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The mechanisms underlying successful immunotherapy are assumed to operate at the level of T helper cells, leading to a modulation of the immune response to allergens. During immunotherapy, increasing doses of allergens are given on a regular basis, and the beneficial effects for the patient depend on the concentration of allergen used. On the other hand, the risk of IgE\u2010mediated anaphylactic side effects also increase with the amount of allergen applied per injection. Therefore, we have proposed the use of hypoallergenic (low IgE binding activity) forms of allergens for immunotherapy. We evaluated by site\u2010directed mutagenesis the contributions of individual amino acid residues\/positions for IgE binding to Bet v 1, the major allergen of birch pollen. We found that IgE binding to Bet v 1 depended on at least six amino acid residues\/positions. Immunoblot analyses and inhibition experiments showed that the multiple\u2010point Bet v 1 mutant exhibited extremely low reactivity with serum IgE from birch pollen\u2010allergic patients. In vivo (skin prick) tests showed that the potency of the multiple\u2010point mutant to induce typical urticarial type I reactions in pollen\u2010allergic patients was significantly lower than for wild\u2010type Bet v 1. Proliferation assays of allergen\u2010specific T cell clones demonstrated that these six amino acid exchanges in the Bet v 1 sequence did not influence T cell recognition. Thus, the Bet v 1 six\u2010point mutant displayed significantly reduced IgE binding activity, but conserved T cell activating capacity, which is necessary for immunomodulation. The approach described here may be generally applied to produce allergen variants to be used in a safe therapy form of immediate\u2010type allergies.\u2014Ferreira, F., Ebner, C., Kramer, B., Casari, G., Briza, P., Kungl, A. J., Grimm, R., Jahn\u2010Schmid, B., Breiteneder, H., Kraft, D., Breitenbach, M., Rheinberger, H.\u2010J., Scheiner, O. Modulation of IgE reactivity of allergens by site\u2010directed mutagenesis: potential use of hypoallergenic variants for immunotherapy.\n                      <jats:italic>FASEB J.<\/jats:italic>\n                      12, 231\u2013242 (1998)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1096\/fasebj.12.2.231","type":"journal-article","created":{"date-parts":[[2018,1,25]],"date-time":"2018-01-25T04:36:15Z","timestamp":1516854975000},"page":"231-242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":206,"title":["Modulation of IgE reactivity of allergens by site\u2010directed mutagenesis: potential use of hypoallergenic variants for immunotherapy"],"prefix":"10.1096","volume":"12","author":[{"given":"F\u00e1tima","family":"Ferreira","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Genetik und Allgemeine Biologie, Universit\u00e4t, Salzburg Salzburg A\u20105020 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Ebner","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Allgemeine und Experimentelle Pathologie, Universit\u00e4t Wien Vienna A\u20101090 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Kramer","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Genetik und Allgemeine Biologie, Universit\u00e4t, Salzburg Salzburg A\u20105020 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Casari","sequence":"additional","affiliation":[{"name":"EMBL\u2010Heidelberg Heidelberg D\u201069012 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Briza","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Genetik und Allgemeine Biologie, Universit\u00e4t, Salzburg Salzburg A\u20105020 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas J.","family":"Kungl","sequence":"additional","affiliation":[{"name":"Novartis Forschungsinstitut A\u20101235 Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Grimm","sequence":"additional","affiliation":[{"name":"Hewlett\u2010Packard Analytical Group Waldbronn D\u201076337 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Jahn\u2010schmid","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Allgemeine und Experimentelle Pathologie, Universit\u00e4t Wien Vienna A\u20101090 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heimo","family":"Breiteneder","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Allgemeine und Experimentelle Pathologie, Universit\u00e4t Wien Vienna A\u20101090 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietrich","family":"Kraft","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Allgemeine und Experimentelle Pathologie, Universit\u00e4t Wien Vienna A\u20101090 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Breitenbach","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Genetik und Allgemeine Biologie, Universit\u00e4t, Salzburg Salzburg A\u20105020 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010j\u00f6rg","family":"Rheinberger","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Genetik und Allgemeine Biologie, Universit\u00e4t, Salzburg Salzburg A\u20105020 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Scheiner","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Allgemeine und Experimentelle Pathologie, Universit\u00e4t Wien Vienna A\u20101090 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[1998,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(89)90140-0"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90464-P"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.03.040185.001321"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/intimm\/1.5.479","article-title":"Structural analysis of a peptide\u2010HLA class II complex: identification of critical interactions for its formation and recognition by T cell receptor","volume":"1","author":"Rothbart J. 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