDPN transcription in a concerted, yet independent manner, whereas Saos-2 cells lack sufficient nuclear Sp protein amounts for transcriptional activation. Moreover, a highly methylated chromatin conformation of the distal promoter region confers cell-type specific podoplanin upregulation versus Saos-2 cells.
BMC Molecular Biology 02/2007; 8:20. · 2.86 Impact Factor
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Brigitte Hantusch,
Regina Knittelfelder,
Julia Wallmann,
Sigurd Krieger,
Krisztina Szalai,
Eva Untersmayr,
Monique Vogel,
Beda M Stadler,
Otto Scheiner,
George Boltz-Nitulescu,
Erika Jensen-Jarolim
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ABSTRACT: The role of anti-idiotypic antibodies in allergic disease is still poorly understood. According to Jerne, anti-idiotypic antibodies to IgE should represent internal images of an allergen. Our aim was to ultimately prove whether this hypothesis holds true in allergy. Here, we describe the selection of anti-idiotypic antibodies against Phl p 5a-specific IgE directly from the B-cell repertoire of a grass pollen allergic individual.
Taking Phleum pratense grass pollen allergen Phl p 5 as a model, we selected anti-idiotypic antibodies against allergen-specific IgE directly from the B-cell repertoire of an allergic individual. We screened a combinatorial phage display library of human monovalent antibody heavy and light chain fragments (Fabs) with anti-Phl p 5a-IgE to identify and characterize Fabs with anti-idiotypic specificity.
Five different Fab clones with anti-idiotypic specificity for anti-Phl p 5a-IgE were identified. Their hypervariable regions revealed partial sequence homology with solvent accessible antigenic sites of Phl p 5a, which have been identified by our previous mimotope approach. Phagemid DNA derived from the phage clones was used to produce two soluble recombinant anti-idiotypic Fab clones in E. coli. As a proof of molecular mimicry, both Fabs induced anti-Phl p 5a-specific antibodies in immunized BALB/c mice. Molecular modeling of the heavy and light chain hypervariable loops of the anti-idiotypic Fabs illustrated structural similarity with dominant IgE epitopes of Phl p 5a.
In this straightforward phage technology approach, antibodies with anti-idiotypic specificities could be isolated from a human allergic's repertoire. As predicted by the immune network hypothesis, their hypervariable domains mimic IgE epitopes like internal images and, more importantly, induce allergen-specific immune responses in the absence of the allergen.
Molecular Immunology 08/2006; 43(14):2180-7. · 2.90 Impact Factor
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ABSTRACT: The expression of podoplanin, a small mucin-like protein, is upregulated in the invasive front of a number of human carcinomas. We have investigated podoplanin function in cultured human breast cancer cells, in a mouse model of pancreatic beta cell carcinogenesis, and in human cancer biopsies. Our results indicate that podoplanin promotes tumor cell invasion in vitro and in vivo. Notably, the expression and subcellular localization of epithelial markers are unaltered, and mesenchymal markers are not induced in invasive podoplanin-expressing tumor cells. Rather, podoplanin induces collective cell migration by filopodia formation via the downregulation of the activities of small Rho family GTPases. In conclusion, podoplanin induces an alternative pathway of tumor cell invasion in the absence of epithelial-mesenchymal transition (EMT).
Cancer Cell 05/2006; 9(4):261-72. · 26.57 Impact Factor
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ABSTRACT: Xylosylated and core alpha1,3-fucosylated N-glycans from plants are immunogenic, and they play a still obscure role in allergy and in the field of plant-made protein pharmaceuticals. We immunized mice to generate monoclonal antibodies (mAbs) binding plant N-glycans specifically via the epitope containing either the xylose or the core alpha1,3-fucose residue. Splenocytes expressing N-glycan-specific antibodies derived from C57BL/6 mice previously immunized with plant glycoproteins were preselected by cell sorting to generate hybridoma lines producing specific antibodies. However, we obtained only mAbs unable to distinguish fucosylated from xylosylated N-glycans and reactive even with the pentasaccharide core Man3GlcNAc2. In contrast, immunization of rabbits yielded polyclonal sera selectively reactive with either fucosylated or xylosylated N-glycans. Purification of these sera using glyco-modified neoglycoproteins coupled to a chromatography matrix provided polyclonal sera suitable for affinity determination. Surface plasmon resonance measurements using sensor chips with immobilized glyco-modified transferrins revealed dissociation constants of around 10(-9) M. This unexpectedly high affinity of IgG antibodies toward carbohydrate epitopes has repercussions on our conception of the binding strength and significance of antiglycan IgE antibodies in allergy.
