Publications by authors named "Stephen J Till"

39 Publications

Non-specific lipid-transfer proteins: Allergen structure and function, cross-reactivity, sensitization, and epidemiology.

Clin Transl Allergy 2021 May 18;11(3):e12010. Epub 2021 May 18.

Peter Gorer Department of Immunobiology King's College London London UK.

Background: Discovered and described 40 years ago, non-specific lipid transfer proteins (nsLTP) are present in many plant species and play an important role protecting plants from stressors such as heat or drought. In the last 20 years, sensitization to nsLTP and consequent reactions to plant foods has become an increasing concern.

Aim: The aim of this paper is to review the evidence for the structure and function of nsLTP allergens, and cross-reactivity, sensitization, and epidemiology of nsLTP allergy.

Materials And Methods: A Task Force, supported by the European Academy of Allergy & Clinical Immunology (EAACI), reviewed current evidence and provide a signpost for future research. The search terms for this paper were "Non-specific Lipid Transfer Proteins", "LTP syndrome", "Pru p 3", "plant food allergy", "pollen-food syndrome".

Results: Most nsLTP allergens have a highly conserved structure stabilised by 4-disulphide bridges. Studies on the peach nsLTP, Pru p 3, demonstrate that nsLTPs are very cross-reactive, with the four major IgE epitopes of Pru p 3 being shared by nsLTP from other botanically related fruits. These nsLTP allergens are to varying degrees resistant to heat and digestion, and sensitization may occur through the oral, inhaled or cutaneous routes. In some populations, Pru p 3 is the primary and sole sensitizing allergen, but many are poly-sensitised both to botanically un-related nsLTP in foods, and non-food sources of nsLTP such as Cannabis sativa, Platanus acerifolia, (plane tree), Ambrosia artemisiifolia (ragweed) and Artemisia vulgaris (mugwort). Initially, nsLTP sensitization appeared to be limited to Mediterranean countries, however more recent studies suggest clinically relevant sensitization occurs in North Atlantic regions and also countries in Northern Europe, with nsLTP sensitisation profiles being broadly similar.

Discussion: These robust allergens have the potential to sensitize and provoke symptoms to a large number of plant foods, including those which are raw, cooked or processed. It is unknown why some sensitized individuals develop clinical symptoms to foods whereas others do not, or indeed what other allergens besides Pru p 3 may be primary sensitising allergens. It is clear that these allergens are also relevant in non-Mediterranean populations and there needs to be more recognition of this.

Conclusion: Non-specific LTP allergens, present in a wide variety of plant foods and pollens, are structurally robust and so may be present in both raw and cooked foods. More studies are needed to understand routes of sensitization and the world-wide prevalence of clinical symptoms associated with sensitization to these complex allergens.
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http://dx.doi.org/10.1002/clt2.12010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129635PMC
May 2021

The diagnosis and management of allergic reactions in patients sensitized to non-specific lipid transfer proteins.

Allergy 2021 08 27;76(8):2433-2446. Epub 2021 Mar 27.

Experimental Allergy Unit, Istituto Dermopatico dell'Immacolata - IRCCS, FLMM, Rome, Italy.

Sensitization to one or more non-specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non-steroidal anti-inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy-focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.
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http://dx.doi.org/10.1111/all.14797DOI Listing
August 2021

Anthony Barrington Kay 1939-2020.

Clin Exp Allergy 2021 02;51(2):206-208

MRC Clinical, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

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http://dx.doi.org/10.1111/cea.13835DOI Listing
February 2021

Basophils from Cancer Patients Respond to Immune Stimuli and Predict Clinical Outcome.

Cells 2020 07 7;9(7). Epub 2020 Jul 7.

St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London SE1 9RT, UK.

Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients ( = 53) with diverse tumor histologies and treatment histories. Ex vivo basophil activation was measured by CD63 expression using the basophil activation test (BAT). Irrespective of prior treatment, basophils could be activated by stimulation with IgE- (anti-FcεRI and anti-IgE) and non-IgE (fMLP) mediated triggers. Basophil activation was detected by ex vivo exposure to paclitaxel, but not to other anti-cancer therapies, in agreement with a clinical history of systemic hypersensitivity reactions to paclitaxel. Protein and gene expression analyses support the presence of basophils (CCR3, CD123, FcεRI) and activated basophils (CD63, CD203c, tryptase) in ovarian tumors. Greater numbers of circulating basophils, cells with greater capacity for ex vivo stimulation ( = 35), and gene signatures indicating the presence of activated basophils in tumors ( = 439) were each associated with improved survival in ovarian cancer. Circulating basophils in cancer patients respond to IgE- and non-IgE-mediated signals and could help identify hypersensitivity to therapeutic agents. Activated circulating and tumor-infiltrating basophils may be potential biomarkers in oncology.
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http://dx.doi.org/10.3390/cells9071631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408103PMC
July 2020

Lemon seed allergy: a case presentation.

Allergy Asthma Clin Immunol 2020 29;16:32. Epub 2020 Apr 29.

1Department of Adult Allergy, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT UK.

Background: We report a case of IgE-mediated hypersensitivity to lemon seed. We demonstrate for the first time a pattern of cross-sensitisation between seeds of citrus hybrid species from similar ancestral species origins.

Case Report: Described is a case of a 26-year-old female with recurrent anaphylaxis on exposure to lemon seed with sensitisation shown on prick to prick testing. Prick to prick testing was also performed to a variety of citrus fruit seeds and edible foods from additional notable families of the Sapindale order.

Conclusion: In cases of unexplained or recurrent anaphylaxis in adult patients, citrus seed allergy should be considered.
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http://dx.doi.org/10.1186/s13223-020-00429-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191823PMC
April 2020

Teicoplanin hypersensitivity in perioperative anaphylaxis.

J Allergy Clin Immunol Pract 2020 Jun 27;8(6):2110-2113. Epub 2020 Feb 27.

Department of Allergy, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.02.015DOI Listing
June 2020

Potential treatment effect of the SQ tree SLIT-tablet on pollen food syndrome caused by apple.

Allergy 2020 08 16;75(8):2059-2061. Epub 2020 Mar 16.

Department of Dermatology and Allergology, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.1111/all.14242DOI Listing
August 2020

Prostaglandin D receptors in human mast cells.

Allergy 2020 06 15;75(6):1477-1480. Epub 2020 Jan 15.

School of Immunology & Microbial Sciences, King's College London, London, UK.

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http://dx.doi.org/10.1111/all.14161DOI Listing
June 2020

Identifying Low-Risk Beta-Lactam Allergy Patients in a UK Tertiary Centre.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2173-2181.e1. Epub 2019 Mar 25.

Department of Adult Allergy, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK; Peter Gorer Department of Immunobiology, Guy's Hospital, King's College London, London, UK.

Background: There are marked geographical as well as temporal differences in patient sensitization profiles to β-lactams (BL).

Objective: To determine the utility of skin test reagents and identify a cohort of patients where skin testing can be safely omitted in a cohort of patients referred to a UK tertiary referral center.

Methods: A retrospective study of the clinical characteristics of 1092 patients referred for BL allergy testing was analyzed using multivariate regression analysis. The effectiveness of skin test reagents was also evaluated.

Results: Multivariate logistic regression identified that a history of anaphylaxis (odds ratio [OR] 10.98, P = .001) and the patients' recall of the index drug (apart from ampicillin and meropenem, OR 3.51-12.43, P < .05) were independent predictors of type I BL allergic status and a time of less than 1 year elapsed since index reaction significantly increasing the odds of a patient with a history of anaphylaxis, having a type I BL allergy (OR 38.66, P = .003). An absence of anaphylactic severity, unknown name of the index drug and a reaction occurring more than 1 year before testing, has a negative predictive value (NPV) of 98.4%, which was similar to the NPV of skin testing of 98.9% for type I BL allergy. The NPV of skin testing with benzylpenicillin + amoxicillin ± index BL was similar with (98.9%) or without (98.1%) the use of benzylpenicillin polylysine and minor determinant for type I BL allergy.

Conclusion: We identified a "low risk" cohort of patients where the history is of similar reliability to skin testing in predicting nonallergic status for BL allergy.
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http://dx.doi.org/10.1016/j.jaip.2019.03.015DOI Listing
September 2020

Multidisciplinary approach to the management of adult eosinophilic oesophagitis in the United Kingdom.

