Publications
803 results found
Gunawardana NC, Durham SR, 2018, New approaches to allergen immunotherapy, Annals of Allergy, Asthma and Immunology, Vol: 121, Pages: 293-305, ISSN: 1081-1206
ObjectiveNew insights into mechanisms should enable strategic improvement of allergen immunotherapy, aiming to make it safer, faster, more effective, and able to induce long-term tolerance. We review novel approaches with potential to translate into clinical use.Data SourcesDatabase searches were conducted in PubMed, Scopus, and Google Scholar.Study SelectionsSearch terms were based on current and novel approaches in immunotherapy. Literature was selected primarily from recent randomized double-blinded placebo-controlled trials and meta-analyses.ResultsAlum, microcrystalline tyrosine, and calcium phosphate are adjuvants in current use. Toll-like receptor-4 agonists combined with allergen have potential to shorten duration of treatment. Other novel adjuvants, nanoparticles, and virus-like particles in combination with allergen have shown early promise. Omalizumab lessens systemic side effects but does not improve efficacy. Intralymphatic immunotherapy for aeroallergens, epicutaneous immunotherapy for food allergens, and use of modified allergens (allergoids), recombinant allergens (and hypoallergenic variants), and T- and B-cell peptide approaches have shown evidence of efficacy and permitted shortened courses but have only rarely been compared with conventional extracts.ConclusionNovel routes of immunotherapy, use of modified allergens, and combination of allergens with immunostimulatory adjuvants or immune modifiers have been developed to augment downregulation of T-helper cell type 2 immunity and/or induce “protective” blocking antibodies. Although these strategies have permitted shortened courses, confirmatory phase 3 trials are required to confirm efficacy and safety and head-to-head trials are required for comparative efficacy. Currently, subcutaneous and sublingual immunotherapies using in-house standardized crude extracts remain the only approaches proved to induce long-term tolerance.
Jakwerth CA, Shamji MH, Kappen JH, et al., 2018, Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper, ALLERGOLOGIE, Vol: 41, Pages: 376-385, ISSN: 0344-5062
Penagos M, Eifan AO, Durham SR, et al., 2018, Duration of allergen immunotherapy for long-term efficacy in allergic rhinoconjunctivitis, Current Treatment Options in Allergy, Vol: 5, Pages: 275-290, ISSN: 2196-3053
RationaleSubcutaneous and sublingual immunotherapy are effective for allergic rhinitis. An important question is whether allergen immunotherapy provides a sustained clinical effect after treatment cessation. In view of potential side effects, cost and the necessary patient commitment, long-term benefit is an important consideration for the recommendation of immunotherapy over standard pharmacotherapy.Purpose of reviewIn this review, we analyse the existing evidence for long-term effects of both routes of administration in the context of double-blind, placebo-controlled, randomised clinical trials that included a follow-up phase of at least 1 year after treatment cessation.Recent findingsOverall, evidence suggests that 3 years of either subcutaneous or sublingual immunotherapy result in clinical benefit and immunological changes consistent with allergen-specific tolerance sustained for at least 2–3 years after treatment cessation.SummaryThe data presented here support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years. Gaps in the evidence remain regarding the long-term efficacy of immunotherapy for perennial rhinitis and studies performed in children.
