06 Canani
52
0
0
Testo completo
(2) ↑ Rischio di persistenza e severità delle manifestazioni cliniche ↑ Necessità di ospedalizzazione ↑ Impatto economico ↑ Rischio di sviluppare altre malattie atopiche (>50% asma, eczema, orticaria, oculorinite). Favorire sviluppo e mantenimento della tolleranza orale Host A, et al. PAI 2002 Skripak JM, et al. JACI 2007 Ross MP, et al. JACI 2008 Wang J, et al. JCI 2011 Chen FM, et al. JMII 2012 Virta LJ et al. JPGN 2013 Gupta R, et al. JAMA Ped 2013 Berni Canani R et al. Clin Exp Allergy 2013 Nocerirno R et al. JACI 2015.
(3) Tolleranza orale: soppressione risposta immunitaria ad Ag della dieta mediata da cellule T regolatorie Ag-specifiche. Modulazione dinamica indotta sin dalle prime epoche della vita dalla esposizione a fattori ambientali (dieta) e dallo sviluppo del microbiota intestinale Di Costanzo M and Berni Canani R JPGN 2016.
(4) Principali fattori coinvolti nell’acquisizione della tolleranza orale: fattori dietetici e microbiota. Kim KS et al. Science, 2016.
(5) L’assenza di peptidi nella dieta inibisce l’acquisizione di tolleranza: effetti della dieta elementare • Ridotti livelli di Ig sieriche • Ridotto numero linfociti nella lamina propria del piccolo intestino • Ridotte dimensioni delle placche del Payer • Ridotto numero di FoxP3+ CD4+ Treg • Aumentata produzione di IgE specifiche • Aumentare severità della risposta allergica Pereira P, et al. Eur J Immunol 1986 Wastmann BS, et al. Proc Soc Exp Biol Med 1991 Kim KS et al. Science 2016.
(6) • Parto cesareo • Formula • Antibiotici • Inibitori dell’acidità gastrica • Dieta ricca di grassi saturi e povera di fibre. Modified from Maynard CL, et al. Nature 2012.
(7) AA IN UN PAESE INDUSTRIALIZZATO. Smith PK, JACI 2016 in press.
(8) AGEs (Advanced Glycation End Products). COMPOSTI CHIMICI PRODOTTI DALLA COMBINAZIONE DI ZUCCHERI CON PROTEINE O GRASSI (GLICAZIONE AVANZATA) Superfici dorate o abbrustolite di cibi fritti o grigliati, pane tostato, ecc.. Smith PK, JACI 2016 in press.
(9) Antibiotic use by the mother. Antibiotic use by the child.
(10)
(11) Modello di topo “umanizzato” Germ Free C3H/HeN 3 wks old. Inoculated by gavage with fecal sample from. CMA infants. Healthy infants.
(12) La colonizzazione del tratto GI con feci di lattante sano protegge dall’AA Oral challenge with 50mg of BLG two times, 30 min apart. Body temperature BLG-specific IgE. GF C3H/HeN 3-4 weeks old. Sensitization with 20 mg of BLG using 10 μg CT as adjuvant. Fecal trasplant weaning. days. 4. 11. 18. 25. 32. 39 40. Berni Canani R and Nagler C, submitted.
(13) MICROBIAL RELATED FACTORS INCREASING RISK OF FOOD ALLERGY. Caesarean delivery. Disinfectant and antiseptic agent. Junk foods. Diet. Antibiotics and Gastric acidity inhibitors. Single children. Pets. Farming lifestyle. Diet Increasing family size and communal childcare. High fiber foods. Home made foods. Raw milk Fermented foods. Probiotics and expouse to increase variety and aboundance of microorganisms. MICROBIAL RELATED FACTORS REDUCING RISK OF FOOD ALLERGY. Berni Canani R et al. Biotascope in press.
(14)
(15) MICROBIOTA e APLV Disbiosi caratterizzata da ridotta presenza di batteri produttori di butirrato Disbiosi precede la comparsa di APLV Alcuni ceppi di probiotici possono modificare composizione e funzioni del microbiota intestinale del bambino affetto da APLV.
(16)
(17) Rare. Strain-specific effects. Neurological effects Immunological effects Endocrinological effects Production of specific bioactives. Frequent. Observed at species level. Vitamin synthesis Direct antagonism Gut barrier reinforcement. Bile salt metabolism Enzymatic activity Neutralization of carcinogens. Widespread. Among studied probiotics. Colonisation resistance Enterocytes growth Regulation of intestinal transit. Normalization of perturbed microbiota Competitive exclusion of pathogens 2014;11:506–14.
