Βρογχικό άσθμα: Χρόνια φαρμακευτική αγωγή ή Απευαισθητοποίηση; Πού και πότε Μιχαήλ Δανιηλίδης Καθηγητής Παθολογίας - Ανοσολογίας Ιατρικής Σχολής Αριστοτέλειου Πανεπιστημίου Θεσσαλονίκης A Παθολογική Κλινική A.Π.Θ., Γ.Π.N. AXEΠA
ANOΣOΛOΓIKA NOΣHMATA (II) II. H ANOΣIAKH AΠANTHΣH YΠEYΘYNH: A) Eξωάνοσα νοσήματα (Eξωαντιγόνο) Aλλεργικά νοσήματα (Νοσήματα υπερευαισθησίας άμεσου τύπου, τύπου Ι) B) Aυτοάνοσα νοσήματα (Aυτοαντιγόνο) Oργανοειδικά και μη οργανοειδικά αυτοάνοσα νοσήματα Γ) Aλλοάνοσα νοσήματα (άλλο ή ισο αντιγόνο) 1. Aπόρριψη μοσχεύματος 2. Aντίδραση μοσχεύματος κατά ξενιστή (GvHD) 3. Aντιδράσεις μεταγγίσεων 4. Aιμολυτική νόσος του νεογνού 5. Aνοσιακές αποβολές Δ) Ξενοάνοσα νοσήματα (Ξενοαντιγόνο)
Source documents EAACI Immunotherapy Position Paper 1993 Position Paper on Allergen Immunotherapy. Report of BSACI Working Party 1993 WHO Position Paper on Immunotherapy 1998 EAACI Local Immunotherapy 1998 ARIA: Allergic Rhinitis Its Impact on Asthma 2001 Allergen Immunotherapy: A Practice Parameter ACAAI 2003
Allergen Immunotherapy for Asthma 76 trials with 3,188 patients Significant improvement in asthma symptom scores Significant reduction of allergen specific bronchial hyperreactivity Some reduction also in non-specific bronchial hyperreactivity Abramson, Weiner and Puy, Cochrane Database Systematic Review 2003
Allergen Immunotherapy for Asthma Safety Millions of subcutaneous immunotherapy injections are administered annually. The risk of a fatal or near-fatal systemic reaction is extremely small, but not completely absent. Physicians prescribing or administering subcutaneous immunotherapy should be aware of these risks and institute appropriate procedures to minimize them.
Schematic representation of the specific immune response Allergen Immunotherapy for Asthma
PYΘMIΣH THΣ ANOΣIAKHΣ AΠANTHΣHΣ 1) Γενετικός έλεγχος 2) Aντιγόνο - Ανοσογόνο (Αλλεργιογόνο) 3) Αντίσωμα 4) Kυτταροκίνες 5)Τ-λεμφοκύτταρα 6) Χημειοκίνες και άλλα μόρια
Chromosomes & genes in Immunoregulation
HLA τάξης II (DRB1, DQA1, DQB1) και παρουσίαση του Ag
HLA-B7,DR2, and HLA-B8,DR3 haplotypes distinguish subjects with asthma from those with rhinitis only in ragweed pollen allergy M Blumenthal, D Marcus-Bagley, Z Awdeh, B Johnson, EJ Yunis and CA Alper. University of Minnesota, Minneapolis 55455. The extended MHC haplotype HLA-B7 / DR2 found almost exclusively among the patients with IgE anti-amb a V.. significantly elevated in patients with asthma. The extended haplotype HLA-B8/DR3 & DR3 in general: increased among patients with rhinitis only, without IgE anti-amb a V HLA-B8DR3: "protective" for asthma & IgE anti-amb a V production? Immume response to an as yet unidentified Ag associated with ragweed allergy and rhinitis only? The Journal of Immunology, Vol 148, Issue 2 411-416, 1992
The influence of HLA-DR4 (0401) on the immune response to type II collagen and the development of collagen induced arthritis in mice Wang D, Hill JA, Cairns E, Bell DA J Autoimmun. 2002 Mar; 18(2): 95-103
HLA antigens in Greek children with allergic bronchial asthma. 60 Greek children with allergic bronchial asthma due to mite sensitivity (D.pteronyssinus and D.farinae) and family members (total 263 subjects). 125 healthy, unrelated Greek children without med. history of atopy (control group) HLA-DRB1*04 & HLA-DQA1*0301 development of atopic asthma in Greek children with sensitivity to mites. HLA-DQB1*0301-4 associated with high levels of total serum IgE in affected children. Parapanissiou E, Papastavrou T, Deligiannidis A, Adam K, Kanakoudi F, Daniilidis M, Polymenidis Z. Tissue Antigens. 2005 May; 65(5):481-4.
Can HLA typing predict the outcome of grass pollen immunotherapy? OBJECTIVE: relationship between HLA molecules and the positive or negative response of atopic patients to specific immunotherapy (SIT). 42 atopic multisensitive pts undergoing grass pollen immunotherapy, 42 parents of pts (30 mothers and 12 fathers) 173 controls HLA- A2, B14 and DRB1*1101-4 response to IT HLA-A28, A28, B8 and DRB1*0301 significantly higher in pts who responded poorly to SIT. HLA molecules : role in the immunological selection & monitoring of allergic patient candidacy for SIT. Fleva A, Daniilidis M, Sidiropoulos J, et al. Exp Clin Immunogenet. 2001;18(1):13-23.