Glycobiology 05/2006; 16(4):349-57. · 3.58 Impact Factor
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Eva Untersmayr,
Krisztina Szalai,
Angelika B Riemer,
Wolfgang Hemmer,
Ines Swoboda, Brigitte Hantusch,
Isabella Schöll,
Susanne Spitzauer,
Otto Scheiner,
Reinhart Jarisch,
George Boltz-Nitulescu,
Erika Jensen-Jarolim
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ABSTRACT: Parvalbumin, the major fish allergen, is recognized by allergen-specific IgE of more than 90% of all fish-allergic patients. A detailed knowledge of allergenic structures is crucial for developing a vaccine inducing blocking antibodies specifically directed towards the IgE binding epitopes. In the present study we aimed to use the phage display technique to generate mimotopes, which mimic epitopes on parvalbumin. Parvalbumin-specific IgE was purified from sera of fish-allergic patients and used for screening of a constrained decamer phage library. After four rounds of biopanning using parvalbumin-specific IgE, five phage clones were selected which were specifically recognized by parvalbumin-specific IgE as well as IgG. DNA sequencing and peptide alignment revealed a high degree of sequence similarities between the mimotopes. Interestingly, on the surface of natural parvalbumin three regions could be defined by computational mimotope matching. In accordance, previously defined allergenic peptides of cod parvalbumin highlighted areas in close proximity or overlapping with the mimotope matching sites. From the presented data we conclude that our approach identified conformational epitopes of parvalbumin relevant for IgE and IgG binding. We suggest that these mimotopes are suitable candidates for an epitope-specific immunotherapy of fish-allergic patients.
Molecular Immunology 04/2006; 43(9):1454-61. · 2.90 Impact Factor
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Isabella Schöll,
Narayana Kalkura,
Yuliya Shedziankova,
Alexander Bergmann,
Petra Verdino,
Regina Knittelfelder,
Tamara Kopp, Brigitte Hantusch,
Christian Betzel,
Karsten Dierks,
Otto Scheiner,
George Boltz-Nitulescu,
Walter Keller,
Erika Jensen-Jarolim
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ABSTRACT: In type I allergy, the cross-linking of membrane IgE on B lymphocytes and of cytophilic IgE on effector cells by their respective allergens are key events. For cross-linking two IgE molecules, allergens need at least two epitopes. On large molecules, these could be different epitopes in a multivalent, or identical epitopes in a symmetrical, fashion. However, the availability of epitopes may be limited on small allergens such as Bet v 1, the major birch pollen allergen. The present work analyzes whether dimerization is required for the cross-linking capacity of this allergen. In immunoblots, murine monoclonal and polyclonal human Bet v 1-specific Abs detected, besides a Bet v 1 monomer of 17 kDa, a dimer of 34 kDa. In dynamic light scattering, Bet v 1 appeared as dimers and even multimers, but a single condition could be defined where it behaved exclusively monomerically. Small-angle x-ray scattering of the monomeric and dimeric samples resulted in diagrams agreeing with the calculated models. Circular dichroism measurements indicated that the structure of Bet v 1 was preserved under monomeric conditions. Skin tests in Bet v 1-allergic mice were positive with Bet v 1 dimer, but remained negative using the monomer. Furthermore, in contrast to dimeric Bet v 1, the monomer was less capable of activating murine memory B cells for IgE production in vivo. Our data indicate that the presentation of two identical epitopes by dimerized allergens is a precondition for cross-linking of IgE on mast cells and B lymphocytes.