(18) “Curare” la disbiosi del bambino con APLV? L.casei CRL431/B. lactis Bb12 L.rhamnosus GG. L.acidophilus LAVRI A1. Berni Canani R et al. Curr Opin Allergy Clin Immunol 2015.
(19) LGG expands protective bacteria in the gut lumen of CMA infants. * p < 0.005. ORDER FAMILY GENUS. Clostridiales Ruminococcaceae Faecalibacterium prausnitzii. Clostridiales Veillonellaceae Acidaminococcus. Erysipelotrichales Erysipelotrichaceae Eubacterium Modified from Berni Canani R, et al. ISME Journal 2015.
(20) Early-life gut microbiome composition and milk allergy resolution. Bunyavanich S edt al. JACI in press.
(21) LGG expands butyrate-producing bacteria in CMA infants. * p < 0.005. Modified from Berni Canani R, et al. ISME Journal 2015.
(22) LGG: The Peace-keeper for CMA LGG. Modified from Velasquez-Manoff M. Nature 2015.
(23) LGG accelerates cow’s milk protein tolerance acquisition Rate of children with IgE-mediated CMA acquiring tolerance at 12 m. % of patients. P=0.046. Berni Canani R, et al. 2012.
(24) EHCF+LGG leads to tolerance at an earlier age than other formulae Rate of children with IgE-mediated CMA acquiring tolerance at 12 m. P<.0001. % of children. P=.002 P=<.0001 P =.027. Berni Canani R, et al. 2013.
(25) p<.01.
(26) EHCF+LGG Fibers/Probiotics. G Protein-coupled Receptors.
(27) Epigenetics mechanisms: heritable changes in gene expression not involving changes in DNA primary sequence Epigenetic mechanisms regulate FA diseases course Berni Canani R et al. Nutr Res Rev 2011 Berni Canani R et al. Clin Epigenet 2015.
(28) Dietary and enviromental factors/ probiotics.
(29) LGG aumenta il numero di batteri produttori di butirrato: attivazione di meccanismi epigenetici •Modulation of histone deacetylases 6 and 9 •Th1 cytokine genes demethylation. Up-regulation of Th1 response. •Treg activation through DNA demethylation. •Selective miRNAs modulation. Down-regulation of Th2 response Berni Canani R et al. Clin Epigenet 2015 Paparo L et al. Clin Epigenet 2016.
(30) Modulation of TSDR FoxP3 demethylation rate during CMA disease course. Paparo L et al. Clin Epigenet 2016.
(31) New Targets: New Strategies of Intervention Genetic programming. Dietary strategy Gut microbiota Epigenetic regulation of gene expression. Offspring phenotype.
(32) Prospective study: Preventive effect elicited by LGG on atopic manifestations in CMA children Children with sure diagnosis of IgE-mediated CMA Randomization Group 1 EHCF. Group 2 EHCF+LGG. 1° year 2° year 3° year. Occurrence of other allergic manifestations (atopic eczema, urticaria, asthma, oculorhinitis). Berni Canani R, et al. 2016 submitted.
(33) Oral Tolerance Acquisition. Berni Canani R 2016 submitted.
(34) Rate of subjects experienced ≥ 1 atopic manifestation ITT, n=110/group. Berni Canani R 2016 submitted.
(35) Conclusioni • Persistenza e severità dell’AA sono sensibilmente aumentate nelle ultime 2 decadi • Ruolo rilevante di fattori ambientali che agiscono direttamente o indirettamente (“disbiosi”) sul sistema immunitario attraverso meccanismi epigenetici • La conoscenza di questi meccanismi ha reso possibile l’individuazione di nuove strategie di intervento • Modulando positivamente questi meccanismi è possibile favorire l’acquisizione della tolleranza e proteggere dalla marcia atopica il bambino con APLV.
(36) Team University of Naples “Federico II”. University of Chicago. CEINGE Advanced Biotechnologies F.Salvatore, M.Capasso, V.D’Argenio, V.Del Monaco. Dept. of Pathology C.Nagler, P.Johnston, T.Feehley. Dept. of Biology M.P.Mollica, G.Trinchese Dept. of Experimental Pharmacology A.Calignano, R.Meli, D.Tronino, C.Pirozzi Dept. of Translational Medical Science Pediatric Allergy Unit R.Nocerino, L.Paparo, R.Aitoro, L.Cosenza, V.Granata, M.diCostanzo, L.Leone, A.Amoroso,T.Cozzolino, C.DiScala, V.Pezzella, Y.Maddalena, B.Buono, G.Gioielli. Argonne National Labs J.Gilbert, D.Antonopoulos, Comer Children's Hospital – Pediatric GI Unit S.Guandalini, T. Patton.
