Summary
Background
Cat‐PAD, the first in a new class of synthetic peptide immuno‐regulatory epitopes (SPIREs), was shown to significantly improve rhinoconjunctivitis symptoms in subjects with cat ...allergy up to 1 year after the start of a short course of treatment.
Objective
To evaluate the long‐term effects of Cat‐PAD on rhinoconjunctivitis symptoms following standardized allergen challenge 2 years after treatment.
Methods
In a randomized, double‐blind, placebo‐controlled, parallel group study, subjects were exposed to cat allergen in an environmental exposure chamber (EEC) before and after treatment with two regimens of Cat‐PAD (either eight doses of 3 nmol or four doses of 6 nmol) given intradermally over a 3‐month period. In this follow‐up study, changes from baseline in rhinoconjunctivitis symptoms were reassessed 2 years after the start of treatment.
Results
The primary endpoint showed a mean reduction in total rhinoconjunctivitis symptom scores of 3.85 units in the 4 × 6 nmol Cat‐PAD group compared to placebo 2 years after the start of treatment (P = 0.13), and this difference was statistically significant in the secondary endpoint at the end of day 4 when the cumulative allergen challenge was greatest (P = 0.02). Consistent reductions in nasal symptoms of between 2 and 3 units were observed for 4 × 6 nmol Cat‐PAD compared to placebo between the 2 and 3 h time points on days 1–4 of EEC challenge at 2 years (P < 0.05). The 8 × 3 nmol dose did not show a meaningful effect in this study.
Conclusion and Clinical Relevance
A persistent, clinically meaningful reduction in rhinoconjunctivitis symptoms was observed on EEC challenge 2 years after the start of a short course of treatment with 4 × 6 nmol Cat‐PAD. This study is the first to provide evidence of a long‐term therapeutic effect with this new class of SPIREs.
The Future of the Allergists and Specific Immunotherapy (FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review ...developments in the field of allergen immunotherapy (AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future.
In this review, we report on relevant current topics in allergen immunotherapy (AIT) which were broadly discussed during the first Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December 2015 by ...leading clinicians, scientists and industry representatives in the field. The aim of this symposium was to highlight AIT‐related aspects of public health, clinical efficacy evaluation, mechanisms, development of new biomarkers and an overview of novel therapeutic approaches. Allergy is a public health issue of high socioeconomic relevance, and development of evidence‐based action plans to address allergy as a public health issue ought to be on national and regional agendas. The underlying mechanisms are in the focus of current research that lays the ground for innovative therapies. Standardization and harmonization of clinical endpoints in AIT trials as well as current knowledge about potential biomarkers have substantiated proof of effectiveness of this disease‐modifying therapeutic option. Novel treatments such as peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large fraction of patients.
Background
Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing ...the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities.
Methods
For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation.
Results
The latter covered the validation process, standardization of challenges and outcomes, intra‐ and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues.
Conclusion
This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future.
Specific allergen immunotherapy has been widely practised for almost 100 years. Whilst this approach is disease-modifying and efficacious, the use of whole allergen preparations is associated with an ...unacceptably high prevalence of allergic adverse events during treatment. Many approaches to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity are under development. One such approach is the use of short synthetic peptides which represent major T-cell epitopes of the allergen. Major potential advantages of this approach include markedly reduced capacity to cross-link immunoglobulin-E and activate mast cells and basophils, and ease of manufacture and standardization. Promising results in preclinical studies have led to the translation of this approach to clinical studies in humans. Peptide immunotherapy is currently under development for allergic and autoimmune diseases.
To cite this article: Shamji MH, Ljørring C, Francis JN, Calderon MA, Larché M, Kimber I, Frew AJ, Ipsen H, Lund K, Würtzen PA, Durham SR. Functional rather than immunoreactive levels of IgG4 ...correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012; 67: 217–226.
Background: Induction of allergen‐specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen‐specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG–associated inhibitory activity such as inhibition of IgE–allergen interactions (IgE‐blocking factor) and inhibition of CD23‐dependent IgE‐facilitated allergen binding (IgE‐FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response.
Methods: In an 8‐month dose–response randomized double‐blind placebo‐controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ‐U, 10 000 SQ‐U or placebo injections. Serum specimens were collected before treatment, after up‐dosing, during the peak season and at the end of the study. Allergen‐specific IgG4 titres and IgG‐associated inhibitory activity were evaluated.
Results: A time‐ and dose‐dependent increase in serum inhibitory activity for both the IgE‐blocking factor and IgE‐FAB was observed, which paralleled increases in grass pollen–specific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom–rescue medication scores (IgE‐FAB: r = −0.25, P = 0.0002; IgE‐blocking factor: r = −0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG4 levels (r = −0.11, P = 0.12).