The Journal of Immunology 12/2005; 175(10):6645-50. · 5.79 Impact Factor
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ABSTRACT: Size and posttranslational modifications are obstacles in the recombinant expression of high-molecular-weight melanoma-associated antigen (HMW-MAA). Creating a tumor antigen mimic via the phage display technology may be a means to overcome this problem for vaccine design. In this study, we aimed to generate an immunogenic epitope mimic of HMW-MAA. Therefore we screened a linear 9mer phage display peptide library, using the anti-HMW-MAA monoclonal antibody (mAb) 225.28S. This antibody mediates antibody-dependent cellular cytotoxicity (ADCC) and has already been used for anti-idiotype therapy trials. Fifteen peptides were selected by mAb 225.28S in the biopanning procedure. They share a consensus sequence, but show only partial homology to the amino acid sequence of the HMW-MAA core protein, indicating mimicry with a conformational epitope. One mimotope was chosen to be fused to albumin binding protein (ABP) as an immunogenic carrier. Immunoassays with 225.28S indicated that the mimotope fusion protein was folded correctly. Subsequently, the fusion protein was tested for immunogenicity in BALB/c mice. The induced anti-mimotope antibodies recognized HMW-MAA of 518A2 human melanoma cells, whereas sera of mice immunized with the carrier ABP alone showed no reactivity. These anti-mimotope antibodies were capable of inducing specific lysis of 518A2 melanoma cells in ADCC assays with murine effector cells. In conclusion, the presented data indicate that mimotopes fused to an immunogenic carrier are suitable tools to elicit epitope-specific anti-melanoma immune responses.
Cancer Immunology and Immunotherapy 08/2005; 54(7):677-84. · 3.70 Impact Factor
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ABSTRACT: Allergen-specific IgE and IgG antibodies coexist in allergic individuals, but only IgE has anaphylactogenic capacity. This study aimed to determine the association, dissociation and equilibrium constants for the interaction of allergen-specific IgE and IgG with the major grass and birch pollen allergens Phl p 5a and Bet v 1a. We isolated specific IgE and IgG antibodies from pollen allergic patients' sera by a two-step affinity chromatography protocol and controlled the high purity in a recombinant allergen chip microarray. Surface plasmon resonance measurements of polyclonal IgE and IgG species revealed that their affinities diverge widely, being in the range of 10(-10) and 10(-11) M for IgE, but only 10(-6)-10(-7) M for IgG. Moreover, murine monoclonal IgG1 antibodies against the allergens showed affinities of 10(-7)-10(-8) M. Thus, we conclude from our data that even stringently affinity matured IgG cannot score the superior affinity of IgE antibodies to allergens.
Immunology Letters 03/2005; 97(1):81-9. · 2.53 Impact Factor
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Brigitte Hantusch,
Sigurd Krieger,
Eva Untersmayr,
Isabella Schöll,
Regina Knittelfelder,
Sabine Flicker,
Susanne Spitzauer,
Rudolf Valenta,
George Boltz-Nitulescu,
Otto Scheiner,
Erika Jensen-Jarolim
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ABSTRACT: Phl p 5 represents a major allergen of timothy grass pollen (Phleum pratense). Detailed knowledge about the structures responsible for IgE binding would allow the design of a novel generation of allergy vaccines.
We aimed to characterize the IgE epitopes of Phl p 5a using phage display combined with a molecular modeling approach.
Phl p 5a-specific IgE from sera of patients with grass pollen allergy was used for screening of a random peptide phage library displaying constrained decamers.
Fifteen phage clones that shared sequence motifs and could be grouped into families were selected by using Phl p 5a-specific IgE. Peptide alignment with the solvent-accessible amino acids of Phl p 5a revealed 3 sequence sections with frequent hits of identical or similar amino acids. On the surface of Phl p 5a, these sections assembled in compact patches, most likely representing conformational IgE epitopes, whereas no matching clusters were found on the back sides of the 2 Phl p 5a halves. In surface plasmon resonance experiments, the high-affinity interaction between IgE and Phl p 5 could be competed by phage-displayed peptides up to 24%, indicating that they represent true epitope mimics (ie, mimotopes). Allergen-specific immunogenicity of the mimotopes was proved in Biozzi mice.
The selected mimotopes facilitated the localization of conformational IgE epitopes of Phl p 5. We suggest them to be suitable candidates for the development of an epitope-specific immunotherapy.
Journal of Allergy and Clinical Immunology 01/2005; 114(6):1294-300. · 11.00 Impact Factor