(37)
(38) Dati da modelli animali C3H/HeJ 3-4 weeks old. • Animali Germ-free • Trattamento con antibiotici • Assenza di TLR4. Maggiore suscettibilità per lo sviluppo di AA. Bashir MEH et al. J Immunol 2004 Sefik E et al. Science 2015 Ohnmacht C et al. Science 2015.
(39) Different DNA methylation rate of IL-4, IL-5, IL-10, INF-γ genes observed in children who outgrew CMA receiving different formulae 90. p=0.026. p=0.001. p=0.037. p=0.014. 80 70 60. %. 50. Tolerants with EHCF+LGG. 40. Tolerants with other formulae (EHCF, RHF, AAF, SF). 30 20 10 0. IL-5. IL-4. IFN γ. IL-10 Berni Canani R, et al. 2015.
(40) Dietary influence on epigenetic mechanisms in children with IgE-mediated cow’s milk allergy IL-4 gene DNA methylation rate. Nocerino R et al. EAACI MEETING 2016.
(41)
(42) IgE-mediated CMA children treated with EHCF+LGG show higher butyrate serum levels. Butyrate concentration in systemic circulation = 0.1 to 1.2 mM (Cummings JH et al. Gut 1987) Berni Canani R data on file.
(43) Butyrate stimulates mucus production and MUC2 expression in human enterocytes Dose. Thickness (µm) p= 0.045. CTRL. -. p=0.0023 p< 0.0001. 0.1mM. 3±2. 0.5mM. 5±2. 1mM. -. 2mM. Berni Canani R data on file.
(44)
(45) Butyrate induces MUC2-DNA demethylation in human enterocytes. mM Berni Canani R data on file.
(46) The Changing Pattern of CMA + Increased risk of persistence until later ages + Increased severity of clinical manifestations + Increased need of hospitalization + Increased economic impact + Increased risk of atopic march (>50% asthma, atopic eczema, allergic rhinitis) = Strong need to develop effective strategies to stimulate oral tolerance acquisition. Skripak JM, et al. JACI 2007 Ross MP, et al. JACI 2008 Wang J, et al. JCI 2011 Chen FM, et al. JMII 2012 Virta LJ et al. JPGN 2013 Gupta R, et al. JAMA Ped 2013 Prescott SL et al. WAO J 2013 Berni Canani R, et al. Clin Exp All 2013 Nocerino R, et al. JACI 2015.
(47) Berni Canani R et al. 2016.
(48) Oral tolerance: suppression of immune response to dietary antigens mediated by Ag-specific regulatory T cells. A dynamic modulation of this network is introduced at birth by exposure to enviromental factors and by acquisition of gut microbiota. Di Costanzo M and Berni Canani R JPGN 2016.
(49) Conflicts of Interest Disclosure In the past 12 months, I have had the following relevant financial relationships with the following manufacturers of any commercial product discussed in this lecture: Danone (research grant), Humana (research grant), Kraft-Heinz (research grant, speaker), Mead Johnson Nutriton (research grant, speaker), Novalac (research grant) as part of publically funded research projects with support of the Italian Ministry of Health..
(50)
(51)
(52) Lactobacillus rhamnosus CGMCC 1.3724, 2x1010 CFU/day.
(53)
Documenti correlati
In this study, we comparatively analyzed the profile of immune reactivity to b-LG in four different groups of children: 1) with IgE-mediated CMA; 2) with non-IgE-mediated CMA; 3)
Subsequently, we stimulated PBMCs from healthy children and IgE-mediated CMA patients, with BLG in the absence, or in the presence of 0.75 mM butyrate to verify whether
Lac- tose intolerance and gastrointestinal cow’s milk allergy in infants and children - common misconceptions revisited.. World Allergy Or-
n EPIGENETIC REGULATION Epigenetic regulatory mechanisms com- prise DNA methylation, a variety of his- tone modifications, and microRNA activ- ity, all of which act
It seems that it is true only for patients with IgE-mediated food allergy; instead, SNAS is not IgE-mediated allergy but sys- temic symptoms are due to nickel ingestion through
AD: Atopic dermatitis; AIT: Allergen ImmunoTherapy; CM: Cow milk; DBPC: Double-blind, placebo controlled; EA: Egg allergy; EPIT: Epi-cutaneous immunotherapy; FA: Food allergy;
• In settings where oral food challenge is considered a requirement for making a diagnosis of IgE-mediated cow’s milk allergy, we recommend using oral food challenge with cow’s milk
Omalizumab therapy in the three pa- tients with moderate-severe asthma and concomitant IgE-mediated CMA was started with the dual purpose of achieving better asthma control