Pfaar O, Bastl K, Berger U, et al., 2018, Defining pollen exposure times for clinical trials of allergen immunotherapy for pollen-induced rhinoconjunctivitis - an EAACI position paper, ALLERGOLOGIE, Vol: 41, Pages: 386-399, ISSN: 0344-5062
Shamji MH, Temblay JN, Cheng W, et al., 2018, Antiapoptotic serine protease inhibitors contribute to survival of allergenic TH2 cells, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 569-581.e5, ISSN: 0091-6749
BACKGROUND: The mechanisms that regulate maintenance of persistent TH2 cells and potentiate allergic inflammation are not well understood. OBJECTIVE: The function of serine protease inhibitor 2A (Spi2A) was studied in mouse TH2 cells, and the serine protease inhibitor B3 (SERPINB3) and SERPINB4 genes were studied in TH2 cells from patients with grass pollen allergy. METHODS: Spi2A-deficient TH2 cells were studied in in vitro culture or in vivo after challenge of Spi2A knockout mice with ovalbumin in alum. Expression of SERPINB3 and SERPINB4 mRNA was measured in in vitro-cultured TH2 cells and in ex vivo CD27-CD4+ cells and innate lymphoid cell (ILC) 2 from patients with grass pollen allergy by using quantitative PCR. SERPINB3 and SERPINB4 mRNA levels were knocked down in cultured CD27-CD4+ cells with small hairpin RNA. RESULTS: There were lower levels of in vitro-polarized TH2 cells from Spi2A knockout mice (P < .005) and in vivo after ovalbumin challenge (P < .05), higher levels of apoptosis (Annexin V positivity, P < .005), and less lung allergic inflammation (number of lung eosinophils, P < .005). In vitro-polarized TH2 cells from patients with grass pollen allergy expressed higher levels of both SERPINB3 and SERPINB4 mRNA (both P < .05) compared with unpolarized CD4 T cells. CD27-CD4+ from patients with grass pollen allergy expressed higher levels of both SERPINB3 and SERPINB4 mRNA (both P < .0005) compared with CD27+CD4+ cells. ILC2 expressed higher levels of both SERPINB3 and SERPINB4 mRNA (both P < .0005) compared with ILC1. Knockdown of either SERPINB3 or SERPINB4 mRNA (both P < .005) levels resulted in decreased viability of CD27-CD4+ compared with control transduced cells. CONCLUSION: The Serpins Spi2A in mice and SERPINB3 and SERPINB4 in allergic patients control the viability of TH2 cells. This provides proof of princ
Layhadi JA, Matsuoka T, Scadding G, et al., 2018, Interleukin (IL)-35 producing T regulatory cells (iTR35) suppresses type II innate lymphoid cell (ILC2) and T helper 2 (Th2) cell function and are induced following grass pollen immunotherapy, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 43-43, ISSN: 0105-4538
Rey-Garcia H, Gunawardana N, Wheeler K, et al., 2018, The predictive value of allergy tests in the diagnosis of peanut allergy in adults, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 422-422, ISSN: 0105-4538
Moesges R, Demoly P, Lehmacher W, et al., 2018, Safety of a 3-week allergen immunotherapy course with grass pollen peptides: A randomised double-blind placebo-controlled trial, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 471-471, ISSN: 0105-4538
Auge J, Vent J, Agache I, et al., 2018, EAACI Position paper on the standardization of nasal allergen challenges, ALLERGY, Vol: 73, Pages: 1597-1608, ISSN: 0105-4538
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- Citations: 144
Dua S, Bond S, Boyle R, et al., 2018, The effect of sleep deprivation and exercise on peanut allergy thresholds: Insights from the Thresholds of Reactivity and Clinical Evaluation (TRACE) Study, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 55-55, ISSN: 0105-4538
Mösges R, Koch AF, Raskopf E, et al., 2018, Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B-cell response in seasonal allergic rhinitis patients, Allergy, Vol: 73, Pages: 1254-1262, ISSN: 0105-4538
BACKGROUND: Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short-course treatment with adjuvant-free Lolium perenne peptides (LPP) following a 6-week dose-escalation protocol. METHODS: In a prospective, dose-escalation study, 61 grass pollen-allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG4and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8). RESULTS: No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG4levels were higher at V6 (8.1-fold, P < .001) and V8 (12.2-fold, P < .001) than at V1. The sIgE:sIgG4ratio decreased at V6 (-54.6%, P < .001) and V8 (-71.6%, P < .001) compared to V1. The absolute decrease in IgE-facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8. CONCLUSION: Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.
Renand A, Shamji MH, Harris KM, et al., 2018, Synchronous immune alterations mirror clinical response during allergen immunotherapy, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1750-1760.e1, ISSN: 0091-6749
BACKGROUND: Three years treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The GRASS∗ trial demonstrated that two years treatment via either route was effective in suppressing the response to nasal allergen challenge, although was insufficient for inhibition one year after discontinuation. OBJECTIVE: To examine in the GRASS trial the time-course of immunologic changes during two years sublingual and subcutaneous immunotherapy and for one year after treatment discontinuation. METHODS: We performed multi-modal immunomonitoring to assess allergen-specific CD4 T cell properties, in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-Facilitated Allergen Binding). RESULTS: All three of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunological effect. Whereas frequencies of antigen-specific Th2 cells in peripheral blood determined by HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE-antibody dependent functional assays remained partially inhibited one year following discontinuation. CONCLUSION: Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific Th2 cells most closely paralleled the transient clinical outcome and it is likely that recurrence of the T cell 'drivers' of allergic immunity abrogated the potential for durable tolerance. On the other hand, persistence of IgE-blocking antibody one year after discontinuation may be an early indicator of a pro-tolerogenic mechanism.
