{"id":247,"date":"2022-07-27T11:10:17","date_gmt":"2022-07-27T09:10:17","guid":{"rendered":"http:\/\/apitoxin.sk\/?p=247"},"modified":"2022-07-27T13:26:59","modified_gmt":"2022-07-27T11:26:59","slug":"alergia-na-jed-blanokridlovcov-ako-imunoterapia-jedom-zabranuje-anafylaxii-po-bodnuti-vcelou-a-osou","status":"publish","type":"post","link":"http:\/\/d.r5.wbsprt.com\/apitoxin.sk\/2022\/07\/27\/alergia-na-jed-blanokridlovcov-ako-imunoterapia-jedom-zabranuje-anafylaxii-po-bodnuti-vcelou-a-osou\/","title":{"rendered":"Alergia na jed blanokr\u00eddlovcov: Ako imunoterapia jedom zabra\u0148uje anafylaxii po bodnut\u00ed v\u010delou a osou?"},"content":{"rendered":"\n

1. Skupina pre imunomodul\u00e1ciu a toleranciu, Alergia a klinick\u00e1 imunol\u00f3gia Z\u00e1pal, oprava a v\u00fdvoj, N\u00e1rodn\u00fd in\u0161tit\u00fat srdca a p\u013e\u00fac, Imperial College London, Lond\u00fdn, Spojen\u00e9 kr\u00e1\u013eovstvo
2. Pediatrick\u00e9 oddelenie pre alergiu, Hacettepe University School of Medicine, Ankara, Turecko
3. MRC and Asthma UK Center in Alergic Mechanisms of Asthma, Lond\u00fdn, Spojen\u00e9 kr\u00e1\u013eovstvo<\/p>\n\n\n\n

U\u0161tipnutie blanokr\u00eddlym hmyzom m\u00f4\u017ee sp\u00f4sobi\u0165 lok\u00e1lne aj syst\u00e9mov\u00e9 alergick\u00e9 reakcie a dokonca aj \u017eivot ohrozuj\u00facu anafylaxiu. Spolu s farmaceutick\u00fdmi liekmi a potravinami je jed blanokr\u00eddlovcov jednou z naj\u010dastej\u0161\u00edch pr\u00ed\u010din anafylaxie u \u013eud\u00ed. Doteraz nebol identifikovan\u00fd \u017eiadny parameter, ktor\u00fd by mohol predpoveda\u0165, ktor\u00ed senzibilizovan\u00ed \u013eudia bud\u00fa ma\u0165 v bud\u00facnosti syst\u00e9mov\u00fa reakciu na bodnutie (SSR), s\u00fa v\u0161ak zn\u00e1me niektor\u00e9 rizikov\u00e9 faktory, ako je mastocyt\u00f3za a vek > 40 rokov. Imunoterapia jedom (VIT) je naj\u00fa\u010dinnej\u0161ou met\u00f3dou lie\u010dby \u013eud\u00ed s SSR, ktor\u00e1 sa ukazuje ako \u00fa\u010dinn\u00e1 aj po preru\u0161en\u00ed lie\u010dby. Rozvoj perif\u00e9rnej tolerancie je hlavn\u00fdm mechanizmom po\u010das imunoterapie. Je sprostredkovan\u00e1 produkciou blokuj\u00facich protil\u00e1tok IgG\/IgG4, ktor\u00e9 m\u00f4\u017eu inhibova\u0165 reakcie z\u00e1visl\u00e9 od IgE prostredn\u00edctvom receptorov IgE s vysokou afinitou (Fc\u03b5RI) aj s n\u00edzkou afinitou (Fc\u03b5RII) na \u017e\u00edrnych bunk\u00e1ch, bazofiloch a B bunk\u00e1ch. Generovanie antig\u00e9novo \u0161pecifick\u00fdch regula\u010dn\u00fdch T buniek produkuje IL-10 a potl\u00e1\u010da Th2 imunitu a imunitn\u00e9 reakcie sa pos\u00favaj\u00fa smerom k reakcii typu Th1. B regula\u010dn\u00e9 bunky sa tie\u017e podie\u013eaj\u00fa na produkcii IL-10 a rozvoji dlhodobej imunitnej tolerancie. Po\u010das VIT tie\u017e kles\u00e1 po\u010det efektorov\u00fdch buniek v cie\u013eov\u00fdch org\u00e1noch, ako s\u00fa \u017e\u00edrne bunky, bazofily, vroden\u00e9 lymfocyty 2. typu a eozinofily. Viacer\u00e9 metaanal\u00fdzy a randomizovan\u00e9 kontrolovan\u00e9 \u0161t\u00fadie preuk\u00e1zali, \u017ee VIT je \u00fa\u010dinn\u00e1 pri prevencii SSR pred bodnut\u00edm a zlep\u0161uje kvalitu \u017eivota. V tomto preh\u013eade sa diskutuje o riziku SSR pri alergii na jed a ako VIT zmenila toto riziko.<\/p>\n\n\n\n

\u00davod<\/strong>
Skupina hmyzu Hymenoptera zah\u0155\u0148a podskupiny Apidae a Vespidae a tie\u017e Formicidae, \u010do je nad r\u00e1mec tohto preh\u013eadu. Apidae pozost\u00e1va z druhov Apis mellifera (v\u010dely medonosn\u00e9) a \u010dmeliakov (\u010dmeliakov) a podtrieda Vespidae zah\u0155\u0148a druhy Vespula (\u201e\u017elt\u00e9 kab\u00e1tiky\u201c, osy a sr\u0161ne) a druhy Polistes (\u201epapierov\u00e9\u201c osy) (1, 2). U\u0161tipnutie v\u010delou nie je vo v\u0161eobecnosti silnej\u0161ie, ale vstrekuje viac jedu. V\u010dely vstrekn\u00fa 50 a\u017e 140 mikrogramov jedu, zatia\u013e \u010do osy dodaj\u00fa takmer 3 mikrogramy jedu s ka\u017ed\u00fdm bodnut\u00edm. V\u010dely m\u00f4\u017eu bodn\u00fa\u0165 raz, ale osy maj\u00fa schopnos\u0165 bodn\u00fa\u0165 viackr\u00e1t (1\u20133). Alergia na bodnutie hmyzom m\u00f4\u017ee sp\u00f4sobi\u0165 lok\u00e1lne, ve\u013ek\u00e9 lok\u00e1lne (>10 cm v priemere) alebo dokonca syst\u00e9mov\u00e9 reakcie (SR) a potenci\u00e1lne \u017eivot ohrozuj\u00face anafylaktick\u00e9 reakcie (4\u20136). Miera syst\u00e9mov\u00fdch reakci\u00ed na bodnutie v epidemiologick\u00fdch \u0161t\u00fadi\u00e1ch v Eur\u00f3pe sa pohybovala medzi 0,3 a 7,5 % u dospel\u00fdch (7) a 0,15 \u2013 3,4 % u det\u00ed (7, 8). Pravdepodobnos\u0165 SR a mo\u017enos\u0165 \u017eivot ohrozuj\u00facej anafylaxie s\u00favis\u00ed s mnoh\u00fdmi faktormi, vr\u00e1tane z\u00e1va\u017enosti predch\u00e1dzaj\u00facej reakcie, alergie na v\u010del\u00ed jed, hladiny z\u00e1kladnej s\u00e9rovej trypt\u00e1zy a pr\u00edtomnosti mastocyt\u00f3zy, zv\u00fd\u0161enej aktiv\u00e1cie bazofilov, veku a z\u00e1kladn\u00e9ho zdravotn\u00e9ho stavu. podmienky (7).<\/p>\n\n\n\n

Imunoterapia jedom (VIT) vedie ku kompletnej ochrane pred SSR v 77\u201384 % pr\u00edpadov v pr\u00edpade v\u010dely medonosnej a v 91\u201396 % v pr\u00edpade jedu vesieho (9\u201311). Frekvencia syst\u00e9mov\u00fdch ne\u017eiaducich \u00fa\u010dinkov po\u010das VIT sa pohybuje medzi 8 a 20 % z ve\u013ek\u00fdch multicentrick\u00fdch \u0161t\u00fadi\u00ed (12, 13). V ned\u00e1vnej \u0161t\u00fadii Stoevesandta a kol. miera syst\u00e9mov\u00fdch reakci\u00ed 11,7 % (ak\u00e9ko\u013evek reakcie vr\u00e1tane subjekt\u00edvnych) bola hl\u00e1sen\u00e1 po\u010das f\u00e1zy budovania VIT; miera SSR v\u0161ak klesla na 3 %, ke\u010f sa pou\u017eili objekt\u00edvne diagnostick\u00e9 krit\u00e9ri\u00e1 anafylaxie (14). Najd\u00f4le\u017eitej\u0161\u00edmi rizikov\u00fdmi faktormi s\u00favisiacimi so syst\u00e9mov\u00fdmi reakciami po\u010das VIT s\u00fa imunoterapia v\u010del\u00edm jedom, r\u00fdchle zv\u00fd\u0161enie d\u00e1vky po\u010das f\u00e1zy budovania a pravdepodobne vysok\u00e9 baz\u00e1lne hladiny trypt\u00e1zy pri alergii na veslopie, ale nie pri alergii na v\u010del\u00ed jed (9). Ochrann\u00fd \u00fa\u010dinok VIT pretrv\u00e1va roky po ukon\u010den\u00ed lie\u010dby. Dlhodob\u00fd v\u00fdsledok syst\u00e9mov\u00fdch reakci\u00ed po preru\u0161en\u00ed VIT je lep\u0161\u00ed u det\u00ed v porovnan\u00ed s dospel\u00fdmi a pre jed veschy v porovnan\u00ed s VIT v\u010dely (15\u201317).<\/p>\n\n\n\n

Cie\u013eom tohto preh\u013eadu je najprv diskutova\u0165 o epidemiol\u00f3gii a rizikov\u00fdch faktoroch anafylaxie hmyz\u00edm jedom, potom sa zameriava na mechanizmy VIT na prevenciu SSR po bodnut\u00ed hmyzom a nakoniec sa zameriava na diskusiu o \u00fa\u010dinnosti, bezpe\u010dnosti a dlhodob\u00fdch \u00fa\u010dinkoch VIT, ako aj o rizikov\u00fdch faktoroch. s\u00favisiace s SSR po\u010das a po VIT.<\/p>\n\n\n\n

Epidemiol\u00f3gia alergie na jed a alergick\u00fdch reakci\u00ed
<\/strong>Prevalencia bodnutia druhmi Hymenoptera po\u010das \u017eivota sa pohybuje od 56,6 do 94,5 % u dospel\u00fdch a 37,5 % u det\u00ed do 14 rokov (7, 8). Miera senzibiliz\u00e1cie, indikovan\u00e1 bu\u010f pozit\u00edvnym ko\u017en\u00fdm prick testom alebo \u0161pecifickou IgE pozitivitou, sa u dospel\u00fdch pohybuje medzi 9,3 a 28,7 %. V jednej \u0161t\u00fadii sa zistilo, \u017ee deti s\u00fa na 3,7 % pozit\u00edvne na druhy blanokr\u00eddlovcov (v\u00e4\u010d\u0161inou v\u010dely medonosn\u00e9) testovan\u00edm vpichom do ko\u017ee (18).<\/p>\n\n\n\n

Miera syst\u00e9mov\u00fdch reakci\u00ed na bodnutie v epidemiologick\u00fdch \u0161t\u00fadi\u00e1ch v Eur\u00f3pe sa pohybuje medzi 0,3 a 7,5 % u dospel\u00fdch (7). Medzi t\u00fdmito reakciami je frekvencia anafylaktick\u00e9ho \u0161oku medzi 0,6 a 42,8 % (18\u201323). Pod\u013ea ned\u00e1vneho pozi\u010dn\u00e9ho dokumentu u dospel\u00fdch sa respira\u010dn\u00e9 a kardiovaskul\u00e1rne sympt\u00f3my m\u00f4\u017eu vyskytn\u00fa\u0165 a\u017e v 70 % syst\u00e9mov\u00fdch reakci\u00ed (24). Tento \u0161irok\u00fd rozsah odzrkad\u013euje nedostato\u010dn\u00fd konsenzus o defin\u00edcii anafylaxie, rozdiely v technik\u00e1ch zberu \u00fadajov a variabilitu stup\u0148a vystavenia bodnutiu v r\u00f4znych klimatick\u00fdch podmienkach (7). U det\u00ed je prevalencia SR ove\u013ea ni\u017e\u0161ia a pohybuje sa od 0,15 do 3,4 % (7, 8). Okrem toho, SR u det\u00ed je pribli\u017ene 60 % miernych a obmedzen\u00fdch len na ko\u017eu (24).<\/p>\n\n\n\n