A common exonic variant of interleukin 21 confers susceptibility to atopic asthma Activated CD4+ T cells IL-21 regulates IgE production (allergic disorders and asthma) Pts (n = 255), controls (n = 245), nuclear families (n = 140) IL21 polymorphism C5250T serum IL-21 levels in atopic asthmatics IL21 exon-3 polymorphism C5250T signif. associated with atopic asthma and serum total IgE Chatterjee et al. 2009.Int Arch Allergy Immunol.;148(2):137-46
Πολυμορφισμοί κυτταροκινών Ασθενείς/ Μάρτυρες Νόσημα IL13 Arg130Gln (Gln/Gln) 133/1513 p<0,05 Ατοπικό άσθμα,αλλεργική ρινίτιδα, IgE Howard 2001 IL13-1055 CT (T/T) 47/746 p<0,05 Άσθμα He 2003 IL4-34C/T p<0,001 Άσθμα -590C/T +33C/T Ατοπικό άσθμα Αλλεργική ρινίτιδα IgE,NFkB IL4RA Arg576Glu p<0,001 Ύπερ-IgE,Ατοπική Δερματίτιδα Chatila 2000 IL4RA R576Q (R576Q/R576Q) 386/1665 p<0,05 Ατοπικό και ήπιο/μέτριο άσθμα Hytonen 2004 IL4RA lle50val (lle/lle) 396/1087 p<0,05 Άσθμα, Ατοπική δερματίτιδα Risma 2002 IL6(-174G>C)GG GC CC IL18(-137G>C)GG GC CC IL10(-1082G>A)GG GA AA IL10(-819C>T) CT TT 393/1112 (NS) 537/1380 (p=0.21) 169/451 (p=0.74) 555/1619 (NS) 468/1117 (p=0.004) 82/217 (p=0.6) 60/48 (NS) 96/50 (p=0.08) 36/26 (p=0.66) 77/42 (p=0.35) 11/12 (p=0.32) Αλλεργική ρινίτιδα (Εποχική) Blumenthal 2004 Imboden 2006 Αλλεργική ρινίτιδα (Εποχική) Blumenthal 2004 Imboden 2006 Αλλεργική ρινίτιδα (Εποχική) Blumenthal 2004 Imboden 2006 Αλλεργική ρινίτιδα (Εποχική) Imboden 2006 IFNγ (rs1861494)a/g 189/270 (p=0.006) Ατοπικό άσθμα και εξέλιξη νόσου Kumar 2008 IL21 C5250T 255/245/ (140 οικογ.) Άσθμα και IgE Chatterjee 2009
CD4+ ρυθμιστικά T λεμφοκύτταρα Σύγκριση των δύο υποπληθυσμών CD4+ CD25+ Treg Ομοιότητες Tr1/ TH3 Πυροδότηση από ειδικό αντιγόνο Έκκριση ΙL-10/ TGFβ Αναπαντητικότητα σε anti-cd3 in vitro Πυροδότηση από ειδικό αντιγόνο Έκκριση ΙL-10/ TGFβ Αναπαντητικότητα σε anti-cd3 in vitro Διαφορές Προέλευση: θύμος Εκφράζουν Foxp3 μεταγραφικό παράγοντα CD25, CD45R Εξάρτηση από κυτταρική επαφή Χρειάζονται IL-2 για καταστολή Προέλευση: περιφέρεια Δεν εκφράζουν Foxp3 παράγοντα Ποικίλλη έκφραση CD25, CD45R, CD45RO Ανεξάρτητα από κυτταρική επαφή Δεν χρειάζονται IL-2 για καταστολή
Συνύπαρξη αλλεργίας και αυτοανοσίας Certain allergies and autoimmunity can be mapped to specific gene loci.
Allergen Immunotherapy Can Modify the Natural History of Allergy? SCIT and SLIT-swallow administered for several years (3 to 5 years) - efficacy is maintained for up to 3 or more years after discontinuation. SCIT could prevent the onset of asthma in children with allergic rhinitis.
Peptide immunotherapy in allergic asthma generates IL-10- dependent immunological tolerance associated with linked epitope suppression. Campbell JD, Buckland KF, McMillan SJ, et al. UK Centre for Allergic Mechanisms of Asthma, London SW7 2 AZ, UK. human asthma and a transgenic mouse model of asthma: induction of IL-10(+) T cells in vivo evidence of linked epitope suppression and IL-10 induction in human allergic disease and a mouse model J Exp Med. 2009 Jul 6;206(7):1535-47. Epub 2009 Jun 15.
How early should we consider Immunotherapy? Prevention of Asthma Onset Preventive Allergy Treatment study in N. Europe: Development of new allergies is decreased and the progression to asthma is decreased 50% reduction in asthma in children with moderate to severe allergic rhinitis who received IT compared to those without IT Moller C. et al, JACI 2002;109:251-256
immunotherapy effectiveness specialist prescription may alter the natural course of the disease patient's education always indicated (Allergic) ASTHMA patient Allergen avoidance indicated when possible pharmacotherapy safety effectiveness easy to be administered
Allergen Immunotherapy for Asthma CONCLUSION I Allergen immunotherapy is the only treatment that can modify the natural history of allergic disease. Safety (patient selection) Efficacy Less expensive Early administration to prevent asthma Combinaion Therapy SCIT and SLIT- swallow can prevent new sensitizations Symtoms reduction also in non-specific bronchial hyperreactivity
Novel Approaches New immunological treatment modalities for allergic diseases are presently under investigation: Peptide vaccination Recombinant allergens cdna vaccines Anti-IgE antibodies combined with IT Liposome vaccines Adjuvants NEW patient s selection criteria?
CONCLUSION II Allergen Specific Immunotherapy VS Pharmacologic Treatment Specific immunotherapy does not take the position of being an ultimate treatment principle. It should be part of the global treatment, and should be used in the early phase of the disease.