Clin Exp Allergy 2018 12 12;48(12):1752-1756. Epub 2018 Oct 12.

Department of Nutrition and Dietetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/cea.13279DOI Listing
December 2018

Synchronous immune alterations mirror clinical response during allergen immunotherapy.

J Allergy Clin Immunol 2018 05 9;141(5):1750-1760.e1. Epub 2017 Nov 9.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address:

Background: Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation.

Objective: We sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation.

Methods: We performed multimodal 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 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years of allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific T2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1 year after discontinuation.

Conclusion: Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific T2 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, the persistence of IgE blocking antibody 1 year after discontinuation might be an early indicator of a protolerogenic mechanism.
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http://dx.doi.org/10.1016/j.jaci.2017.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938141PMC
May 2018

Eosinophilic esophagitis linked to pollen food syndrome.

J Allergy Clin Immunol Pract 2018 Mar - Apr;6(2):667-668. Epub 2017 Sep 6.

Division of Asthma, Allergy and Lung Biology, King's College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2017.06.040DOI Listing
November 2019

Sesame allergy in adults: Investigation and outcomes of oral food challenges.

Ann Allergy Asthma Immunol 2017 Sep 23;119(3):285-287. Epub 2017 Jul 23.

Department of Allergy, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Division of Asthma, Allergy and Lung Biology, Kings College London, School of Medicine, Guys Hospital, London, United Kingdom; Medical Research Council and Asthma UK Centre for Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2017.06.013DOI Listing
September 2017

Intradermal grass pollen immunotherapy increases T2 and IgE responses and worsens respiratory allergic symptoms.

J Allergy Clin Immunol 2017 Jun 20;139(6):1830-1839.e13. Epub 2016 Oct 20.

Division of Asthma, Allergy and Lung Biology, King's College London, School of Medicine, Guy's Hospital, London, United Kingdom; MRC-Asthma UK Centre for Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address:

Background: Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy.

Objective: We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis.

Methods: We randomly assigned 93 adults with grass pollen-induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment.

Results: There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, -172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, -11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense-specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the T2 surface marker CRTH2 (P = .04) and lower expression of the T1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03).

Conclusion: Intradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms.
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http://dx.doi.org/10.1016/j.jaci.2016.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457129PMC
June 2017

Potential Mechanisms for IgG4 Inhibition of Immediate Hypersensitivity Reactions.

Curr Allergy Asthma Rep 2016 Mar;16(3):23

Division of Asthma, Allergy and Lung Biology, King's College London and Department of Allergy, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK.

IgG4 is the least abundant IgG subclass in human serum, representing less than 5% of all IgG. Increases in IgG4 occur following chronic exposure to antigen and are generally associated with states of immune tolerance. In line with this, IgG4 is regarded as an anti-inflammatory antibody with a limited ability to elicit effective immune responses. Furthermore, IgG4 attenuates allergic responses by inhibiting the activity of IgE. The mechanism by which IgG4 inhibits IgE-mediated hypersensitivity has been investigated using a variety of model systems leading to two proposed mechanisms. First by sequestering antigen, IgG4 can function as a blocking antibody, preventing cross-linking of receptor bound IgE. Second IgG4 has been proposed to co-stimulate the inhibitory IgG receptor FcγRIIb, which can negatively regulate FcεRI signaling and in turn inhibit effector cell activation. Recent advances in our understanding of the structural features of human IgG4 have shed light on the unique functional and immunologic properties of IgG4. The aim of this review is to evaluate our current understanding of IgG4 biology and reassess the mechanisms by which IgG4 functions to inhibit IgE-mediated allergic responses.
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http://dx.doi.org/10.1007/s11882-016-0600-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759210PMC
March 2016

IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa.

J Allergy Clin Immunol 2016 05 10;137(5):1514-24. Epub 2015 Dec 10.

Division of Asthma, Allergy and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address:

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown.

Objective: We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP.

Methods: Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable β-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis.

Results: IL-25 receptor (IL-17RB)-expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB(+)CD4(+) polyp-derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB(+)CD4(+) T cells, several identical T-cell receptor variable β-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17-producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells.

Conclusion: IL-25 and IL-33 can interact locally with IL-17RB(+)ST2(+) polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis.
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http://dx.doi.org/10.1016/j.jaci.2015.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852988PMC
May 2016

Grass pollen immunotherapy for treatment of allergic rhinitis.