V\u010del\u00e1ri s\u00fa zranite\u013enou a vysoko rizikovou popul\u00e1ciou pre rozvoj alergick\u00fdch reakci\u00ed na u\u0161tipnutie v\u010delou. V tejto \u0161pecifickej skupine s\u00fa miery SR vy\u0161\u0161ie ako v be\u017enej popul\u00e1cii a pohybuj\u00fa sa od 14 do 38 % (25). Prijatie viac ako 200 \u017eihadiel za rok takmer \u00faplne chr\u00e1ni pred SR, zatia\u013e \u010do prijatie menej ako 25 \u017eihadiel za rok s\u00favis\u00ed s mierou SR 45 % (25). V prieskume britsk\u00fdch v\u010del\u00e1rov sa zistilo, \u017ee rizikov\u00e9 faktory pre SR s\u00fa \u017eensk\u00e9 pohlavie, pozit\u00edvna rodinn\u00e1 anamn\u00e9za alergie na v\u010del\u00ed jed, premedik\u00e1cia antihistaminikami pred n\u00e1v\u0161tevou \u00fa\u013ea a 2 a viac rokov v\u010del\u00e1renia pred prvou SR (26).<\/p>\n\n\n\n

Pod\u013ea Eur\u00f3pskej siete z\u00e1va\u017en\u00fdch alergick\u00fdch reakci\u00ed (NORA) bolo 20,2 % v\u0161etk\u00fdch pr\u00edpadov anafylaxie u det\u00ed a 48,2 % dokumentovanej anafylaxie u dospel\u00fdch sp\u00f4soben\u00fdch hmyz\u00edm jedom. V tejto \u0161t\u00fadii 59 terci\u00e1rnych centier pre alergiu, dermatol\u00f3giu a pediatriu z 10 r\u00f4znych kraj\u00edn hl\u00e1silo 3 333 pr\u00edpadov anafylaxie (27). Len 27,6 % pr\u00edpadov anafylaxie hmyzu dostalo adrenal\u00edn na mieste (27). V popula\u010dn\u00fdch \u0161t\u00fadi\u00e1ch uskuto\u010dnen\u00fdch po\u010das prvej dek\u00e1dy 21. storo\u010dia sa miera anafylaxie v d\u00f4sledku hmyzieho jedu pohybovala od 7,3 do 59 % a bola zisten\u00e1 v\u00e4\u010d\u0161inou u dospel\u00fdch (7).<\/p>\n\n\n\n

\u00damrtia na bodnutie hmyzom boli predt\u00fdm sk\u00faman\u00e9 v mnoh\u00fdch \u0161t\u00fadi\u00e1ch. \u0160t\u00fadia z Kostariky uv\u00e1dza 52 \u00famrt\u00ed za 22 rokov, \u010do predstavuje 0,74 \u00famrt\u00ed na mili\u00f3n obyvate\u013eov za rok (28), \u010do je ove\u013ea viac ako \u0161t\u00fadia z USA s po\u010dtom 0,14 \u00famrt\u00ed na mili\u00f3n obyvate\u013eov za rok (29). . Ned\u00e1vna spr\u00e1va zo Spojen\u00e9ho kr\u00e1\u013eovstva uv\u00e1dzala 93 \u00famrt\u00ed na anafylaxiu jedom medzi rokmi 1992 a 2012, \u010do predstavuje 0,09 \u00famrt\u00ed na mili\u00f3n obyvate\u013eov za rok (30). Najm\u00e4 predch\u00e1dzaj\u00faca anamn\u00e9za alergie na blanokr\u00eddlovce, mu\u017esk\u00e9 pohlavie, vy\u0161\u0161\u00ed vek a oneskoren\u00e9 pod\u00e1vanie adrenal\u00ednu s\u00fa d\u00f4le\u017eit\u00fdmi rizikov\u00fdmi faktormi pre fat\u00e1lne reakcie (31, 32).<\/p>\n\n\n\n

Rizikov\u00e9 faktory s\u00favisiace so SSR u\u0161tipnut\u00edm blanokr\u00eddlym hmyzom s\u00fa zhrnut\u00e9 v tabu\u013eke 1.<\/p>\n\n\n\n

\"\"
TABU\u013dKA 1. Rizikov\u00e9 faktory z\u00e1va\u017en\u00fdch syst\u00e9mov\u00fdch reakci\u00ed\/anafylaxie na bodnutie blanokr\u00eddlym hmyzom.<\/figcaption><\/figure>\n\n\n\n

Alergia na jed, poruchy aktiv\u00e1cie \u017e\u00edrnych buniek a anafylaxia
<\/strong>Mastocyt\u00f3za je klon\u00e1lna neoplastick\u00e1 porucha \u017e\u00edrnych buniek, ktor\u00e1 je charakterizovan\u00e1 predov\u0161etk\u00fdm ko\u017en\u00fdmi alebo syst\u00e9mov\u00fdmi podtypmi a niekedy zriedkav\u00fdmi formami. Mastocyt\u00f3za zvy\u010dajne zah\u0155\u0148a somatick\u00fa mut\u00e1ciu KIT D816V, vykazuje aberantn\u00fa expresiu CD25 alebo CD2 na \u017e\u00edrnych bunk\u00e1ch a je \u010dasto sprev\u00e1dzan\u00e1 zv\u00fd\u0161enou baz\u00e1lnou s\u00e9rovou trypt\u00e1zou (BST) (40). U pacientov s ko\u017enou mastocyt\u00f3zou sa agreg\u00e1ty mastocytov nach\u00e1dzaj\u00fa iba v ko\u017ei a t\u00e1to forma je v\u00e4\u010d\u0161inou diagnostikovan\u00e1 u doj\u010diat a det\u00ed (41). Syst\u00e9mov\u00e1 mastocyt\u00f3za (SM) sa \u010dasto vyskytuje u dospel\u00fdch a je rozdelen\u00e1 do \u0161tyroch podtypov (indolentn\u00e1 SM, SM spojen\u00e1 s hematologickou poruchou, agres\u00edvna SM a sark\u00f3m mastocytov); najbe\u017enej\u0161ou z nich je indolentn\u00e1 syst\u00e9mov\u00e1 mastocyt\u00f3za (ISM). ISM sa m\u00f4\u017ee prejavi\u0165 norm\u00e1lnym BST a nedostatkom ko\u017en\u00fdch l\u00e9zi\u00ed (42). Prevalencia mastocyt\u00f3zy u pacientov s alergiou na jed blanokr\u00eddleho hmyzu m\u00f4\u017ee by\u0165 a\u017e 7,9 %, \u010do je v\u00fdrazne viac ako u be\u017enej popul\u00e1cie (3\u201313\/100 000 obyvate\u013eov) (43, 44). Podobne bodnutie blanokr\u00eddlovcov je naj\u010dastej\u0161ou pr\u00ed\u010dinou anafylaxie u \u013eud\u00ed s mastocyt\u00f3zou a prevalencia je takmer 30 % (45). U zna\u010dn\u00e9ho po\u010dtu pacientov s ISM m\u00f4\u017ee by\u0165 anafylaxia jedu blanokr\u00eddlovcov (HVA) prv\u00fdm pr\u00edznakom ochorenia. T\u00edto pacienti s ISM bez ko\u017en\u00fdch l\u00e9zi\u00ed s\u00fa v\u00e4\u010d\u0161inou mu\u017ei s ni\u017e\u0161\u00edmi hladinami BST a ni\u017e\u0161ou frekvenciou mut\u00e1ci\u00ed KIT (46). Anafylaxia u pacientov s mastocyt\u00f3zou je v\u00e4\u010d\u0161inou charakterizovan\u00e1 srdcov\u00fdmi sympt\u00f3mami, ako je hypotenzia a synkop\u00e1lne epiz\u00f3dy, zatia\u013e \u010do ko\u017en\u00e9 sympt\u00f3my, ako je urtik\u00e1ria a angioed\u00e9m, s\u00fa zriedkav\u00e9. Preto, ak sa u pacienta s VHA vyskytne hypotenzia a synkopa bez ko\u017en\u00fdch sympt\u00f3mov, treba ma\u0165 podozrenie na mastocyt\u00f3zu (47). Ned\u00e1vno bol pre pr\u00edpady HVA vyvinut\u00fd syst\u00e9m hodnotenia s n\u00e1zvom REMA na z\u00e1klade pohlavia, klinick\u00fdch sympt\u00f3mov a BST na identifik\u00e1ciu pacientov s klon\u00e1lnym syst\u00e9mov\u00fdm ochoren\u00edm \u017e\u00edrnych buniek. Sk\u00f3re \u22652 nazna\u010duje, \u017ee ISM by sa malo vyl\u00fa\u010di\u0165 so senzitivitou 92 % a \u0161pecificitou 81 % (47).<\/p>\n\n\n\n

Presn\u00e9 mechanizmy zv\u00fd\u0161en\u00e9ho v\u00fdskytu HVA pri mastocyt\u00f3ze nie s\u00fa dobre pochopen\u00e9. Mo\u017en\u00e9 vysvetlenia tejto koexistencie s\u00fa v\u0161ak nasledovn\u00e9: (1) Zv\u00fd\u0161en\u00e1 z\u00e1\u0165a\u017e \u017e\u00edrnych buniek m\u00f4\u017ee vies\u0165 k vy\u0161\u0161iemu uvo\u013e\u0148ovaniu medi\u00e1tora v pr\u00edpade bodnutia; (2) Perivaskul\u00e1rne umiestnenie mastocytov m\u00f4\u017ee sp\u00f4sobi\u0165 priamy pr\u00edstup medi\u00e1torov do syst\u00e9mov\u00e9ho obehu, \u010do zvy\u0161uje z\u00e1va\u017enos\u0165 reakcie; (3) Zisk funk\u010dnej mut\u00e1cie, KIT D816V, m\u00f4\u017ee zabr\u00e1ni\u0165 apopt\u00f3ze \u017e\u00edrnych buniek a zv\u00fd\u0161i\u0165 prolifer\u00e1ciu a diferenci\u00e1ciu \u017e\u00edrnych buniek, a napokon (4) Fosfolip\u00e1za A2, zlo\u017eka jedu blanokr\u00eddlovcov, m\u00f4\u017ee sp\u00f4sobi\u0165 priame uvo\u013enenie medi\u00e1tora zo \u017e\u00edrnych buniek. (36).<\/p>\n\n\n\n

VIT sa jav\u00ed ako najvhodnej\u0161ia mo\u017enos\u0165 lie\u010dby u pacientov s mastocyt\u00f3zou a HVA. VIT je zvy\u010dajne dobre tolerovan\u00e1, bezpe\u010dn\u00e1 a \u00fa\u010dinn\u00e1. Zatia\u013e nie je jasn\u00e9, \u010di BST zvy\u0161uje riziko ne\u017eiaducich udalost\u00ed po\u010das VIT. Napriek preferencii celo\u017eivotnej VIT u pacientov s mastocyt\u00f3zou neexistuje v literat\u00fare d\u00f4kaz o celo\u017eivotnej lie\u010dbe. Pre istotu sa v\u0161ak odpor\u00fa\u010da, aby sa VIT pred\u013a\u017eila u pacientov so zv\u00fd\u0161enou SBT (>11,4 \u03bcg\/l) alebo overenou mastocyt\u00f3zou, ak bola po\u010diato\u010dn\u00e1 SSR z\u00e1va\u017en\u00e1 (9).<\/p>\n\n\n\n

Mechanizmy imunoterapie jedom
<\/strong>VIT je jedin\u00e1 \u00fa\u010dinn\u00e1 a imunomodula\u010dn\u00e1 lie\u010dba u pacientov s anamn\u00e9zou anafylaxie a preuk\u00e1zala sa ako \u00fa\u010dinn\u00e1 u 80 a\u017e 95 % pacientov s alergiou na v\u010del\u00ed jed a na vespulov\u00fd jed (9\u201311). Spo\u010diatku interakcia medzi alerg\u00e9nmi, epitelov\u00fdmi bunkami a dendritick\u00fdmi bunkami sp\u00fa\u0161\u0165a reakciu produkovan\u00fa vroden\u00fdm imunitn\u00fdm syst\u00e9mom a n\u00e1sledne sa vyv\u00edjaj\u00fa adapt\u00edvne imunitn\u00e9 reakcie. Na rozvoji perif\u00e9rnej imunitnej tolerancie a v sieti r\u00f4znych typov buniek sa podie\u013eaj\u00fa r\u00f4zne \u010dasti imunitn\u00e9ho syst\u00e9mu, a to bu\u010f priamo kontaktom medzi bunkami alebo uvo\u013e\u0148ovan\u00edm r\u00f4znych cytok\u00ednov a produkciou \u0161pecifick\u00fdch protil\u00e1tok (IgE, IgG1, IgG4, IgA ). \u010eal\u0161ie podrobnosti o mechanizmoch VIT s\u00fa zn\u00e1zornen\u00e9 na obr\u00e1zku 1.<\/p>\n\n\n\n