Durham SR, Smurthwaite L, Gould HJ, 2018, Local IgE production, AMERICAN JOURNAL OF RHINOLOGY, Vol: 14, Pages: 305-307, ISSN: 1050-6586
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- Citations: 21
Muraro A, Roberts G, Halken S, et al., 2018, EAACI guidelines on allergen immunotherapy: Executive statement, ALLERGY, Vol: 73, Pages: 739-743, ISSN: 0105-4538
Roberts G, Pfaar O, Akdis CA, et al., 2018, EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis, ALLERGY, Vol: 73, Pages: 765-798, ISSN: 0105-4538
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- Citations: 388
Turner PJ, Garcia MR, Skypala IJ, et al., 2018, CHANGES IN METABONOMIC PROFILE DURING PEANUT-INDUCED ANAPHYLAXIS AND CORRELATION WITH SYMPTOM, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB85-AB85, ISSN: 0091-6749
Singh I, Sharif H, Kouser L, et al., 2018, Short Course of <i>Lolium Perenne</i> Peptides (LPP) Immunotherapy Induces IL-35<SUP>+</SUP> T Regulatory Cells (iTr35) that Promote B Regulatory Cells (Bregs) and Blocking Antibodies, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB122-AB122, ISSN: 0091-6749
Mosges R, Bachert C, Creticos PS, et al., 2018, Quality of Life during the hay fever season after short-course subcutaneous immunotherapy with Lolium perenne peptides (LPP) in grass pollen related rhinoconjunctivitis: A RDBPCT, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB291-AB291, ISSN: 0091-6749
Sharif H, Karamani A, Parkin R, et al., 2018, Short Course of Lolium Perenne Peptides (LPP) Immunotherapy Deletes Circulating IL-4<SUP>+</SUP>IL-21<SUP>+</SUP> T follicular helper cells and Induces FoxP3<SUP>+</SUP> T follicular regulatory cells: A Randomized Controlled Trial, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB197-AB197, ISSN: 0091-6749
Rajakulasingam RK, Farah N, Huber PAJ, et al., 2018, Practice and safety of allergen-specific immunotherapy for allergic rhinitis in the UK national health service: A report of "real world" clinical practice, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 48, Pages: 89-92, ISSN: 0954-7894
Mösges R, Kasche EM, Raskopf E, et al., 2017, A randomized, double-blind, placebo-controlled, dose-finding trial with Lolium perenne peptide immunotherapy, Allergy, Vol: 73, Pages: 896-904, ISSN: 0105-4538
BACKGROUND: A novel subcutaneous allergen immunotherapy formulation (gpASIT+™) containing Lolium perenne peptides (LPP) and having a short up-dosing phase has been developed to treat grass pollen-induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety. METHODS: This prospective, double-blind, placebo-controlled, phase IIb, parallel, four-arm, dose-finding study randomized 198 grass pollen-allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen-specific immunoglobulins were analysed before and after treatment. RESULTS: Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per-protocol set). Also, 39% of patients in the 170-μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen-binding assays revealed a highly significant (P < .001) dose-dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG4 levels increased to 1.6-fold (70 μg), 3.1-fold (170 μg) and 3.9-fold (370 μg) (mPP). CONCLUSION: Three-week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies.
Shamji M, Durham SR, 2017, Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers, Journal of Allergy and Clinical Immunology, Vol: 140, Pages: 1485-1498, ISSN: 0091-6749
Allergen immunotherapy is effective in patients with IgEdependentallergic rhinitis and asthma. When immunotherapyis given continuously for 3 years, there is persistent clinicalbenefit for several years after its discontinuation. This diseasemodifyingeffect is both antigen-specific and antigen-driven.Clinical improvement is accompanied by decreases in numbersof effector cells in target organs, including mast cells, basophils,eosinophils, and type 2 innate lymphoid cells. Immunotherapyresults in the production of blocking IgG/IgG4 antibodies thatcan inhibit IgE-dependent activation mediated through bothhigh-affinity IgE receptors (FcεRI) on mast cells and basophilsand low-affinity IgE receptors (FcεRII) on B cells. Suppressionof TH2 immunity can occur as a consequence of either deletionor anergy of antigen-specific T cells; induction of antigenspecificregulatory T cells; or immune deviation in favor of TH1responses. It is not clear whether the altered long-term memoryresides within the T-cell or the B-cell compartment. Recent datahighlight the role of IL-10–producing regulatory B cells and‘‘protective’’ antibodies that likely contribute to long-termtolerance. Understanding mechanisms underlying induction andpersistence of tolerance should identify predictive biomarkers ofclinical response and discover novel and more effectivestrategies for immunotherapy.