BMJ 2014 Nov 17;349:g6586. Epub 2014 Nov 17.

Division of Asthma, Allergy and Lung Biology, King's College London, School of Medicine, Guy's Hospital, London SE1 9RT, UK Department of Allergy, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK

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http://dx.doi.org/10.1136/bmj.g6586DOI Listing
November 2014

Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner.

J Allergy Clin Immunol 2014 Mar 25;133(3):872-9.e7. Epub 2013 Dec 25.

Benaroya Research Institute at Virginia Mason, Seattle, Wash; Department of Medicine, University of Washington, Seattle, Wash. Electronic address:

Background: Understanding the mechanisms by which the immune system induces and controls allergic inflammation at the T-cell epitope level is critical for the design of new allergy vaccine strategies.

Objective: We sought to characterize allergen-specific T-cell responses linked with allergy or peripheral tolerance and to determine how CD4(+) T-cell responses to individual allergen-derived epitopes change over allergen-specific immunotherapy.

Methods: Timothy grass pollen (TGP) allergy was used as a model for studying grass pollen allergies. The breadth, magnitude, epitope hierarchy, and phenotype of the DR04:01-restricted TGP-specific T-cell responses in 10 subjects with grass pollen allergy, 5 nonatopic subjects, and 6 allergy vaccine-treated subjects was determined by using an ex vivo peptide-MHC class II tetramer approach.

Results: CD4(+) T cells in allergic subjects are directed to a broad range of TGP epitopes characterized by defined immunodominance hierarchy patterns and with distinct functional profiles that depend on the epitope recognized. Epitopes that are restricted specifically to either TH2 or TH1/TR1 responses were identified. Allergen-specific immunotherapy was associated with preferential deletion of allergen-specific TH2 cells and without a significant change in the frequency of TH1/TR1 cells.

Conclusions: Preferential allergen-specific TH2 cell deletion after repeated high-dose antigen stimulation can be another independent mechanism to restore tolerance to allergen during immunotherapy.
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http://dx.doi.org/10.1016/j.jaci.2013.10.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961577PMC
March 2014

Peptide-induced immune regulation by a promiscuous and immunodominant CD4T-cell epitope of Timothy grass pollen: a role of Cbl-b and Itch in regulation.

Thorax 2014 Apr 20;69(4):335-45. Epub 2013 Nov 20.

Department of Asthma, Allergy and Respiratory Science, Division of Asthma, Allergy & Lung Biology, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, , London, UK.

Background: T-cell targeted peptide epitope tolerogens from grass pollen allergens may be useful in treating seasonal allergic rhinitis, but there is urgent need for optimisation of approaches from improved understanding of mechanism.

Objective: We sought to identify human leukocyte antigen (HLA)-DR1-restricted epitopes from the Timothy grass pollen allergen, Phleum pratense, and characterise T-cell immune regulation following intranasal administration of a single, immunodominant epitope.

Methods: T-cell epitopes within P pratense were identified using HLA-DR1 transgenic mice and tetramer-guided epitope mapping (TGEM) in HLA-DR1-positive individuals with grass allergy. An immunodominant epitope was tested in HLA-DR1 transgenics for impact on responses to whole Phl p5 b or peptide. Microarrays and quantitative PCR were used to characterise T-cell immunity.

Results: Peptide 26 (p26) was identified in HLA-DR1 transgenic mice and by TGEM analysis of HLA-DR1-positive individuals with grass allergy. p26 shows promiscuous binding to a wide range of HLA class II alleles, making it of relevance across immunogenetically diverse patients. The epitope is conserved in rye and velvet grass, making it applicable across a spectrum of grass pollen allergy. Intranasal pretreatment of mice with p26 results in significantly reduced T-cell responses. Transcriptomic array analysis in mice showed T-cell regulation in the intranasal treatment group associated with increased expression of members of the Cbl-b and Itch E3 ubiquitin ligase pathway.