\"\"
OBR\u00c1ZOK 1. Mechanizmy imunoterapie jedom alerg\u00e9nu. Vysok\u00e1 d\u00e1vka jedu blanokr\u00eddlovcov stimuluje dendritick\u00e9 bunky a indukuje bunky Treg a B reg, ako aj \u010fal\u0161ie podskupiny B buniek, ktor\u00e9 produkuj\u00fa alerg\u00e9n \u0161pecifick\u00e9 blokuj\u00face protil\u00e1tky typu IgG1, IgG4 a IgA. Pri indukcii imunitnej tolerancie tie\u017e prebieha nieko\u013eko cytok\u00ednov a v d\u00f4sledku toho doch\u00e1dza k posunu imunitnej odch\u00fdlky typu Th2 na Th1. \u010cerven\u00e9 \u0161\u00edpky ukazuj\u00fa blokuj\u00facu aktivitu indukovan\u00fa po\u010das VIT. LTs, leukotri\u00e9ny; PG, prostagland\u00edny; iTreg, indukovate\u013en\u00e9 Tregula\u010dn\u00e9 bunky; nTreg, prirodzen\u00e9 T regula\u010dn\u00e9 bunky; Tfh, T folikul\u00e1rne heplerove bunky; Tfr, T folikul\u00e1rne regula\u010dn\u00e9 bunky; DC reg, regula\u010dn\u00e9 dendritick\u00e9 bunky; TSLP, Thymic stromal Lymphopoetin.g\/L) alebo overen\u00e1 mastocyt\u00f3za, ak bola po\u010diato\u010dn\u00e1 SSR z\u00e1va\u017en\u00e1 (9).<\/figcaption><\/figure>\n\n\n\n

Reakcie \u0161pecifick\u00fdch alerg\u00e9nov\u00fdch protil\u00e1tok
<\/strong>Spo\u010diatku subkut\u00e1nna VIT je spojen\u00e1 s prechodn\u00fdm skor\u00fdm zv\u00fd\u0161en\u00edm hlad\u00edn s\u00e9rov\u00fdch alerg\u00e9n \u0161pecifick\u00fdch IgE (sIgE) a potom nast\u00e1va pokles sIgE v priebehu nieko\u013ek\u00fdch rokov (48\u201350). AIT je tie\u017e spojen\u00e1 so zv\u00fd\u0161en\u00edm alerg\u00e9n-\u0161pecifick\u00fdch protil\u00e1tok IgA, IgG1 a IgG4, ktor\u00e9 sa naz\u00fdvaj\u00fa blokuj\u00face protil\u00e1tky (48, 51). \u0160t\u00fadie s aeroalerg\u00e9nmi uk\u00e1zali v\u00fdznamn\u00e9 zv\u00fd\u0161enie s\u00e9rov\u00fdch koncentr\u00e1ci\u00ed blokuj\u00facich protil\u00e1tok a\u017e 100-kr\u00e1t v z\u00e1vislosti od \u010dasu a d\u00e1vky (52\u201354). Produkcia blokuj\u00facich protil\u00e1tok, najm\u00e4 typu IgG4, m\u00f4\u017ee s\u00fa\u0165a\u017ei\u0165 s sIgE o alerg\u00e9n a zabr\u00e1ni\u0165 interakcii alerg\u00e9n-sIgE. Blokovanie interakci\u00ed alerg\u00e9n-sIgE zabra\u0148uje zosie\u0165ovaniu vysokoafinitn\u00fdch IgE receptorov (Fc\u03b5RI) na bazofiloch a mastocytoch, \u010do inhibuje degranul\u00e1ciu t\u00fdchto buniek a m\u00f4\u017ee zabr\u00e1ni\u0165 rozvoju anafylaxie (55, 56). Blokuj\u00face protil\u00e1tky, IgG\/IgG4, inhibuj\u00fa IgE-u\u013eah\u010den\u00fa prezent\u00e1ciu alerg\u00e9nu T bunk\u00e1m blokovan\u00edm n\u00edzkoafinitn\u00fdch receptorov (FcgRIIb) na B bunk\u00e1ch a zastavuj\u00fa alerg\u00e9nom indukovan\u00e9 zv\u00fd\u0161enie produkcie pam\u00e4\u0165ov\u00fdch IgE (54, 57, 58). Jeden z hlavn\u00fdch cytok\u00ednov produkovan\u00fdch T regs, IL-10, sa nielen podie\u013ea na supresii alerg\u00e9n-\u0161pecifick\u00fdch T efektorov\u00fdch buniek po\u010das AIT, ale tie\u017e inhibuje produkciu celkov\u00e9ho IgE a \u0161pecifick\u00e9ho IgE, pri\u010dom zvy\u0161uje hladiny IgG4 (59 , 60). U nealergick\u00fdch v\u010del\u00e1rov s\u00fa s\u00e9rov\u00e9 \u200b\u200bkoncentr\u00e1cie IgG4 takmer tis\u00edckr\u00e1t vy\u0161\u0161ie ako s\u00e9rov\u00e9 \u200b\u200b\u0161pecifick\u00e9 hladiny IgE. Koncentr\u00e1cie IgG4 v s\u00e9re \u00fazko koreluj\u00fa s po\u010dtom bodnut\u00ed za rok a \u010dasom str\u00e1ven\u00fdm vo v\u010del\u00e1rstve (31, 61). Na zvieracom modeli alergie na v\u010del\u00ed jed bol hlavn\u00fd alerg\u00e9n na v\u010del\u00ed jed PLA2 injikovan\u00fd do inguin\u00e1lnych lymfatick\u00fdch uzl\u00edn a bola pozorovan\u00e1 alerg\u00e9n-\u0161pecifick\u00e1 IgG odpove\u010f s produkciou IgG2a (62). V \u010fal\u0161ej \u0161t\u00fadii peptidovej VIT sa zistilo zn\u00ed\u017eenie alerg\u00e9n-\u0161pecifick\u00e9ho IgE a zv\u00fd\u0161enie \u0161pecifick\u00e9ho IgG2a, pri\u010dom obe mali prevent\u00edvnu funkciu proti alerg\u00e9nom indukovanej anafylaxii (63).<\/p>\n\n\n\n

Po ukon\u010den\u00ed AIT pre alergiu na tr\u00e1vov\u00fd pe\u013e sa uk\u00e1zalo, \u017ee blokuj\u00face hladiny IgG\/IgG4 sa v priebehu 1 roka zn\u00ed\u017eili takmer o 80\u201390 %. Na rozdiel od toho, s\u00e9rov\u00e1 inhibi\u010dn\u00e1 aktivita IgE spojen\u00e1 s IgG pretrv\u00e1vala nieko\u013eko rokov a korelovala s klinickou \u00fa\u010dinnos\u0165ou (64). To nazna\u010duje, \u017ee presnej\u0161\u00edm meradlom klinickej \u00fa\u010dinnosti m\u00f4\u017ee by\u0165 sk\u00f4r funk\u010dn\u00e1 aktivita blokuj\u00facich protil\u00e1tok ne\u017e ich hladiny a zd\u00e1 sa, \u017ee \u00fazko koreluje s dlhodobou imunitnou toleranciou (54). To v\u0161ak nemus\u00ed plati\u0165 pre imunoterapiu v\u010del\u00edm jedom, kde hoci bola \u00faspe\u0161n\u00e1 desenzibiliz\u00e1cia sprev\u00e1dzan\u00e1 zv\u00fd\u0161en\u00edm inhibi\u010dnej aktivity IgG4 aj IgE, zv\u00fd\u0161en\u00e9 \u0161pecifick\u00e9 hladiny IgG4 aj inhibi\u010dn\u00e1 aktivita IgE-FAB sa vr\u00e1tili na z\u00e1kladn\u00fa hodnotu v priebehu mesiacov po preru\u0161en\u00ed lie\u010dby VIT a \u010fal\u0161ie sledovanie odhalili trvalej\u0161\u00ed pokles hlad\u00edn IgE \u0161pecifick\u00fdch pre jed (65), \u010do predstavuje predpokladan\u00fd alternat\u00edvny mechanizmus pred\u013a\u017eenej ochrany po vysaden\u00ed IgG. Podporuje to aj pozorovanie n\u00edzkych\/nepr\u00edtomn\u00fdch hlad\u00edn IgE u tolerantn\u00fdch v\u010del\u00e1rov (66).<\/p>\n\n\n\n

Odpovede efektorov\u00fdch buniek
<\/strong>VIT prejavuje svoje p\u00f4sobenie prostredn\u00edctvom komplexn\u00fdch imunologick\u00fdch mechanizmov. Po\u010diato\u010dn\u00fd mechanizmus \u00fa\u010dinku pozorovan\u00fd na efektorov\u00fdch bunk\u00e1ch je desenzibiliz\u00e1cia \u017e\u00edrnych buniek a bazofilov (9). Po\u010det t\u00fdchto buniek sa po\u010das imunoterapie jedom zni\u017euje a navy\u0161e ich prahy uvo\u013e\u0148ovania cytok\u00ednov sa \u010dasom zvy\u0161uj\u00fa. Po\u010das r\u00fdchlej VIT na za\u010diatku lie\u010dby doch\u00e1dza k poklesu po\u010dtu bazofilov v perif\u00e9rnej krvi a tie\u017e k zn\u00ed\u017eeniu produkcie a uvo\u013e\u0148ovania cytok\u00ednov odvoden\u00fdch od bazofilov, ako s\u00fa IL-4 a IL-13 (67). Baz\u00e1lna hladina trypt\u00e1zy v s\u00e9re, ktor\u00e1 je markerom z\u00e1\u0165a\u017ee \u017e\u00edrnych buniek a funkcie \u017e\u00edrnych buniek, sa v priebehu VIT \u010dasom zni\u017euje (68). U pacientov s VIT sa u\u017e predt\u00fdm preuk\u00e1zala supresia povrchov\u00fdch antig\u00e9nov na krvn\u00fdch bazofiloch (69). Okrem zmien pozorovan\u00fdch v bazofiln\u00fdch povrchov\u00fdch antig\u00e9noch sa u pacientov s VIT zn\u00ed\u017eilo aj mno\u017estvo histam\u00ednu uvo\u013enen\u00e9ho z bazofilov po stimul\u00e1cii bodnut\u00edm v z\u00e1vislosti od ich klinickej reaktivity (70). Reaktivita bazofilov hodnoten\u00e1 prietokov\u00fdm cytometrick\u00fdm hodnoten\u00edm expresie CD63 sa uk\u00e1zala ako spo\u013eahliv\u00fd diagnostick\u00fd test na diagnostiku alergie na jed blanokr\u00eddleho hmyzu (71). Senzitivita bazofilov, d\u00e1vka, pri ktorej nastane polovica maxim\u00e1lnej bazofilnej odpovede, bola navrhnut\u00e1 na monitorovanie VIT (72\u201374). Nov\u00fd sp\u00f4sob funk\u010dn\u00e9ho testu, ktor\u00fd meria intracelul\u00e1rne farbenie daim\u00ednoxid\u00e1zy konjugovanej s fykoerytr\u00ednom (DAO), bol overen\u00fd na detekciu mno\u017estva histam\u00ednu uvo\u013enen\u00e9ho z bazofilov. Po stimul\u00e1cii alerg\u00e9nom sa intracelul\u00e1rne hladiny DAO zni\u017euj\u00fa \u00famerne s uvo\u013enen\u00fdm intracelul\u00e1rnym histam\u00ednom. Toto zn\u00ed\u017eenie sa preuk\u00e1zalo u pacientov lie\u010den\u00fdch vespula VIT, \u010do je d\u00f4le\u017eit\u00e9 pre zv\u00fd\u0161enie prahu pre jed na vyvolanie anafylaktickej reakcie u pacientov s VIT (75). U pacientov po VIT kles\u00e1 nielen vopred vytvoren\u00e9 uvo\u013e\u0148ovanie medi\u00e1torov, ale aj produkcia a uvo\u013e\u0148ovanie novovytvoren\u00fdch medi\u00e1torov, ako je leukotri\u00e9n C4 v krvn\u00fdch bazofiloch (76).<\/p>\n\n\n\n

Po r\u00fdchlej VIT bol v kult\u00farach mononukle\u00e1rnych buniek perif\u00e9rnej krvi (PBMC) hl\u00e1sen\u00fd pokles produkcie prote\u00ednu exprimovan\u00e9ho a secernovan\u00e9ho T-bunkami (RANTES), IL-8 a monocytov\u00e9ho chemoatraktantov\u00e9ho prote\u00ednu 1 (MCP-1) na \u00farovni prote\u00ednu a mRNA. \u00farovne (77).<\/p>\n\n\n\n