Saleh AD, Clarke NK, Meng C, et al., 2017, DEVELOPMENT OF ASSAYS TO ASSESS SAFETY AND EFFICACY OF LENTIVIRAL GENE THERAPY FOR CYSTIC FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A57-A57, ISSN: 0040-6376
Garcia HR, Gunawardana N, Scadding G, et al., 2017, The value of allergy tests in predicting the outcome of oral food challenges to peanuts and tree nuts in adults, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY, Pages: 1718-1718, ISSN: 0954-7894
Fedina A, Scadding G, Durham S, 2017, Patient experiences of clinical research participation survey, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY, Pages: 1715-1715, ISSN: 0954-7894
Gunawardana N, Matthews D, Rey-Garcia H, et al., 2017, Adherence to BSACI guidance on drug allergy testing at a UK allergy centre, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY, Pages: 1687-1687, ISSN: 0954-7894
Eifan A, Scadding G, Calderon M, et al., 2017, Relationship between response to grass pollen nasal allergen challenge and seasonal symptoms and the effect of treatment compliance, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY, Pages: 1686-1687, ISSN: 0954-7894
Dhami S, Nurmatov U, Roberts G, et al., 2017, Erratum to: Allergen immunotherapy for allergic rhinoconjunctivitis: protocol for a systematic review., Clinical and Translational Allergy, Vol: 7, ISSN: 2045-7022
[This corrects the article DOI: 10.1186/s13601-016-0099-6.].
Qaseem AS, Singh I, Pathan AA, et al., 2017, A Recombinant Fragment of Human Surfactant Protein D Suppresses Basophil Activation, Th2 and B Cell Responses in Grass Pollen-induced Allergic Inflammation., American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1526-1534, ISSN: 1073-449X
RATIONALE: rfhSP-D has been shown to suppress house dust mite and Aspergillus fumigatus-induced allergic inflammation in murine models. OBJECTIVES: We sought to elucidate the effect of rfhSP-D on FcεRI and CD23-mediated grass pollen induced allergic inflammatory responses. METHODS: rfhSP-D, containing homotrimeric neck and lectin domains, was expressed in Escherichia coli BL21 (λDE3) pLysS. PBMCs and sera were obtained from grass pollen allergic individuals (n=27). The effect of rfhSP-D on basophil activation and histamine release was measured by flow cytometry. IgE-facilitated allergen binding and presentation was assessed by flow cytometry. Th2 cytokines were measured in cell culture supernatants. The effect of rfhSP-D on IgE production by B cells when stimulated with CD40L, IL-4 and IL-21 was also determined. RESULTS: rfhSP-D bound to Phleum pratense in a dose- and calcium-dependent manner. Allergen-induced basophil responsiveness and histamine release was inhibited in the presence of rfhSP-D, as measured by CD63, CD203c (P=0.0086,P=0.04205), and intracellular-labelled DAO (P=0.0003,P=0.0148). The binding of allergen-IgE complexes to B cells was reduced by 51%(P=0.002) in the presence of rfhSP-D. This decrease was concomitant with reduction in CD23 expression on B cells (P<0.001). rfhSP-D suppressed allergen-driven CD27-CD4+CRTH2+ T cell proliferation (P<0.01), IL-4 and IL-5 levels (all,P<0.01). Moreover, rfhSP-D inhibited CD40L/IL-4 and IL-21-mediated IgE production(77.12%; P=0.02) by B cells. CONCLUSION: For the first time, we show that rfhSP-D inhibited allergen-induced basophil responses at a single cell, level and suppressed CD23-mediated facilitated allergen presentation and Th2 cytokine production. In addition, rfhSP-D inhibited IgE synthesis by B cells, which is also a novel observation.
Hellings PW, Fokkens WJ, Bachert C, et al., 2017, Positioning the principles of precision medicine in care pathways for allergic rhinitis and chronic rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS ICP statement, Allergy, Vol: 72, Pages: 1297-1305, ISSN: 0105-4538
Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second‐level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long‐term therapeutic strategy. Endotype‐driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment.
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