Conclusions: We defined an immunodominant P pratense epitope, p26, with broad binding across multiple HLA class II alleles. Intranasal treatment of mice with p26 results in T-cell regulation to whole allergen, involving the Cbl-b and Itch regulatory pathway.
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http://dx.doi.org/10.1136/thoraxjnl-2013-204324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368902PMC
April 2014

Protocol for a double-blind randomised controlled trial of low dose intradermal grass pollen immunotherapy versus a histamine control on symptoms and medication use in adults with seasonal allergic rhinitis (PollenLITE).

Clin Transl Allergy 2013 Aug 21;3(1):27. Epub 2013 Aug 21.

Division of Asthma, Allergy & Lung Biology, King's College London, 5th Floor Tower Wing, Guy's Hospital Campus, London SE1 9RT, UK.

Background: Subcutaneous immunotherapy with high dose grass pollen (typically microgram quantities) was first described over 100 years ago. This treatment suppresses allergen-induced cutaneous late responses, with lesser effects on early responses. We previously reported that repeated 2-weekly intradermal injections of grass pollen - containing approximately 7 ng of major allergen Phl p 5 - led to a progressive suppression of the allergen-induced cutaneous response, and that by the sixth injection, this was inhibited by over 90%. The purpose of this trial is to investigate the clinical efficacy of intradermal desensitisation with low doses (i.e. nanogram quantities) of grass pollen allergen for seasonal allergic rhinitis.

Methods/design: The Pollen Low dose Intradermal therapy Evaluation (PollenLITE) is a single centre double-blind randomised parallel group controlled trial of the efficacy and safety of intradermal grass pollen injections plus standard treatment, versus histamine injections plus standard treatment, in adults with moderate-severe grass pollen-induced allergic rhinitis ('summer hay fever'). A minimum of ninety adults with a history of moderate-severe persistent allergic rhinitis during the UK grass pollen season will be randomised into two equal groups to receive 7 or 8 intradermal injections of grass pollen extract (containing approximately 7 ng of major allergen Phl p 5) or histamine, before the grass pollen season. In the summer, participants will score their symptoms, medication requirements, visual analogue scores, and complete EuroQOL (EQ-5D-5 L) and mini Rhinoconjunctivitis Quality of Life Questionnaires. Global assessments will also be recorded at the end of the pollen season. Blood samples will be collected from all participants for mechanistic immune assays. Skin punch biopsies will also be collected in 40 participants selected at random from intradermal injection sites after the grass pollen season for mechanistic assays. Finally, to investigate if the desensitising effect of intradermal immunotherapy on cutaneous responses is long-lasting, all participants will be randomised to receive a follow up intradermal injection after 3, 6 or 12 months with measurement of early and late response sizes.

Discussion: Randomisation began in February 2013 and the final participant will complete the trial protocol in August 2014.

Trial Registration: ISRCTN 78413121EudraCT number 2012-002193-31.
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http://dx.doi.org/10.1186/2045-7022-3-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765857PMC
August 2013

Cell-free detection of allergen-IgE cross-linking with immobilized phase CD23: inhibition by blocking antibody responses after immunotherapy.

J Allergy Clin Immunol 2013 Oct 1;132(4):1003-5.e1-4. Epub 2013 Jul 1.

Section of Allergy and Clinical Immunology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, United Kingdom; Medical Research Council and Asthma UK Centre for Allergic Mechanisms of Asthma, London, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2013.05.025DOI Listing
October 2013

Repeated low-dose intradermal allergen injection suppresses allergen-induced cutaneous late responses.

J Allergy Clin Immunol 2012 Oct 9;130(4):918-24.e1. Epub 2012 Sep 9.

Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: Subcutaneous immunotherapy with high-dose grass pollen was first described more than 100 years ago. This treatment suppresses allergen-induced cutaneous late responses, with lesser effects on early responses. In contrast, low-dose subcutaneous immunotherapy has not shown clinical benefit. Uncontrolled reports from the early 20th century describe low-dose allergen inoculation directly into the dermis, an immunologically active area containing abundant dendritic cells and lymphatics.

Objective: We sought to investigate the effect of low-dose intradermal grass pollen administration on cutaneous reactivity to allergen.

Methods: Thirty adults sensitized to grass and tree pollens were randomized to receive (1) 6 repeat intradermal injections at 2-week intervals of grass pollen extract (estimated 7 ng of the major grass allergen Phl p 5 per injection), (2) 2 intradermal injections separated by 10 weeks, or (3) a single intradermal injection at 10 weeks. At the end of the study, cutaneous early and late responses were measured after double-blind intradermal injection with grass and birch pollen.