Po\u010das po\u010diato\u010dn\u00fdch f\u00e1z VIT nie s\u00fa \u00faplne pochopen\u00e9 mechanizmy, ktor\u00e9 sp\u00fa\u0161\u0165aj\u00fa desenzibiliz\u00e1ciu. V roku 2010 Bussmann a spol. vykonali \u0161t\u00fadiu na pacientoch s n\u00e1hlou VIT. Analyzovali hladiny expresie r\u00f4znych tolerog\u00e9nnych markerov na hladin\u00e1ch prote\u00ednov a mRNA po\u010das prv\u00fdch 5 dn\u00ed VIT. Pozorovali v\u00fdrazn\u00fa degrad\u00e1ciu tryptof\u00e1nu, ktor\u00e1 je spojen\u00e1 so supresiou reakci\u00ed T buniek a indukciou tolerancie; zv\u00fd\u0161en\u00e9 ILT3 a ILT4, ktor\u00e9 s\u00fa inhibi\u010dn\u00fdmi receptormi pre monocyty, a produkcia IL-10 CD3+ T buniek a monocytov nasledovan\u00e1 zv\u00fd\u0161en\u00fdmi hladinami IL-10 v s\u00e9re, \u010do je d\u00f4le\u017eit\u00fd regula\u010dn\u00fd interleuk\u00edn na potla\u010denie alerg\u00e9nom indukovan\u00fdch reakci\u00ed (78).<\/p>\n\n\n\n

V \u0161t\u00fadi\u00e1ch s aeroalerg\u00e9nmi sa uk\u00e1zalo, \u017ee AIT inhibuje skor\u00fa a neskor\u00fa f\u00e1zu alergick\u00fdch reakci\u00ed v miestach alergick\u00fdch tkan\u00edv prostredn\u00edctvom supresie nieko\u013ek\u00fdch cytok\u00ednov a zn\u00ed\u017eenia po\u010dtu eozinofilov, mastocytov a bazofilov (54). Tieto inform\u00e1cie nazna\u010duj\u00fa, \u017ee alerg\u00e9nov\u00e1 imunoterapia je \u00fa\u010dinn\u00e1 na syst\u00e9movej aj lok\u00e1lnej \u00farovni. Podobn\u00e9 mechanizmy sa pravdepodobne uplat\u0148uj\u00fa aj pri VIT.<\/p>\n\n\n\n

Reakcie T a B buniek po\u010das VIT
<\/strong>Uk\u00e1zalo sa, \u017ee rozvoj imunitnej tolerancie po\u010das VIT s\u00favis\u00ed s modifik\u00e1ciou odpoved\u00ed T a B buniek (79). Po\u010das VIT doch\u00e1dza k posunu Th2 na Th1 a pozoruje sa zv\u00fd\u0161enie hlad\u00edn interfer\u00f3nu gama (IFN-\u03b3) paralelne s poklesom IL-4 a IL-13 v plnej krvi (80, 81). Th2 odpovede po\u010das VIT s\u00fa zn\u00ed\u017een\u00e9 a doch\u00e1dza tie\u017e k zv\u00fd\u0161eniu po\u010dtu a funkci\u00ed Treg buniek (80, 82). Treg bunky s\u00fa rozdelen\u00e9 do 2 podskup\u00edn ako prirodzen\u00e9 regula\u010dn\u00e9 T (nTreg) bunky, ktor\u00e9 s\u00fa charakterizovan\u00e9 transkrip\u010dn\u00fdm faktorom forkhead box P3 (FOXP3), a indukovate\u013en\u00e9 regula\u010dn\u00e9 T (iTreg) bunky, ako s\u00fa IL-10 produkuj\u00face Tr1 bunky a TGF- b produkuj\u00face bunky TH3 (83\u201385). IL-10 hr\u00e1 inhibi\u010dn\u00fa \u00falohu v B bunk\u00e1ch blokovan\u00edm B7\/CD28 dr\u00e1hy. To m\u00e1 za n\u00e1sledok supres\u00edvny \u00fa\u010dinok na dozrievanie dendritick\u00fdch buniek a na expresiu MHC triedy II a kostimula\u010dn\u00fdch ligandov (86). TGF-b downreguluje expresiu FceRI na Langerhansov\u00fdch bunk\u00e1ch a tie\u017e upreguluje FOXP3 a RUNX a napom\u00e1ha expresii CTLA-4 na T bunk\u00e1ch (87, 88).<\/p>\n\n\n\n

U v\u010del\u00e1rov Treg bunky produkuj\u00face IL-10 inhibuj\u00fa prolifer\u00e1ciu PLA-\u0161pecifick\u00fdch efektorov\u00fdch T buniek kr\u00e1tko po za\u010diatku sez\u00f3ny v\u010delieho jedu. Tento supres\u00edvny \u00fa\u010dinok mo\u017eno zvr\u00e1ti\u0165 blokovan\u00edm receptorov CTLA-4, PD-1 a IL-10 (89). Okrem toho indukcia enz\u00fdmu indolam\u00edn 2,3-dioxygen\u00e1zy v dendritick\u00fdch bunk\u00e1ch \u00fa\u010dinkom Tregs sp\u00f4sobuje transform\u00e1ciu z\u00e1palov\u00fdch dendritick\u00fdch buniek na regula\u010dn\u00e9 dendritick\u00e9 bunky (90). Podobn\u00fdm sp\u00f4sobom, po\u010das VIT, je prolifer\u00e1cia Treg buniek typu Tr1 prominentn\u00e1 a antig\u00e9n-\u0161pecifick\u00e9 proliferat\u00edvne a cytok\u00ednov\u00e9 odpovede proti hlavn\u00e9mu alerg\u00e9nu v\u010delieho jedu, fosfolip\u00e1ze A2 (PLA), boli do konca prv\u00e9ho t\u00fd\u017ed\u0148a VIT v\u00fdznamne potla\u010den\u00e9. (91). Alerg\u00e9nom indukovan\u00e1 sekr\u00e9cia Th2 cytok\u00ednov, ako je IL-4, IL-5 a IL-13, bola zru\u0161en\u00e1 (92). Okrem produkcie IL-10 m\u00f4\u017eu Treg bunky tie\u017e potl\u00e1\u010da\u0165 imunitn\u00e9 reakcie prostredn\u00edctvom interakci\u00ed medzi bunkami.<\/p>\n\n\n\n

\u00daloha zv\u00fd\u0161en\u00fdch hlad\u00edn IL-10 je v\u00fdznamn\u00e1 pri rozvoji klinickej a imunologickej tolerancie po\u010das VIT. Blokovanie IL-10 v PBMC rekon\u0161tituuje \u0161pecifick\u00e9 proliferat\u00edvne a cytok\u00ednov\u00e9 reakcie. T\u00fato situ\u00e1ciu mo\u017eno pozorova\u0165 aj u v\u010del\u00e1rov, ktor\u00ed dostali viacn\u00e1sobn\u00e9 v\u010delie bodnutie (91). Pr\u00edtomnos\u0165 zv\u00fd\u0161en\u00e9ho po\u010dtu CD4+CD25+FOXP3+ Treg buniek v cie\u013eovom org\u00e1ne, nosovej sliznici, po alerg\u00e9novej imunoterapii tr\u00e1vov\u00fdm pe\u013eom nazna\u010duje, \u017ee Treg bunky hraj\u00fa d\u00f4le\u017eit\u00fa \u00falohu pri rozvoji alerg\u00e9n-\u0161pecifickej imunitnej tolerancie (93). Podobn\u00fdm sp\u00f4sobom sa zistilo, \u017ee VIT s\u00favis\u00ed s progres\u00edvnou expanziou po\u010dtu cirkuluj\u00facich CD4+CD25+FOXP3+ Treg buniek (94). Po\u010das v\u0161etk\u00fdch typov AIT bola hl\u00e1sen\u00e1 odch\u00fdlka smerom k regula\u010dnej\/supresorovej T bunkovej odpovedi (95). V \u0161t\u00fadii Nassera et al sa alerg\u00e9nom indukovan\u00e9 zmeny v cytok\u00ednovej mRNA a bunkov\u00fdch profiloch z ko\u017en\u00fdch biopsi\u00ed porovn\u00e1vali pred a 3 mesiace po osej VIT. Do\u0161lo k v\u00fdznamn\u00e9mu poklesu IL-4 mRNA a zv\u00fd\u0161eniu IL-10+ buniek. Okrem toho bol tie\u017e pozorovan\u00fd trend k zv\u00fd\u0161eniu IL-10 mRNA (96). V \u010fal\u0161ej \u0161t\u00fadii Schuerwegha et al sa hodnotil \u00fa\u010dinok VIT na CD4+CD8+ T lymfocyty pred VIT, na konci 5-d\u0148ovej semi-rush VIT a 6 mesiacov po\u010das VIT. V\u00fdznamn\u00fd pokles po\u010dtu CD4+ a CD8+ T buniek produkuj\u00facich IL v porovnan\u00ed s bunkami produkuj\u00facimi cytok\u00edny pred VIT bol pozorovan\u00fd na konci 5-d\u0148ovej semi-rush VIT. Po 6 mesiacoch VIT sa zistilo vy\u0161\u0161ie mno\u017estvo CD4+CD8+ T lymfocytov produkuj\u00facich IL-2 a IFN-\u03b3, \u010do potvrdzuje posun z imunitnej odch\u00fdlky typu Th2 na Th1 (81). Hladiny IL-10 v s\u00e9re sa za\u010dali zvy\u0161ova\u0165 od druh\u00e9ho d\u0148a VIT (78) a na 28. de\u0148 lie\u010dby sa v alerg\u00e9n-\u0161pecifick\u00fdch T bunk\u00e1ch objavil desenzibilizovan\u00fd stav spojen\u00fd s priamymi supres\u00edvnymi \u00fa\u010dinkami IL-10 (94).<\/p>\n\n\n\n

T folikul\u00e1rne pomocn\u00e9 bunky (TFH) s\u00fa definovan\u00e9 povrchov\u00fdm receptorom CXCR5+ a pom\u00e1haj\u00fa pri dozrievan\u00ed B-buniek a pri prep\u00ednan\u00ed triedy imunoglobul\u00ednov. CXCR5+ FoxP3+ Treg bunky s\u00fa podskupinou Tregs, naz\u00fdvan\u00fdch ako folikul\u00e1rne regula\u010dn\u00e9 T (TFR) bunky, ktor\u00e9 s\u00fa schopn\u00e9 potla\u010di\u0165 reakcie T- a B-buniek migr\u00e1ciou do germin\u00e1lnych centier lymfatick\u00fdch uzl\u00edn (97, 98). \u0160t\u00fadia imunoterapie tr\u00e1vov\u00fdm pe\u013eom preuk\u00e1zala v\u00fdznamn\u00fd pokles po\u010dtu pam\u00e4\u0165ov\u00fdch TFH buniek po imunoterapii (99). Okrem toho sa zistilo, \u017ee bunky TFR produkuj\u00fa viac IL-10 v porovnan\u00ed s bunkami TFH. Plasticita medzi TFH a TFR bunkami bola preuk\u00e1zan\u00e1 v tej istej \u0161t\u00fadii, \u010do nazna\u010duje, \u017ee TFR bunky m\u00f4\u017eu hra\u0165 d\u00f4le\u017eit\u00fa \u00falohu pri potl\u00e1\u010dan\u00ed TH2 odpoved\u00ed a produkcie alerg\u00e9novo \u0161pecifick\u00fdch IgE po\u010das imunoterapie (99). Je pravdepodobn\u00e9, \u017ee po\u010das imunoterapie jedom s\u00fa pr\u00edtomn\u00e9 podobn\u00e9 mechanizmy TFR a TFH buniek ako pri imunoterapii pe\u013eom tr\u00e1v.<\/p>\n\n\n\n

Ned\u00e1vno boli u v\u010del\u00e1rov toleruj\u00facich v\u010del\u00ed jed a u pacientov, ktor\u00fdm sa pod\u00e1vala VIT, identifikovan\u00e9 bunky Breg \u0161pecifick\u00e9 pre alerg\u00e9n vylu\u010duj\u00face IL-10 (100). Breg bunky s\u00fa charakterizovan\u00e9 ako CD73\u2212 CD25+CD71+ B bunky, ktor\u00e9 s\u00fa schopn\u00e9 potl\u00e1\u010da\u0165 CD4+ T bunky \u0161pecifick\u00e9 pre v\u010del\u00ed jed a schopn\u00e9 produkova\u0165 alerg\u00e9n \u0161pecifick\u00e9 IgG4 protil\u00e1tky po v\u010delej VIT (100). Okrem toho m\u00f4\u017eu Breg bunky tie\u017e preuk\u00e1za\u0165 svoju inhibi\u010dn\u00fa kapacitu produkciou IL-35 a TGF-beta (101). Okrem Treg a B reg buniek sa uk\u00e1zalo, \u017ee prirodzen\u00e9 zab\u00edja\u010dsk\u00e9 regula\u010dn\u00e9 bunky vylu\u010duj\u00face IL-10 potl\u00e1\u010daj\u00fa alerg\u00e9nom stimulovan\u00fa prolifer\u00e1ciu T buniek u \u013eud\u00ed a m\u00f4\u017eu by\u0165 d\u00f4le\u017eit\u00e9 pri indukcii tolerancie ako in\u00e9 typy regula\u010dn\u00fdch buniek (102).<\/p>\n\n\n\n