Conclusions: Functional assays of inhibitory IgG4 and IgE‐blocking factor may be more useful surrogates of clinical response than IgG4. Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.
Background
Food allergy, in particular peanut allergy, is a growing concern in Western countries. The prevalence of allergy to peanut, which currently stands at 1.4%, nearly tripled between 1997 and ...2008. Allergic sensitization is a particularly difficult process to study as it is clinically silent.
We sought to identify key pathways and mediators critically involved in the induction of allergic sensitization to peanut.
Methods
Comprehensive metabolomics analysis with liquid chromatography–mass spectrometry was used to detect metabolite changes in mice (C57BL/6) undergoing sensitization. Loss‐of‐function and gain‐of‐function studies were performed in mice subjected to two models of peanut sensitization and anaphylaxis that involved either oral or epicutaneous sensitization. Flow cytometric analyses on dendritic cells (DCs) in vitro and in vivo were used to investigate the mechanisms of immune activation.
Results
Elevated levels of uric acid (UA) were detected in mice undergoing sensitization as well as in peanut‐allergic children who were not challenged with peanut. In mice, the depletion of UA during sensitization prevented the development of peanut‐specific immunoglobulins IgE and IgG1 as well as anaphylaxis while exogenous delivery of UA crystals (monosodium urate, MSU) restored the allergic phenotype. Monosodium urate enhanced CD86 and OX40L expression on DCs, independent of Toll‐like receptors 2 and 4, the NLRP3 inflammasome, and IL‐1β, via a PI3K signaling pathway.
Conclusion
Overproduction of the UA alarmin in the local microenvironment plays a critical role in the induction of peanut‐allergic sensitization, likely due to its ability to activate DCs. These finding suggest that cellular damage or tissue injury may be an essential requisite for the development of allergic sensitization to foods.
Summary
Background
The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector ...cells.
Objective
We tested whether treatment with an anti‐OX40L monoclonal antibody (MAb) would inhibit allergen‐induced responses in subjects with asthma.
Methods
Twenty‐eight mild, atopic asthmatic subjects were recruited for a double‐blind, randomized, placebo‐controlled, parallel‐group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti‐OX40L MAb to placebo‐administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late‐phase asthmatic response. Other outcomes included the early‐phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability.
Results
Treatment with anti‐OX40L MAb did not attenuate the early‐ or late‐phase asthmatic responses at days 56 or 113 compared with placebo. In the anti‐OX40L MAb treatment group, total IgE was reduced 17% from pre‐dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti‐OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups.
Conclusion and Clinical Relevance
Pharmacological activity of anti‐OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post‐dosing, but there was no effect on allergen‐induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.
Summary
Background
An unresolved issue in T regulatory cells' cell biology is the lack of consensus on phenotypic markers that accurately define the natural Treg (nTreg) population.
Objectives
To ...examine nTreg frequency and functional capacity in healthy controls and their frequency in asthmatic subjects using three different phenotypic strategies. We hypothesized that phenotypically different nTreg are quantitatively and functionally different.
Methods
Thirty‐four healthy, non‐asthmatic and 17 asthmatic subjects were studied. Three nTreg phenotypes were defined as follows: nTreg1 (CD4+CD25+Foxp3+), nTreg2 (CD4+CD25+CD127lowFoxp3+), and nTreg3 (CD4+CD25highFoxp3+). The flow cytometric determination of nTreg frequency in peripheral blood (PB) and bronchoalveolar lavage (BAL) was performed using fluorescently labelled antibodies. Peripheral blood nTreg functional capacity was assessed using a CFSE‐based suppression assay.
Results
There was a significantly lower frequency of PB nTreg3 compared to nTreg2 and nTreg1 (P < 0.05). Both nTreg2 and nTreg3 had a significantly greater suppressive capacity than nTreg1 at T responder (Tresp) to nTreg ratios of 16 : 1 up to 1 : 1 (P < 0.01). Asthmatics exhibited a significantly lower PB nTreg3 and nTreg1 frequency than healthy controls (P < 0.05). There were no differences between healthy controls and asthmatic subjects when comparing BAL nTreg frequency.
Conclusions and Clinical Relevance
Phenotypically different nTreg subsets are quantitatively and functionally different and are variably observed in asthma. The CD4+CD25highFoxp3+ phenotype was the least frequent, but demonstrated the greatest suppression, and was significantly lower in PB of asthmatic subjects. Consequently, it is imperative that nTreg phenotypes be clearly defined and that the interpretation of their frequency and function be phenotype specific.
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