Results: Participants who received 6 fortnightly intradermal grass pollen injections had markedly smaller cutaneous late responses to grass pollen than control subjects who received 2 injections separated by 10 weeks (P < .01) or a single injection (P < .001) and showed induction of grass pollen-specific IgG antibodies. Suppression was observed whether late responses were measured on the arms or the back. However, early responses were equivalent in all groups.

Conclusion: Low-dose intradermal allergen, like conventional subcutaneous high-dose immmunotherapy, suppresses allergen-induced cutaneous late responses in a manner that is allergen specific, systemic, and associated with induction of IgG antibodies.
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http://dx.doi.org/10.1016/j.jaci.2012.06.052DOI Listing
October 2012

Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies.

J Allergy Clin Immunol 2011 Feb;127(2):509-516.e1-5

Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, part of the Medical Research Council and Asthma UK Centre for Allergic Mechanisms of Asthma, UK.

Background: Grass pollen immunotherapy for allergic rhinitis is a disease-modifying treatment that results in long-term clinical tolerance lasting years after treatment discontinuation. Active treatment is associated with generation of inhibitory grass pollen-specific IgG antibodies capable of blocking allergen-IgE interactions.

Objectives: We sought to investigate the involvement of IgG-associated inhibitory antibodies with long-term clinical tolerance after discontinuation of grass pollen immunotherapy.

Methods: We conducted a 4-year study in which patients who had moderate-to-severe allergic rhinitis underwent a randomized, double-blind, placebo-controlled discontinuation of subcutaneous grass pollen immunotherapy. All subjects received grass pollen immunotherapy injections for 2 years (n = 13), followed by a further 2 years of either active (n = 7) or placebo (n = 6) injections. Clinical outcomes included seasonal symptoms and use of rescue medication. Serum specimens were collected at baseline and after 2 and 4 years for quantification of allergen-specific IgG antibodies. Sera were also tested for IgG-dependent inhibitory bioactivity against IgE-allergen binding in cellular assays by using flow cytometry and confocal microscopy to detect binding of IgE-grass pollen allergen complexes to B cells.

Results: Clinical improvement was maintained after 2 years of discontinuation. Although immunotherapy-induced grass pollen-specific IgG1 and IgG4 levels decreased to near-preimmunotherapy levels during discontinuation, inhibitory bioactivity of allergen-specific IgG antibodies was maintained unchanged.

Conclusion: Grass pollen immunotherapy induces a subpopulation of allergen-specific IgG antibodies with potent inhibitory activity against IgE that persists after treatment discontinuation and that could account for long-term clinical tolerance.
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http://dx.doi.org/10.1016/j.jaci.2010.12.1080DOI Listing
February 2011

Immunologic responses to subcutaneous allergen immunotherapy.

Clin Allergy Immunol 2008 ;21:59-70

Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, UK.

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January 2009

Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity.

J Allergy Clin Immunol 2008 May 18;121(5):1120-1125.e2. Epub 2008 Apr 18.

Allergy and Clinical Immunology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: Grass pollen immunotherapy is an effective treatment for seasonal allergic rhinitis that provides the opportunity to study the induction and maintenance of allergen-specific immune tolerance.

Objectives: We investigated the relationship between clinical responsiveness, regulatory cytokine production, and antibody responses to allergen during 1 year of immunotherapy.

Methods: Eighteen subjects with severe seasonal allergic rhinitis were randomized double-blind to receive active or placebo injections of an alum-adsorbed grass pollen vaccine (Alutard SQ). Subjects underwent repeated testing of early- and late-phase skin responses to intradermal allergen, and cellular responses to grass pollen allergen were tested. Sera were tested for allergen-specific IgG4, IgA, and inhibitory activity in biologic assays of IgE responses.

Results: Grass pollen immunotherapy was effective in reducing overall symptom scores (P < .05) and conjunctival reactivity (P < .05). In the active group significant IL-10 production occurred early at low allergen doses and at a similar time as inhibition of late skin responses at 2 to 4 weeks. Serum allergen-specific IgG4, IgA, and inhibitory antibody activity for basophil histamine release and IgE-facilitated allergen binding to B cells occurred later, at 6 to 12 weeks, at higher allergen doses and preceded inhibition of early skin responses.