Vroden\u00e9 lymfoidn\u00e9 bunky a alerg\u00e9nov\u00e1 imunoterapia
<\/strong>\u00da\u010dinok alerg\u00e9novej imunoterapie na vroden\u00e9 lymfoidn\u00e9 bunky, ILC typu 2, bol \u0161tudovan\u00fd pri alergii na pe\u013e tr\u00e1v v perif\u00e9rnej krvi. AIT potla\u010dila sez\u00f3nne zv\u00fd\u0161enia ILC2 u pacientov lie\u010den\u00fdch imunoterapiou v porovnan\u00ed s nelie\u010den\u00fdmi kontrolami (103). Pokles ILC2 koreloval so sympt\u00f3mami, ktor\u00e9 sami hl\u00e1sili. Okrem toho sa tie\u017e zn\u00ed\u017eil podiel IL-13+ ILC2. V \u010fal\u0161ej \u0161t\u00fadii sez\u00f3nnych astmatick\u00fdch pacientov Lombardi et al nedok\u00e1zali preuk\u00e1za\u0165 \u017eiadnu zmenu v po\u010dte ILC2 po\u010das imunoterapie, \u010do bolo vysvetlen\u00e9 nesez\u00f3nnymi meraniami, zatia\u013e \u010do pacienti boli asymptomatick\u00ed (104). Doteraz neexistuje d\u00f4kaz, \u017ee imunoterapia m\u00e1 nejak\u00fd \u00fa\u010dinok na cytok\u00edny odvoden\u00e9 z epitelu, ako s\u00fa IL-25, IL-33 a TSLP, ktor\u00e9 maj\u00fa regula\u010dn\u00e9 \u00fa\u010dinky na lok\u00e1lny z\u00e1pal typu 2 a ILC (54).<\/p>\n\n\n\n

Histam\u00edn a histam\u00ednov\u00e9 receptory na VIT
<\/strong>Po\u010das VIT sa v priebehu nieko\u013ek\u00fdch dn\u00ed alebo dokonca hod\u00edn rozvinie skor\u00e1 desenzibiliz\u00e1cia v z\u00e1vislosti od typu pou\u017eit\u00e9ho imunoterapeutick\u00e9ho protokolu, ako je n\u00e1hly a ultrar\u00fdchly typ VIT. Doch\u00e1dza k poklesu po\u010dtu bazofilov, vopred vytvoren\u00fdch medi\u00e1torov a uvo\u013e\u0148ovania medi\u00e1torov v z\u00e1vislosti od \u010dasu (75, 105, 106). Medzi \u0161tyrmi r\u00f4znymi typmi histam\u00ednov\u00fdch receptorov hr\u00e1 d\u00f4le\u017eit\u00fa \u00falohu histam\u00ednov\u00fd receptor typu 2 (HR2) s toleranciou perif\u00e9rneho antig\u00e9nu (89). Potla\u010denie bazofilov za\u010d\u00edna aktiv\u00e1ciou histam\u00ednov\u00fdch receptorov typu 2 (HR2). H2R zni\u017euje alerg\u00e9nom indukovan\u00fa degranul\u00e1ciu bazofilov sprostredkovan\u00fa FceRI a uvo\u013e\u0148ovanie medi\u00e1tora (107). HR2 sa podie\u013ea hlavne na tolerog\u00e9nnych imunitn\u00fdch odpovediach. Je upregulovan\u00fd v Th2 bunk\u00e1ch a oba potl\u00e1\u010daj\u00fa alerg\u00e9nom stimulovan\u00e9 reakcie T buniek a zvy\u0161uj\u00fa produkciu IL-10 u v\u010del\u00e1rov (89), \u010do vyvol\u00e1va rozvoj perif\u00e9rnej tolerancie (76, 108, 109). Histam\u00edn prostredn\u00edctvom HR2 indukuje produkciu IL-10 dendritick\u00fdmi bunkami a Th2 bunkami (110); zvy\u0161uje supres\u00edvny \u00fa\u010dinok TGF-b na T bunky (111) a zni\u017euje produkciu IL-4 a IL-13, \u010do s\u00fa hlavn\u00e9 cytok\u00edny typu Th2 (112).<\/p>\n\n\n\n

\u00da\u010dinnos\u0165 a bezpe\u010dnos\u0165 imunoterapie jedom
<\/strong>\u00da\u010dinnos\u0165 VIT sa pohybuje od 77 do 84 % pre v\u010delu medonosn\u00fa a od 91 do 96 % pre jed osy (9\u201311). Niektor\u00e9 faktory, ako napr\u00edklad vy\u0161\u0161ie mno\u017estvo alerg\u00e9nu prenesen\u00e9ho po\u010das ka\u017edej reakcie na bodnutie, konzistencia v\u010delieho bodnutia, r\u00f4znorodos\u0165 vzoru senzibiliz\u00e1cie v\u010delieho jedu, patria medzi navrhovan\u00e9 faktory, ktor\u00e9 m\u00f4\u017eu vysvetli\u0165 ni\u017e\u0161iu mieru \u00faspe\u0161nosti spojen\u00fa s VIT v\u010delou (9). Zistilo sa, \u017ee VIT je \u00fa\u010dinn\u00e1 dokonca aj po f\u00e1ze nahromadenia a v jednej \u0161t\u00fadii s jedom v\u010diel bola hl\u00e1sen\u00e1 89 % \u00faspe\u0161nos\u0165 pri stimul\u00e1cii bodnut\u00edm 1 t\u00fd\u017ede\u0148 po dosiahnut\u00ed udr\u017eiavacej d\u00e1vky (113).<\/p>\n\n\n\n

Vzh\u013eadom na imunoterapiu v\u010del\u00edm jedom m\u00f4\u017ee pou\u017eitie vzorcov senzibiliz\u00e1cie s rozl\u00ed\u0161en\u00fdmi komponentmi pom\u00f4c\u0165 zv\u00fd\u0161i\u0165 \u00faspe\u0161nos\u0165 lie\u010dby. Niektor\u00ed pacienti s\u00fa senzibilizovan\u00ed predov\u0161etk\u00fdm na Api m 10, \u010do je nedostato\u010dne zast\u00fapen\u00fd alerg\u00e9n v niektor\u00fdch pr\u00edpravkoch VIT, ktor\u00fd m\u00f4\u017ee sp\u00f4sobi\u0165 zlyhanie lie\u010dby (114, 115).<\/p>\n\n\n\n

Po\u010das f\u00e1zy budovania VIT, ak je SSR probl\u00e9mom dosiahnu\u0165 udr\u017eiavaciu d\u00e1vku, m\u00f4\u017ee by\u0165 alternat\u00edvou premedik\u00e1cia omalizumabom, anti-IgE protil\u00e1tkou (116).<\/p>\n\n\n\n

Na prevenciu zlyhania lie\u010dby je d\u00f4le\u017eit\u00e1 aj d\u00e1vka jedu pou\u017eit\u00e1 po\u010das VIT. Zvy\u010dajne na ochranu posta\u010duje udr\u017eiavacia d\u00e1vka 100 \u03bcg jedu po\u010das VIT (9). Ke\u010f s\u00fa rizikov\u00e9 faktory vysok\u00e9, ako u v\u010del\u00e1rov, vy\u0161\u0161ia d\u00e1vka jedu d\u00e1va lep\u0161ie v\u00fdsledky (117). Ak sa syst\u00e9mov\u00e1 reakcia rozvinie po ter\u00e9nnom bodnut\u00ed alebo stimul\u00e1cii bodnut\u00edm po\u010das konven\u010dnej d\u00e1vky 100 \u03bcg, odpor\u00fa\u010da sa vy\u0161\u0161ia d\u00e1vka, 200 \u03bcg (118).<\/p>\n\n\n\n

Miera relapsov a\u017e do 10 % bola hl\u00e1sen\u00e1 za 1\u20135 rokov po ukon\u010den\u00ed vespula VIT a \u010dastej\u0161ie pri VIT v\u010diel (9). V jednej \u0161t\u00fadii bola 3\u20135 rokov po ukon\u010den\u00ed VIT hl\u00e1sen\u00e1 miera relapsov 7,5 % pre vespula VIT a 15,8 % pre VIT v\u010diel (17). U det\u00ed m\u00e1 VIT lep\u0161iu progn\u00f3zu v porovnan\u00ed s dospel\u00fdmi a len u 5 % det\u00ed sa vyvin\u00fa stredne \u0165a\u017ek\u00e9 a\u017e \u0165a\u017ek\u00e9 syst\u00e9mov\u00e9 reakcie na bodnutie do 20 rokov sledovania po ukon\u010den\u00ed VIT (15).<\/p>\n\n\n\n

Trvanie VIT je d\u00f4le\u017eit\u00e9 pre \u00fa\u010dinnos\u0165. Jeden rok lie\u010dby zlyhal u takmer jednej \u0161tvrtiny pacientov, ke\u010f ich \u0161t\u00edpalo 3\u20134 roky po VIT (119). Zd\u00e1 sa, \u017ee \u0161t\u00fadie s najmenej 5-ro\u010dnou lie\u010dbou preukazuj\u00fa lep\u0161iu ochranu v porovnan\u00ed s 3-ro\u010dnou lie\u010dbou (120). Lerch et al preuk\u00e1zali ni\u017e\u0161ie miery syst\u00e9mov\u00fdch reakci\u00ed u pacientov, ktor\u00ed dost\u00e1vali VIT \u2265 50 mesiacov v porovnan\u00ed s pacientmi lie\u010den\u00fdmi 33\u201349 mesiacov (5 vs. 18 %) (17). V inej \u0161t\u00fadii Golden et al. hodnotili pacientov lie\u010den\u00fdch VIT aspo\u0148 5 rokov a zistili mieru syst\u00e9movej reakcie 9,5 % do 5 rokov po ukon\u010den\u00ed VIT (121).<\/p>\n\n\n\n

Ned\u00e1vna metaanal\u00fdza zah\u0155\u0148aj\u00faca p\u00e4\u0165 systematick\u00fdch preh\u013eadov, p\u00e4\u0165 RCT, tri kontrolovan\u00e9 \u0161t\u00fadie (pred a po) a \u0161tyri s\u00e9rie pr\u00edpadov uk\u00e1zali, \u017ee VIT v\u00fdznamne zn\u00ed\u017eila riziko z\u00e1va\u017en\u00fdch syst\u00e9mov\u00fdch reakci\u00ed (OR = 0,08, 95 % CI 0,03\u20130,26); zlep\u0161en\u00e1 kvalita \u017eivota (rozdiel rizika: 1,41, 95 % CI 1,04\u20131,79) a m\u00f4\u017ee by\u0165 n\u00e1kladovo efekt\u00edvna u t\u00fdch, ktor\u00ed zaznamenali opakovan\u00e9 syst\u00e9mov\u00e9 reakcie a zhor\u0161en\u00fa kvalitu \u017eivota (122).<\/p>\n\n\n\n

Ne\u017eiaduce udalosti s\u00fa po\u010das VIT zvy\u010dajne mierne. U pacientov so syst\u00e9mov\u00fdmi reakciami doch\u00e1dza k relapsu ove\u013ea \u010dastej\u0161ie v porovnan\u00ed s pacientmi, ktor\u00ed ho nemali (16,4\u201338 % vs. 5,4\u20138 %) (11).<\/p>\n\n\n\n

Niektor\u00e9 z predch\u00e1dzaj\u00facich rizikov\u00fdch faktorov syst\u00e9mov\u00fdch ne\u017eiaducich udalost\u00ed po\u010das VIT sa u\u017e nepova\u017euj\u00fa za d\u00f4le\u017eit\u00e9 rizikov\u00e9 faktory. K t\u00fdmto star\u0161\u00edm rizikov\u00fdm faktorom patr\u00ed mastocyt\u00f3za, ACE inhib\u00edtory, u\u017e\u00edvanie betablok\u00e1torov, vysok\u00e9 hladiny \u0161pecifick\u00fdch IgE a pozitivita ko\u017en\u00fdch prick testov pri n\u00edzkej z\u00e1\u0165a\u017ei testov (9). Vysok\u00e9 baz\u00e1lne hladiny trypt\u00e1zy pri alergii na vespid m\u00f4\u017eu by\u0165 rizikov\u00fdm faktorom pre syst\u00e9mov\u00e9 ne\u017eiaduce udalosti pri VIT (12), ale nie pri alergii na v\u010del\u00ed jed (123).<\/p>\n\n\n\n

Rizikov\u00e9 faktory relapsu SSR po ukon\u010den\u00ed VIT s\u00fa uveden\u00e9 v tabu\u013eke 2.<\/p>\n\n\n\n

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TABU\u013dKA 2. Rizikov\u00e9 faktory relapsu z\u00e1va\u017en\u00fdch syst\u00e9mov\u00fdch reakci\u00ed po ukon\u010den\u00ed VIT (9, 11, 15, 124\u2013127).<\/figcaption><\/figure>\n\n\n\n

