T Cell Epitope Peptide Therapy for Allergic Diseas

Authors: Robyn E O’Hehir Sara R Prickett Jennifer M Rolland

Publish Date: 2016/01/14

Volume: 16, Issue: 2, Pages: 14-

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Abstract

Careful selection of dominant T cell epitope peptides of major allergens that display degeneracy for binding to a wide array of MHC class II molecules allows induction of clinical and immunological tolerance to allergen in a refined treatment strategy From the original concept of peptideinduced T cell anergy arising from in vitro studies proofofconcept murine models and flourishing human trials followed Current randomized doubleblind placebocontrolled clinical trials of mixtures of T cellreactive short allergen peptides or long contiguous overlapping peptides are encouraging with intradermal administration into noninflamed skin a preferred delivery Definitive immunological mechanisms are yet to be resolved but specific anergy Th2 cell deletion immune deviation and Treg induction seem implicated Significant efficacy particularly with short treatment courses in a range of aeroallergen therapies cat house dust mite grass pollen with inconsequential nonsystemic adverse events likely heralds a new class of therapeutic for allergy Synthetic Peptide ImmunoRegulatory Epitopes SPIREIn 1911 Noon pioneered allergen immunotherapy AIT for treatment of grass pollen allergy 1 The administration of allergen extracts using various regimens and routes is now established therapeutic practice in the management of allergic diseases and currently the only therapy proven to modify the natural course of an allergic disease However treatment with whole allergen extracts is contraindicated in patients with unstable asthma and food allergies due to the risk of severe IgEmediated adverse events including anaphylaxis or even death 2 3 4 These risks together with the typically prolonged and frequent dosing regimens command poor adherence in real life situations 5 and less than desirable availability of specific allergy treatments for the burgeoning allergy epidemic 6The pivotal role of the CD4+ T cell in driving immune responsiveness to allergen together with distinct differences between T cell and B cell epitopes facilitates development of refined therapeutics for redirecting the cellular immune response towards peripheral tolerance 7 8•• Allergen T cell epitopes are typically short without conformational structure They fail to crosslink cellbound IgE or activate inflammatory mast cells and basophils In contrast allergen B cell epitopes are usually conformational although linear epitopes are described On native allergen molecules B cell epitopes can bind and crosslink specific IgE on effector cells to trigger degranulation with inflammatory mediator release and synthesis eliciting the wellrecognized features of allergy Carefully selected dominant T cell epitope peptides of major clinically relevant allergens that display degeneracy for binding to a wide array of MHC class II molecules can safely induce clinical and immunological tolerance in a breakthrough new class of allergy treatment recently termed Synthetic Peptide ImmunoRegulatory Epitopes SPIRE 8•• 9 Evolution from the idea of allergen T cell epitopebased peptide anergy 10 through proofofconcept murine experimental models 11 12 13 progressed to human clinical translation 14 15 In recent years there have been randomized doubleblind placebocontrolled clinical trials of two types of T cell epitopebased therapeutics for allergy short T cell epitope peptide mixtures and longer Contiguous Overlapping Peptides COPs 9 16• Significant efficacy has been achieved in cat house dust mite HDM and pollen allergy with short treatment courses and inconsequential nonsystemic adverse events 17 18•• 19 Underlying immunological mechanisms are yet to be clarified but likely include similar changes in allergenspecific T cell responses to those seen in conventional AIT 8•• 20•• Whether induction of blocking IgG4 antibodies is required for efficacy of peptide immunotherapy is not so clear and may only be seen using longer peptides such as COPs or on reexposure to native allergen 16• Promisingly T cell epitope peptide therapies suggest efficacy with enhanced safety allowing wider uptake across a range of allergic conditionsThe focus of this review is the rationale design and utilization of T cell epitopebased peptides for specific treatment of allergic diseases Selected peptides comprise immunodominant T cell epitopes but not IgEbinding epitopes and have minimal stimulatory potential for inflammatory cells Their presentation is in a form that induces longlasting allergenspecific T cell nonresponsiveness after only a short course of treatment Recent highly encouraging clinical trials of this new class of allergy therapy and associated data on immunological mechanisms are discussedT cell epitope peptide therapy harnesses the established immunological dogma that dominant T cell epitope peptides can induce anergy of specific T cells if delivered in a way that fails to activate the T cell 21 Induction of specific anergy utilizes the functional cytokine plasticity of Th cells to downregulate aberrant effector T cell responses while providing the cytokine milieu and impetus for naive T cells to establish protective responses 22 23 Additionally the pattern of conserved T cell epitope repertoires observed in HDMallergic individuals during longitudinal screening over 2 years supports this approach in contrast to the more changeable T cell specificities observed in longitudinal screening in autoimmune disease 24 25 Human T cell receptor repertoire analysis identified TCRVα and TCRVβ gene segment usage bias together with in vivo clonal dominance by longlived HDMspecific T cell clones 26 Similar in vivo longevity of venomspecific T cell clones was reported 27 Most importantly functional plasticity of T cells derived from the same clonal origin allows switching from dominant IL4 to IL10 or IFNγ production during anergy induction in vitro or AIT 27 28 29 Another study demonstrated preferential loss deletion of pathogenic Th2 T cells specific for dominant allergen epitopes following successful pollen immunotherapy using fluorochromeconjugated HLA class IIpeptide tetramers to quantify these T cells directly ex vivo 30•• These features support the view that induction of specific anergy or selective elimination of dominant clonal populations of pathogenic allergenspecific T cells would be of therapeutic benefit in the treatment of allergic diseasesT cell epitope peptide therapies rely on the identification of immunodominant CD4+ T cell epitopes within major clinically relevant allergens Molecular cloning characterization and sequencing of allergens allow the synthesis of nested sets of overlapping peptides covering the full allergen sequence Mapping of T cell epitopes can then be performed using peripheral blood mononuclear cells PBMC from individuals with the specific allergy of interest either directly ex vivo or after enrichment for allergenspecificity as T cell lines oligoclonal populations or T cell clones monoclonal populations The most critical peptides are identified by a range of immunological assays utilising sophisticated and/or highthroughput methodologies These include flow cytometry using dyes such as carboxyfluorescein diacetate succinimidyl ester CFSE to detect proliferating cells by decreased intensity of staining 31 32 cytokine capture 33 and fluorochromeconjugated HLA class IIpeptide tetramers 27 34 CFSEbased approaches are sensitive for detection of peptideresponsive T cells particularly when combined with other activation markers such as CD25 our unpublished observation but bystander proliferation may reduce specificity 35• ELISPOTbased approaches can be used for highthroughput screening of PBMC for T cell epitope peptide recognition 33 36 37 Identified T cell epitopes are then validated by screening large patient population cohorts and using rigorous assay design and appropriate statistical methods eg 34HLApeptide tetrameric complexes are sensitive and specific analytes for identification and characterization of allergenspecific T cells directly ex vivo but tetramer synthesis is expensive and many HLA class II molecules are not easily isolated for use in tetramers limiting the HLAcoverage obtainable 27 34 Unlike CFSEapproaches tetramerbased methodologies may lack sensitivity despite high specificity 35• Alternatively in silico algorithms consider thousands of known epitope sequences to predict CD4+ T cell epitopes by detecting theoretical HLA class II binding motifs within protein sequences 38 While algorithms provide preliminary guidance costeffectively comprehensiveness is limited and HLAbinding motif predictions require validation in functional peripheral blood T cell assays 35• 39

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