Conclusion: IL-10 responses occur early but at immunotherapy doses that are not clinically effective. Later induction of inhibitory antibodies, including IgG4 and IgA, might be required for efficacy through modulation of IgE-mediated events.
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http://dx.doi.org/10.1016/j.jaci.2008.01.072DOI Listing
May 2008

Mechanisms of immunotherapy.

J Allergy Clin Immunol 2004 Jun;113(6):1025-34; quiz 1035

Upper Respiratory Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Doverhouse Street, London SW3 6LY, United Kingdom.

Specific allergen injection immunotherapy is highly effective in IgE-mediated diseases, such as allergic rhinitis and venom anaphylaxis. Immunotherapy inhibits both early and late responses to allergen exposure. Immunotherapy is accompanied by increases in allergen-specific IgG, particularly the IgG4 isotype, which blocks not only IgE-dependent histamine release from basophils but also IgE-mediated antigen presentation to T cells. Immunotherapy acts on T cells to modify peripheral and mucosal T(H)2 responses to allergen in favor of T(H)1 responses. Recent studies have identified increased IL-10 production in peripheral blood and mucosal surfaces after immunotherapy. IL-10 has numerous potential antiallergic properties, including suppression of mast cell, eosinophil, and T-cell responses, as well as acting on B cells to favor heavy chain class switching to IgG4. These IL-10-producing cells might be so-called regulatory T cells and appear to be identified by the CD4(+)CD25(+) phenotype. Studies in mice suggest that dendritic cells play a vital role in induction of regulatory T cells. Novel approaches to immunotherapy currently being explored include the use of adjuvants, such as monophosphoryl lipid A or nucleotide immunostimulatory sequences derived from bacteria that potentiate T(H)1 responses. Alternative strategies include the use of allergen-derived peptides or modified recombinant allergen vaccines that act on T cells while minimizing the IgE-dependent mast cell activation that is dependent on the native allergen conformation.
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http://dx.doi.org/10.1016/j.jaci.2004.03.024DOI Listing
June 2004

Immunological responses to allergen immunotherapy.

Clin Allergy Immunol 2004 ;18:85-104

Imperial College, London, England.

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April 2004

Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity.

J Immunol 2004 Mar;172(5):3252-9

Upper Respiratory Medicine, Imperial College London, National Heart and Lung Institute, London, United Kingdom.

T regulatory cells and IL-10 have been implicated in the mechanism of immunotherapy in patients with systemic anaphylaxis following bee stings. We studied the role of IL-10 in the induction of clinical, cellular, and humoral tolerance during immunotherapy for local mucosal allergy in subjects with seasonal pollinosis. Local and systemic IL-10 responses and serum Ab concentrations were measured before/after a double-blind trial of grass pollen (Phleum pratense, Phl P) immunotherapy. We observed local increases in IL-10 mRNA-positive cells in the nasal mucosa after 2 years of immunotherapy, but only during the pollen season. IL-10 protein-positive cells were also increased and correlated with IL-10 mRNA(+) cells. These changes were not observed in placebo-treated subjects or in healthy controls. Fifteen and 35% of IL-10 mRNA signals were colocalized to CD3(+) T cells and CD68(+) macrophages, respectively, whereas only 1-2% of total CD3(+) cells and 4% of macrophages expressed IL-10. Following immunotherapy, peripheral T cells cultured in the presence of grass pollen extract also produced IL-10. Immunotherapy resulted in blunting of seasonal increases in serum allergen Phl p 5-specific IgE, 60- to 80-fold increases in Phl p 5-specific IgG, and 100-fold increases in Phl p 5-specific IgG4. Post-immunotherapy serum exhibited inhibitory activity, which coeluted with IgG4, and blocked IgE-facilitated binding of allergen-IgE complexes to B cells. Both the increases in IgG and the IgG "blocking" activity correlated with the patients' overall assessment of improvement. Thus, grass pollen immunotherapy may induce allergen-specific, IL-10-dependent "protective" IgG4 responses.
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http://dx.doi.org/10.4049/jimmunol.172.5.3252DOI Listing
March 2004
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