V s\u00fa\u010dasnosti je zlat\u00fdm \u0161tandardom na identifik\u00e1ciu \u00fa\u010dinnosti VIT a na odl\u00ed\u0161enie respondentov od pacientov, ktor\u00ed nereaguj\u00fa, test bodnutia. Met\u00f3dy pou\u017e\u00edvan\u00e9 na monitorovanie VIT s\u00fa uveden\u00e9 v tabu\u013eke 3.<\/p>\n\n\n\n

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TABU\u013dKA 3. Met\u00f3dy pou\u017e\u00edvan\u00e9 na monitorovanie imunoterapie jedom (VIT) (9, 17, 74, 125, 129).<\/figcaption><\/figure>\n\n\n\n

Z\u00e1ver<\/strong>
Alergia na hmyz\u00ed jed je jednou z naj\u010dastej\u0161\u00edch pr\u00ed\u010din anafylaxie u \u013eud\u00ed a ide o zdravotn\u00fa pohotovos\u0165. V s\u00fa\u010dasnosti neexistuje \u017eiadny biomarker na predpovedanie rizika anafylaxie. VIT je naj\u00fa\u010dinnej\u0161ou lie\u010dbou na prevenciu SSR po bodnut\u00ed a zni\u017euje riziko anafylaxie. St\u00e1le v\u0161ak treba odpoveda\u0165 na niektor\u00e9 ot\u00e1zky, ako s\u00fa n\u00e1klady na \u00fa\u010dinnos\u0165, vplyv na kvalitu \u017eivota, trvanie lie\u010dby, optim\u00e1lna d\u00e1vka a sp\u00f4soby hodnotenia. Rozvoj perif\u00e9rnej tolerancie je hlavn\u00fdm mechanizmom po\u010das VIT, ktor\u00fd je riaden\u00fd T regula\u010dn\u00fdmi bunkami. T regs produkuj\u00fa IL-10 a potl\u00e1\u010daj\u00fa Th2 imunitu a imunitn\u00e9 reakcie sa pos\u00favaj\u00fa smerom k z\u00e1palu typu Th1. Blokuj\u00face protil\u00e1tky IgG1\/IgG4 inhibuj\u00fa reakcie z\u00e1visl\u00e9 od IgE na \u017e\u00edrnych bunk\u00e1ch, bazofiloch a B bunk\u00e1ch. Na rozvoji dlhodobej imunitnej tolerancie sa podie\u013ea aj nieko\u013eko \u010fal\u0161\u00edch mechanizmov, ako s\u00fa epitelov\u00e9 bunky, nieko\u013eko cytok\u00ednov, dendritick\u00e9 bunky, ILC2 a B regula\u010dn\u00e9 bunky.<\/p>\n\n\n\n

Faktory, ak\u00fdmi s\u00fa zvy\u0161ovanie vedomost\u00ed o rizikov\u00fdch faktoroch anafylaxie jedom, lep\u0161ia eduk\u00e1cia pacientov, v\u00fdvoj efekt\u00edvnej\u0161\u00edch produktov VIT s men\u0161\u00edmi ved\u013eaj\u0161\u00edmi \u00fa\u010dinkami a n\u00e1jdenie \u00fa\u010dinn\u00fdch biomarkerov na predpovedanie bud\u00facich syst\u00e9mov\u00fdch reakci\u00ed na individu\u00e1lnej \u00farovni, v\u00fdrazne zlep\u0161ia starostlivos\u0165 o pacienta.<\/p>\n\n\n\n

Autorsk\u00e9 pr\u00edspevky
USA vykonali re\u0161er\u0161 literat\u00fary, pripravili obr\u00e1zok a tabu\u013eky a nap\u00edsali \u010dl\u00e1nok pod doh\u013eadom SD. SD napl\u00e1noval cel\u00fd text, pre\u010d\u00edtal rukopis, urobil potrebn\u00e9 opravy a podrobne diskutoval o mechanizmoch imunoterapie.<\/p>\n\n\n\n

Vyhl\u00e1senie o konflikte z\u00e1ujmov
SD vykazuje granty od ALK, D\u00e1nsko, osobn\u00e9 poplatky od Anergis, \u0160vaj\u010diarsko, osobn\u00e9 poplatky od Biomay, Rak\u00fasko, osobn\u00e9 poplatky od Allergy Therapeutics, UK, osobn\u00e9 poplatky od ALK, Horsholm, D\u00e1nsko, osobn\u00e9 poplatky od Allergy Therapeutics, mimo zaslanej pr\u00e1ce.<\/p>\n\n\n\n

Zost\u00e1vaj\u00faci autor vyhlasuje, \u017ee v\u00fdskum bol vykonan\u00fd bez ak\u00fdchko\u013evek obchodn\u00fdch alebo finan\u010dn\u00fdch vz\u0165ahov, ktor\u00e9 by mohli by\u0165 ch\u00e1pan\u00e9 ako potenci\u00e1lny konflikt z\u00e1ujmov.<\/p>\n\n\n\n

Referencie<\/h2>\n\n\n\n

<\/a>1. Krishna MT, Ewan PW, Diwakar L, Durham SR, Frew AJ, Leech SC, et al. Diagnosis and management of hymenoptera venom allergy: British society for allergy and clinical immunology (BSACI) guidelines. Clin Exp Allergy<\/em>. (2011) 41:1201\u201320. doi: 10.1111\/j.1365-2222.2011.03788.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>2. Tan JW, Campbell DE. Insect allergy in children. J Paediatr Child Health<\/em>. (2013) 49:E381\u20137. doi: 10.1111\/jpc.12178<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>3. Hoffman DR, Jacobson RS. Allergens in hymenoptera venom XII: how much protein is in a sting? Ann Allergy<\/em>. (1984) 52:276\u20138.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>4. Ellis AK, Day JH. Clinical reactivity to insect stings. Curr Opin Allergy Clin Immunol<\/em>. (2005) 5:349\u201354. doi: 10.1097\/01.all.0000174159.55756.58<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>5. Mauriello PM, Barde SH, Georgitis JW, Reisman RE. Natural history of large local reactions from stinging insects. J Allergy Clin Immunol<\/em>. (1984) 74(4 Pt 1):494\u20138. doi: 10.1016\/0091-6749(84)90384-1<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>6. Ludman SW, Boyle RJ. Stinging insect allergy: current perspectives on venom immunotherapy. J Asthma Allergy<\/em>. (2015) 8:75\u201386. doi: 10.2147\/JAA.S62288<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>7. Bilo BM, Bonifazi F. Epidemiology of insect-venom anaphylaxis. Curr Opin Allergy Clin Immunol<\/em>. (2008) 8:330\u20137. doi: 10.1097\/ACI.0b013e32830638c5<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>8. Jennings A, Duggan E, Perry IJ, Hourihane JO. Epidemiology of allergic reactions to hymenoptera stings in Irish school children. Pediatr Allergy Immunol<\/em>. (2010) 21:1166\u201370. doi: 10.1111\/j.1399-3038.2010.01054.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>9. Sturm GJ, Varga EM, Roberts G, Mosbech H, Bilo MB, Akdis CA, et al. EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Allergy<\/em>. (2018) 73:744\u201364. doi: 10.1111\/all.13262<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>10. Muller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety. J Allergy Clin Immunol<\/em>. (1992) 89:529\u201335. doi: 10.1016\/0091-6749(92)90319-W<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>11. Rueff F, Vos B, Oude Elberink J, Bender A, Chatelain R, Dugas-Breit S, et al. Predictors of clinical effectiveness of Hymenoptera venom immunotherapy. Clin Exp Allergy<\/em>. (2014) 44:736\u201346. doi: 10.1111\/cea.12275<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>12. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase. J Allergy Clin Immunol<\/em>. (2010) 126:105\u201311.e5. doi: 10.1016\/j.jaci.2010.04.025<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>13. Mosbech H, Muller U. Side-effects of insect venom immunotherapy: results from an EAACI multicenter study. European Academy of Allergology and Clinical Immunology. Allergy<\/em>. (2000) 55:1005\u201310. doi: 10.1034\/j.1398-9995.2000.00587.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>14. Stoevesandt J, Hain J, Stolze I, Kerstan A, Trautmann A. Angiotensin-converting enzyme inhibitors do not impair the safety of Hymenoptera venom immunotherapy build-up phase. Clin Exp Allergy<\/em>. (2014) 44:747\u201355. doi: 10.1111\/cea.12276<\/p>\n\n\n\n

CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>15. Golden DB, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM. Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med<\/em>. (2004) 351:668\u201374. doi: 10.1056\/NEJMoa022952<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>16. Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. J Allergy Clin Immunol<\/em>. (1993) 92:831\u20136. doi: 10.1016\/0091-6749(93)90060-S<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>17. Lerch E, Muller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in 200 patients. J Allergy Clin Immunol<\/em>. (1998) 101:606\u201312. doi: 10.1016\/S0091-6749(98)70167-8<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>18. Novembre E, Cianferoni A, Bernardini R, Veltroni M, Ingargiola A, Lombardi E, et al. Epidemiology of insect venom sensitivity in children and its correlation to clinical and atopic features. Clin Exp Allergy<\/em>. (1998) 28:834\u20138. doi: 10.1046\/j.1365-2222.1998.00313.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>19. Grigoreas C, Galatas ID, Kiamouris C, Papaioannou D. Insect-venom allergy in Greek adults. Allergy<\/em>. (1997) 52:51\u20137. doi: 10.1111\/j.1398-9995.1997.tb02545.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>20. Incorvaia C, Mauro M, Pastorello EA. Hymenoptera stings in conscripts. Allergy<\/em>. (1997) 52:680\u20131. doi: 10.1111\/j.1398-9995.1997.tb01056.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>21. Fernandez J, Blanca M, Soriano V, Sanchez J, Juarez C. Epidemiological study of the prevalence of allergic reactions to Hymenoptera in a rural population in the Mediterranean area. Clin Exp Allergy<\/em>. (1999) 29:1069\u201374. doi: 10.1046\/j.1365-2222.1999.00614.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>22. Navarro LA, Pelaez A, de la Torre F, Tenias Burillo JM, Megias J, Martinez I. Epidemiological factors on hymenoptera venom allergy in a Spanish adult population. J Investig Allergol Clin Immunol<\/em>. (2004) 14:134\u201341.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>23. Fernandez J, Soriano V, Mayorga L, Mayor M. Natural history of Hymenoptera venom allergy in Eastern Spain. Clin Exp Allergy<\/em>. (2005) 35:179\u201385. doi: 10.1111\/j.1365-2222.2005.02169.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>24. Bilo MB, Cichocka-Jarosz E, Pumphrey R, Oude-Elberink JN, Lange J, Jakob T, et al. Self-medication of anaphylactic reactions due to Hymenoptera stings-an EAACI task force consensus statement. Allergy<\/em>. (2016) 71:931\u201343. doi: 10.1111\/all.12908<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>25. Muller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol<\/em>. (2005) 5:343\u20137. doi: 10.1097\/01.all.0000173783.42906.95<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>26. Richter AG, Nightingale P, Huissoon AP, Krishna MT. Risk factors for systemic reactions to bee venom in British beekeepers. Ann Allergy Asthma Immunol<\/em>. (2011) 106:159\u201363. doi: 10.1016\/j.anai.2010.11.005<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>27. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V, et al. First European data from the network of severe allergic reactions (NORA). Allergy<\/em>. (2014) 69:1397\u2013404. doi: 10.1111\/all.12475<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>28. Prado M, Quiros D, Lomonte B. Mortality due to Hymenoptera stings in Costa Rica, 1985-2006. Rev Panam Salud Publica<\/em>. (2009) 25:389\u201393. doi: 10.1590\/S1020-49892009000500002<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>29. Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol<\/em>. (1973) 52:259\u201364. doi: 10.1016\/0091-6749(73)90044-4<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>30. Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T, et al. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012. J Allergy Clin Immunol<\/em>. (2015) 135:956\u201363.e1. doi: 10.1016\/j.jaci.2014.10.021<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>31. Bilo BM, Rueff F, Mosbech H, Bonifazi F, Oude-Elberink JN, EAACI Interest Group on Insect Venom Hypersensitivity. Diagnosis of Hymenoptera venom allergy. Allergy<\/em>. (2005) 60:1339\u201349. doi: 10.1111\/j.1398-9995.2005.00963.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>32. Clark S, Camargo CA Jr. Epidemiology of anaphylaxis. Immunol Allergy Clin North Am<\/em>. (2007) 27:145\u201363. doi: 10.1016\/j.iac.2007.03.002<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>33. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol<\/em>. (2009) 124:1047\u201354. doi: 10.1016\/j.jaci.2009.08.027<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>34. Arzt L, Bokanovic D, Schwarz I, Schrautzer C, Massone C, Horn M, et al. Hymenoptera stings in the head region induce impressive, but not severe sting reactions. Allergy<\/em>. (2016) 71:1632\u20134. doi: 10.1111\/all.12967<\/p>\n\n\n\n

CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>35. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy<\/em>. (2008) 63:226\u201332. doi: 10.1111\/j.1398-9995.2007.01569.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>36. Castells MC, Hornick JL, Akin C. Anaphylaxis after hymenoptera sting: is it venom allergy, a clonal disorder, or both? J Allergy Clin Immunol Pract<\/em>. (2015) 3:350\u20135. doi: 10.1016\/j.jaip.2015.03.015<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>37. Bonadonna P, Bonifacio M, Lombardo C, Zanotti R. Hymenoptera allergy and mast cell activation syndromes. Curr Allergy Asthma Rep<\/em>. (2016) 16:5. doi: 10.1007\/s11882-015-0582-5<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>38. Stoevesandt J, Hain J, Kerstan A, Trautmann A. Over- and underestimated parameters in severe Hymenoptera venom-induced anaphylaxis: cardiovascular medication and absence of urticaria\/angioedema. J Allergy Clin Immunol<\/em>. (2012) 130:698\u2013704.e1. doi: 10.1016\/j.jaci.2012.03.024<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>39. Mueller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol<\/em>. (2007) 7:337\u201341. doi: 10.1097\/ACI.0b013e328259c328<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>40. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest<\/em>. (2007) 37:435\u201353. doi: 10.1111\/j.1365-2362.2007.01807.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>41. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol<\/em>. (2011) 12:259\u201370. doi: 10.2165\/11588890-000000000-00000<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>42. Akin C, Valent P. Diagnostic criteria and classification of mastocytosis in 2014. Immunol Allergy Clin North Am<\/em>. (2014) 34:207\u201318. doi: 10.1016\/j.iac.2014.02.003<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>43. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol<\/em>. (2009) 123:680\u20136. doi: 10.1016\/j.jaci.2008.11.018<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>44. Alfaya Arias T, Soriano Gomis V, Soto Mera T, Vega Castro A, Vega Gutierrez JM, Alonso Llamazares A, et al. Hymenoptera allergy committee of the: key issues in hymenoptera venom allergy: an update. J Investig Allergol Clin Immunol<\/em>. (2017) 27:19\u201331. doi: 10.18176\/jiaci.0123<\/p>\n\n\n\n

CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>45. Gonzalez de Olano D, de la Hoz Caballer B, Nunez Lopez R, Sanchez Munoz L, Cuevas Agustin M, Dieguez MC, et al. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA). Clin Exp Allergy<\/em>. (2007) 37:1547\u201355. doi: 10.1111\/j.1365-2222.2007.02804.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>46. Alvarez-Twose I, Zanotti R, Gonzalez-de-Olano D, Bonadonna P, Vega A, Matito A, et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol<\/em>. (2014) 133:520\u20138. doi: 10.1016\/j.jaci.2013.06.020<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>47. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito A, Esteban-Lopez MI, Vega A, et al. Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol<\/em>. (2010) 125:1269\u201378.e2. doi: 10.1016\/j.jaci.2010.02.019<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>48. Muller U, Helbling A, Bischof M. Predictive value of venom-specific IgE, IgG and IgG subclass antibodies in patients on immunotherapy with honey bee venom. Allergy<\/em>. (1989) 44:412\u20138. doi: 10.1111\/j.1398-9995.1989.tb04172.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>49. Kemeny DM, Lessof MH, Patel S, Youlten LJ, Williams A, Lambourn E. IgG and IgE antibodies after immunotherapy with bee and wasp venom. Int Arch Allergy Appl Immunol<\/em>. (1989) 88:247\u20139. doi: 10.1159\/000234799<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>50. Michils A, Baldassarre S, Ledent C, Mairesse M, Gossart B, Duchateau J. Early effect of ultrarush venom immunotherapy on the IgG antibody response. Allergy<\/em>. (2000) 55:455\u201362. doi: 10.1034\/j.1398-9995.2000.00412.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>51. Aalberse RC, Dieges PH, Knul-Bretlova V, Vooren P, Aalbers M, van Leeuwen J. IgG4 as a blocking antibody. Clin Rev Allergy<\/em>. (1983) 1:289\u2013302.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>52. Wachholz PA, Soni NK, Till SJ, Durham SR. Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J Allergy Clin Immunol<\/em>. (2003) 112:915\u201322. doi: 10.1016\/S0091-6749(03)02022-0<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>53. Oefner CM, Winkler A, Hess C, Lorenz AK, Holecska V, Huxdorf M, et al. Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. J Allergy Clin Immunol<\/em>. (2012) 129:1647\u201355.e13. doi: 10.1016\/j.jaci.2012.02.037<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>54. Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol<\/em>. (2017) 140:1485\u201398. doi: 10.1016\/j.jaci.2017.10.010<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>55. Rispens T, Ooijevaar-de Heer P, Bende O, Aalberse RC. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc<\/em>. (2011) 133:10302\u201311. doi: 10.1021\/ja203638y<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>56. Flicker S, Valenta R. Renaissance of the blocking antibody concept in type I allergy. Int Arch Allergy Immunol<\/em>. (2003) 132:13\u201324. doi: 10.1159\/000073260<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>57. van Neerven RJ, Wikborg T, Lund G, Jacobsen B, Brinch-Nielsen A, Arnved J, et al. Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+<\/sup> T cells by inhibiting serum-IgE-facilitated allergen presentation. J Immunol<\/em>. (1999) 163:2944\u201352.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>58. Wurtzen PA, Lund G, Lund K, Arvidsson M, Rak S, Ipsen H. A double-blind placebo-controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation. Clin Exp Allergy<\/em>. (2008) 38:1290\u2013301. doi: 10.1111\/j.1365-2222.2008.03020.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>59. Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, et al. Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases. J Allergy Clin Immunol<\/em>. (2011) 127:701\u201321.e1\u201370. doi: 10.1016\/j.jaci.2010.11.050<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>60. Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy<\/em>. (2008) 63:1455\u201363. doi: 10.1111\/j.1398-9995.2008.01774.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>61. Carballido JM, Carballido-Perrig N, Kagi MK, Meloen RH, Wuthrich B, Heusser CH, et al. T cell epitope specificity in human allergic and nonallergic subjects to bee venom phospholipase A2. J Immunol<\/em>. (1993) 150(8 Pt 1):3582\u201391.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>62. Martinez-Gomez JM, Johansen P, Erdmann I, Senti G, Crameri R, Kundig TM. Intralymphatic injections as a new administration route for allergen-specific immunotherapy. Int Arch Allergy Immunol<\/em>. (2009) 150:59\u201365. doi: 10.1159\/000210381<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>63. von Garnier C, Astori M, Kettner A, Dufour N, Heusser C, Corradin G, et al. Allergen-derived long peptide immunotherapy down-regulates specific IgE response and protects from anaphylaxis. Eur J Immunol<\/em>. (2000) 30:1638\u201345. doi: 10.1002\/1521-4141(200006)30:6<1638::AID-IMMU1638>3.0.CO;2-R<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>64. James LK, Shamji MH, Walker SM, Wilson DR, Wachholz PA, Francis JN, et al. Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol<\/em>. (2011) 127:509\u201316.e1\u20135. doi: 10.1016\/j.jaci.2010.12.1080<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>65. Varga EM, Francis JN, Zach MS, Klunker S, Aberer W, Durham SR. Time course of serum inhibitory activity for facilitated allergen-IgE binding during bee venom immunotherapy in children. Clin Exp Allergy<\/em>. (2009) 39:1353\u20137. doi: 10.1111\/j.1365-2222.2009.03303.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>66. Varga EM, Kausar F, Aberer W, Zach M, Eber E, Durham SR, et al. Tolerant beekeepers display venom-specific functional IgG4 antibodies in the absence of specific IgE. J Allergy Clin Immunol<\/em>. (2013) 131:1419\u201321. doi: 10.1016\/j.jaci.2012.08.037<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>67. Plewako H, Wosinska K, Arvidsson M, Bjorkander J, Skov PS, Hakansson L, et al. Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy. Int Arch Allergy Immunol<\/em>. (2006) 141:346\u201353. doi: 10.1159\/000095461<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>68. Dugas-Breit S, Przybilla B, Dugas M, Arnold A, Pfundstein G, Kuchenhoff H, et al. Serum concentration of baseline mast cell tryptase: evidence for a decline during long-term immunotherapy for Hymenoptera venom allergy. Clin Exp Allergy<\/em>. (2010) 40:643\u20139. doi: 10.1111\/j.1365-2222.2009.03436.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>69. Siegmund R, Vogelsang H, Machnik A, Herrmann D. Surface membrane antigen alteration on blood basophils in patients with Hymenoptera venom allergy under immunotherapy. J Allergy Clin Immunol<\/em>. (2000) 106:1190\u20135. doi: 10.1067\/mai.2000.110928<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>70. Eberlein-Konig B, Ullmann S, Thomas P, Przybilla B. Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization. Clin Exp Allergy<\/em>. (1995) 25:704\u201312. doi: 10.1111\/j.1365-2222.1995.tb00007.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>71. Sturm GJ, Bohm E, Trummer M, Weiglhofer I, Heinemann A, Aberer W. The CD63 basophil activation test in Hymenoptera venom allergy: a prospective study. Allergy<\/em>. (2004) 59:1110\u20137. doi: 10.1111\/j.1398-9995.2004.00400.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>72. Mikkelsen S, Bibby BM, Dolberg MK, Dahl R, Hoffmann HJ. Basophil sensitivity through CD63 or CD203c is a functional measure for specific immunotherapy. Clin Mol Allergy<\/em>. (2010) 8:2. doi: 10.1186\/1476-7961-8-2<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>73. Zitnik SE, Vesel T, Avcin T, Silar M, Kosnik M, Korosec P. Monitoring honeybee venom immunotherapy in children with the basophil activation test. Pediatr Allergy Immunol<\/em>. (2012) 23:166\u201372. doi: 10.1111\/j.1399-3038.2011.01233.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>74. Erzen R, Kosnik M, Silar M, Korosec P. Basophil response and the induction of a tolerance in venom immunotherapy: a long-term sting challenge study. Allergy<\/em>. (2012) 67:822\u201330. doi: 10.1111\/j.1398-9995.2012.02817.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>75. Nullens S, Sabato V, Faber M, Leysen J, Bridts CH, De Clerck LS, et al. Basophilic histamine content and release during venom immunotherapy: insights by flow cytometry. Cytometry B Clin Cytom<\/em>. (2013) 84:173\u20138. doi: 10.1002\/cyto.b.21084<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>76. Jutel M, Muller UR, Fricker M, Rihs S, Pichler WJ, Dahinden C. Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils. Clin Exp Allergy<\/em>. (1996) 26:1112\u20138. doi: 10.1046\/j.1365-2222.1996.d01-259.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>77. Akoum H, Duez C, Vorng H, Fahy O, Wallaert B, Tonnel AB, et al. Early modifications of chemokine production and mRNA expression during rush venom immunotherapy. Cytokine<\/em>. (1998) 10:706\u201312. doi: 10.1006\/cyto.1998.0348<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>78. Bussmann C, Xia J, Allam JP, Maintz L, Bieber T, Novak N. Early markers for protective mechanisms during rush venom immunotherapy. Allergy<\/em>. (2010) 65:1558\u201365. doi: 10.1111\/j.1398-9995.2010.02430.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>79. Lesourd B, Paupe J, Thiollet M, Moulias R, Sainte-Laudy J, Scheinmann P. Hymenoptera venom immunotherapy. I. Induction of T cell-mediated immunity by honeybee venom immunotherapy: relationships with specific antibody responses. J Allergy Clin Immunol<\/em>. (1989) 83:563\u201371. doi: 10.1016\/0091-6749(89)90067-5<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>80. Mamessier E, Birnbaum J, Dupuy P, Vervloet D, Magnan A. Ultra-rush venom immunotherapy induces differential T cell activation and regulatory patterns according to the severity of allergy. Clin Exp Allergy<\/em>. (2006) 36:704\u201313. doi: 10.1111\/j.1365-2222.2006.02487.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>81. Schuerwegh AJ, De Clerck LS, Bridts CH, Stevens WJ. Wasp venom immunotherapy induces a shift from IL-4-producing towards interferon-gamma-producing CD4+<\/sup> and CD8+<\/sup> T lymphocytes. Clin Exp Allergy<\/em>. (2001) 31:740\u20136. doi: 10.1046\/j.1365-2222.2001.01066.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>82. Tilmant L, Dessaint JP, Tsicopoulos A, Tonnel AB, Capron A. Concomitant augmentation of CD4+<\/sup> CD45R+<\/sup> suppressor\/inducer subset and diminution of CD4+<\/sup> CDw29+<\/sup> helper\/inducer subset during rush hyposensitization in hymenoptera venom allergy. Clin Exp Immunol<\/em>. (1989) 76:13\u20138.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>83. Shamji MH, Ljorring C, Francis JN, Calderon MA, Larche M, Kimber I, et al. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy<\/em>. (2012) 67:217\u201326. doi: 10.1111\/j.1398-9995.2011.02745.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>84. Shamji MH, Ljorring C, Wurtzen PA. Predictive biomarkers of clinical efficacy of allergen-specific immunotherapy: how to proceed. Immunotherapy<\/em>. (2013) 5:203\u20136. doi: 10.2217\/imt.13.6<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>85. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol<\/em>. (2007) 120:707\u201313. doi: 10.1016\/j.jaci.2007.06.013<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>86. Jutel M, Akdis M, Blaser K, Akdis CA. Mechanisms of allergen specific immunotherapy\u2013T-cell tolerance and more. Allergy<\/em>. (2006) 61:796\u2013807. doi: 10.1111\/j.1398-9995.2006.01175.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>87. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+<\/sup>CD25\u2212<\/sup> naive T cells to CD4+<\/sup>CD25+<\/sup> regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med<\/em>. (2003) 198:1875\u201386. doi: 10.1084\/jem.20030152<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>88. Klunker S, Chong MM, Mantel PY, Palomares O, Bassin C, Ziegler M, et al. Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+<\/sup> inducible regulatory T cells. J Exp Med<\/em>. (2009) 206:2701\u201315. doi: 10.1084\/jem.20090596<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>89. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M. In vivo<\/em> switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med<\/em>. (2008) 205:2887\u201398. doi: 10.1084\/jem.20080193<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>90. Fallarino F, Grohmann U. Using an ancient tool for igniting and propagating immune tolerance: IDO as an inducer and amplifier of regulatory T cell functions. Curr Med Chem<\/em>. (2011) 18:2215\u201321. doi: 10.2174\/092986711795656027<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>91. Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest<\/em>. (1998) 102:98\u2013106. doi: 10.1172\/JCI2250<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>92. Botturi K, Vervloet D, Magnan A. T cells and allergens relationships: are they that specific? Clin Exp Allergy<\/em>. (2007) 37:1121\u20133. doi: 10.1111\/j.1365-2222.2007.02773.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>93. Radulovic S, Jacobson MR, Durham SR, Nouri-Aria KT. Grass pollen immunotherapy induces Foxp3-expressing CD4+<\/sup> CD25+<\/sup> cells in the nasal mucosa. J Allergy Clin Immunol<\/em>. (2008) 121:1467\u201372, 1472 e1. doi: 10.1016\/j.jaci.2008.03.013<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>94. Pereira-Santos MC, Baptista AP, Melo A, Alves RR, Soares RS, Pedro E, et al. Expansion of circulating Foxp3+<\/sup>)D25bright CD4+<\/sup> T cells during specific venom immunotherapy. Clin Exp Allergy<\/em>. (2008) 38:291\u20137. doi: 10.1111\/j.1365-2222.2007.02887.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>95. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol<\/em>. (2003) 33:1205\u201314. doi: 10.1002\/eji.200322919<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>96. Nasser SM, Ying S, Meng Q, Kay AB, Ewan PW. Interleukin-10 levels increase in cutaneous biopsies of patients undergoing wasp venom immunotherapy. Eur J Immunol<\/em>. (2001) 31:3704\u201313. doi: 10.1002\/1521-4141(200112)31:12<3704::AID-IMMU3704>3.0.CO;2-3<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>97. Varricchi G, Harker J, Borriello F, Marone G, Durham SR, Shamji MH. T follicular helper (Tfh) cells in normal immune responses and in allergic disorders. Allergy<\/em>. (2016) 71:1086\u201394. doi: 10.1111\/all.12878<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>98. Sage PT, Sharpe AH. T follicular regulatory cells. Immunol Rev<\/em>. (2016) 271:246\u201359. doi: 10.1111\/imr.12411<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>99. Schulten V, Tripple V, Seumois G, Qian Y, Scheuermann RH, Fu Z, et al. Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells. J Allergy Clin Immunol<\/em>. (2018) 141:775\u2013777.e6. doi: 10.1016\/j.jaci.2017.04.032<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>100. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Sollner S, Akdis DG, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol<\/em>. (2013) 131:1204\u201312. doi: 10.1016\/j.jaci.2013.01.014<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>101. Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity<\/em>. (2015) 42:607\u201312. doi: 10.1016\/j.immuni.2015.04.005<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>102. Deniz G, van de Veen W, Akdis M. Natural killer cells in patients with allergic diseases. J Allergy Clin Immunol<\/em>. (2013) 132:527\u201335. doi: 10.1016\/j.jaci.2013.07.030<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>103. Lao-Araya M, Steveling E, Scadding GW, Durham SR, Shamji MH. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol<\/em>. (2014) 134:1193\u20135.e4. doi: 10.1016\/j.jaci.2014.07.029<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>104. Lombardi V, Beuraud C, Neukirch C, Moussu H, Morizur L, Horiot S, et al. Circulating innate lymphoid cells are differentially regulated in allergic and nonallergic subjects. J Allergy Clin Immunol<\/em>. (2016) 138:305\u20138. doi: 10.1016\/j.jaci.2015.12.1325<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>105. Novak N, Mete N, Bussmann C, Maintz L, Bieber T, Akdis M, et al. Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2. J Allergy Clin Immunol<\/em>. (2012) 130:1153\u20138.e2. doi: 10.1016\/j.jaci.2012.04.039<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>106. Maintz L, Bussmann C, Bieber T, Novak N. Contribution of histamine metabolism to tachyphylaxis during the buildup phase of rush immunotherapy. J Allergy Clin Immunol<\/em>. (2009) 123:701\u20133. doi: 10.1016\/j.jaci.2008.11.009<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>107. Cavkaytar O, Akdis CA, Akdis M. Modulation of immune responses by immunotherapy in allergic diseases. Curr Opin Pharmacol<\/em>. (2014) 17:30\u20137. doi: 10.1016\/j.coph.2014.07.003<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>108. Akdis CA, Jutel M, Akdis M. Regulatory effects of histamine and histamine receptor expression in human allergic immune responses. Chem Immunol Allergy<\/em>. (2008) 94:67\u201382. doi: 10.1159\/000154858<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>109. Jutel M, Akdis M, Akdis CA. Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy<\/em>. (2009) 39:1786\u2013800. doi: 10.1111\/j.1365-2222.2009.03374.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>110. Mazzoni A, Young HA, Spitzer JH, Visintin A, Segal DM. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. J Clin Invest<\/em>. (2001) 108:1865\u201373. doi: 10.1172\/JCI200113930<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>111. Osna N, Elliott K, Khan MM. Regulation of interleukin-10 secretion by histamine in TH2 cells and splenocytes. Int Immunopharmacol<\/em>. (2001) 1:85\u201396. doi: 10.1016\/S0162-3109(00)00268-X<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>112. Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, Malolepszy J, et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature<\/em>. (2001) 413:420\u20135. doi: 10.1038\/35096564<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>113. Goldberg A, Confino-Cohen R. Bee venom immunotherapy\u2013how early is it effective? Allergy<\/em>. (2010) 65:391\u20135. doi: 10.1111\/j.1398-9995.2009.02198.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>114. Frick M, Fischer J, Helbling A, Rueff F, Wieczorek D, Ollert M, et al. Predominant Api m 10 sensitization as risk factor for treatment failure in honey bee venom immunotherapy. J Allergy Clin Immunol<\/em>. (2016) 138:1663\u201371.e9. doi: 10.1016\/j.jaci.2016.04.024<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>115. Blank S, Seismann H, Michel Y, McIntyre M, Cifuentes L, Braren I, et al. Api m 10, a genuine A. mellifera venom allergen, is clinically relevant but underrepresented in therapeutic extracts. Allergy<\/em>. (2011) 66:1322\u20139. doi: 10.1111\/j.1398-9995.2011.02667.x<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>116. Stretz E, Oppel EM, Rawer HC, Chatelain R, Mastnik S, Przybilla B, et al. Overcoming severe adverse reactions to venom immunotherapy using anti-IgE antibodies in combination with a high maintenance dose. Clin Exp Allergy<\/em>. (2017) 47:1631\u20139. doi: 10.1111\/cea.12997<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>117. Bousquet J, Menardo JL, Velasquez G, Michel FB. Systemic reactions during maintenance immunotherapy with honey bee venom. Ann Allergy<\/em>. (1988) 61:63\u20138.<\/p>\n\n\n\n

PubMed Abstract<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>118. Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol<\/em>. (2001) 108:1027\u201332. doi: 10.1067\/mai.2001.119154<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>119. Golden DB, Johnson K, Addison BI, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Clinical and immunologic observations in patients who stop venom immunotherapy. J Allergy Clin Immunol<\/em>. (1986) 77:435\u201342. doi: 10.1016\/0091-6749(86)90177-6<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>120. Muller UR, Ring J. When can immunotherapy for insect sting allergy be stopped? J Allergy Clin Immunol Pract<\/em>. (2015) 3:324\u20138. doi: 10.1016\/j.jaip.2014.11.018<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>121. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Discontinuing venom immunotherapy: outcome after five years. J Allergy Clin Immunol<\/em>. (1996) 97:579\u201387. doi: 10.1016\/S0091-6749(96)70302-0<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>122. Dhami S, Zaman H, Varga EM, Sturm GJ, Muraro A, Akdis CA, et al. Allergen immunotherapy for insect venom allergy: a systematic review and meta-analysis. Allergy<\/em>. (2017) 72:342\u201365. doi: 10.1111\/all.13077<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>123. Korosec P, Ziberna K, Silar M, Dezman M, Celesnik Smodis N, Rijavec M, et al. Immunological and clinical factors associated with adverse systemic reactions during the build-up phase of honeybee venom immunotherapy. Clin Exp Allergy<\/em>. (2015) 45:1579\u201389. doi: 10.1111\/cea.12582<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>124. Golden DB. Long-term outcome after venom immunotherapy. Curr Opin Allergy Clin Immunol<\/em>. (2010) 10:337\u201341. doi: 10.1097\/ACI.0b013e32833bc0ba<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>125. Muller U, Berchtold E, Helbling A. Honeybee venom allergy: results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients. J Allergy Clin Immunol<\/em>. (1991) 87:702\u20139. doi: 10.1016\/0091-6749(91)90392-2<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>126. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Seitz MJ, et al. Clinical effectiveness of hymenoptera venom immunotherapy: a prospective observational multicenter study of the European academy of allergology and clinical immunology interest group on insect venom hypersensitivity. PLoS ONE<\/em>. (2013) 8:e63233. doi: 10.1371\/journal.pone.0063233<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>127. Slade CA, Douglass JA. Changing practice: no need to stop ACE inhibition for venom immunotherapy. Clin Exp Allergy<\/em>. (2014) 44:617\u20139. doi: 10.1111\/cea.12295<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>128. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol<\/em>. (1998) 101:298\u2013305. doi: 10.1016\/S0091-6749(98)70239-8<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

<\/a>129. Mobs C, Muller J, Rudzio A, Pickert J, Blank S, Jakob T, et al. Decline of Ves v 5-specific blocking capacity in wasp venom-allergic patients after stopping allergen immunotherapy. Allergy<\/em>. (2015) 70:715\u20139. doi: 10.1111\/all.12606<\/p>\n\n\n\n

PubMed Abstract<\/a> | CrossRef Full Text<\/a> | Google Scholar<\/a><\/p>\n\n\n\n

Zdroj: https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2019.01959\/full<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

1. Skupina pre imunomodul\u00e1ciu a toleranciu, Alergia a klinick\u00e1 imunol\u00f3gia Z\u00e1pal, oprava a v\u00fdvoj, N\u00e1rodn\u00fd in\u0161tit\u00fat srdca a p\u013e\u00fac, Imperial College London, Lond\u00fdn, Spojen\u00e9 kr\u00e1\u013eovstvo2. Pediatrick\u00e9 oddelenie pre alergiu, Hacettepe University School of Medicine, Ankara, Turecko3. MRC and Asthma UK Center in Alergic Mechanisms of Asthma, Lond\u00fdn, Spojen\u00e9 kr\u00e1\u013eovstvo U\u0161tipnutie blanokr\u00eddlym hmyzom m\u00f4\u017ee sp\u00f4sobi\u0165 lok\u00e1lne […]<\/p>\n","protected":false},"author":1,"featured_media":257,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"ngg_post_thumbnail":0},"categories":[7],"tags":[],"yoast_head":"\nAlergia na jed blanokr\u00eddlovcov: Ako imunoterapia jedom zabra\u0148uje anafylaxii po bodnut\u00ed v\u010delou a osou? - apitoxin.sk<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"http:\/\/apitoxin.sk\/2022\/07\/27\/alergia-na-jed-blanokridlovcov-ako-imunoterapia-jedom-zabranuje-anafylaxii-po-bodnuti-vcelou-a-osou\/\" \/>\n<meta property=\"og:locale\" content=\"sk_SK\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Alergia na jed blanokr\u00eddlovcov: Ako imunoterapia jedom zabra\u0148uje anafylaxii po bodnut\u00ed v\u010delou a osou? - apitoxin.sk\" \/>\n<meta property=\"og:description\" content=\"1. 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