Update about Oralair® as a treatment for grass pollen allergic rhinitis.

Sublingual immunotherapy (SLIT) is a well-tolerated, safe, and effective approach to treating allergic rhinitis (AR). Oralair® is a five-grass pollen SLIT tablet containing natural pollen allergens from five of the major grass species responsible for seasonal AR due to grass pollen allergy. Recommended use is in a pre-coseasonal regimen, starting daily treatment approximately 4 months before the start of the pollen season, with treatment then continued daily throughout the season; treatment should continue for 3-5 y. Clinical efficacy and safety of Oralair® in patients with grass pollen-induced AR has been demonstrated in a comprehensive clinical development program of randomized controlled trials. Effectiveness has been substantiated in subsequent observational studies with sustained efficacy following treatment cessation and a favorable level of adherence, quality of life, benefit, and satisfaction for the patients. Supportive evidence for a benefit in reducing the risk or delaying the development of allergic asthma is emerging.

Immunoregulatory T cell epitope peptides: the new frontier in allergy therapy.

Allergen immunotherapy (AIT) has been practised since 1911 and remains the only therapy proven to modify the natural history of allergic diseases. Although efficacious in carefully selected individuals, the currently licensed whole allergen extracts retain the risk of IgE-mediated adverse events, including anaphylaxis and occasionally death. This together with the need for prolonged treatment regimens results in poor patient adherence. The central role of the T cell in orchestrating the immune response to allergen informs the choice of T cell targeted therapies for down-regulation of aberrant allergic responses. Carefully mapped short synthetic peptides that contain the dominant T cell epitopes of major allergens and bind to a diverse array of HLA class II alleles, can be delivered intradermally into non-inflamed skin to induce sustained clinical and immunological tolerance. The short peptides from allergenic proteins are unable to cross-link IgE and possess minimal inflammatory potential. Systematic progress has been made from in vitro human models of allergen T cell epitope-based peptide anergy in the early 1990s, through proof-of-concept murine allergy models and early human trials with longer peptides, to the current randomized, double-blind, placebo-controlled clinical trials with the potential new class of synthetic short immune-regulatory T cell epitope peptide therapies. Sustained efficacy with few adverse events is being reported for cat, house dust mite and grass pollen allergy after only a short course of treatment. Underlying immunological mechanisms remain to be fully delineated but anergy, deletion, immune deviation and Treg induction all seem contributory to successful outcomes, with changes in IgG4 apparently less important compared to conventional AIT. T cell epitope peptide therapy is promising a safe and effective new class of specific treatment for allergy, enabling wider application even for more severe allergic diseases.

Functional immunoglobulin E cross-reactivity between Pas n 1 of Bahia grass pollen and other group 1 grass pollen allergens.

BACKGROUND: Grass pollens are major triggers of allergic rhinitis and asthma, but the immunological relationships between pollen allergens of the subtropical Bahia grass, Paspalum notatum, and temperate grasses are unresolved. OBJECTIVE: To assess serum IgE cross-reactivity between subtropical P. notatum and temperate Lolium perenne (Ryegrass) pollen allergens. METHODS: Serum IgE reactivities of grass pollen-allergic patients with P. notatum, L. perenne and Cynodon dactylon (Bermuda grass) pollen extracts and their respective purified group 1 allergens, Pas n 1, Lol p 1 and Cyn d 1, were compared by immunoblotting, ELISA and basophil activation. RESULTS: In a cohort of 51 patients from a temperate region, a high frequency of IgE reactivity with each grass pollen was detected, but reactivity with L. perenne pollen was substantially greater than with P. notatum and C. dactylon pollen. Similarly, serum IgE reactivity with Lol p 1 was greater than with Pas n 1 or Cyn d 1. For seven of eight sera studied in detail, asymmetric serum IgE cross-reactivity was observed; L. perenne pollen inhibited IgE reactivity with P. notatum pollen but not the converse, and IgE reactivity with Pas n 1 was inhibited by Lol p 1 but IgE reactivity with Lol p 1 was not inhibited by Pas n 1 or Cyn d 1. Importantly, P. notatum pollen and Pas n 1 activated basophils in grass pollen-allergic patients from a temperate region, although stimulation was greater by pollen of L. perenne than P. notatum or C. dactylon, and by Lol p 1 than Pas n 1 or Cyn d 1. In contrast, a cohort of 47 patients from a subtropical region showed similar IgE reactivity with P. notatum and L. perenne pollen, and reciprocal cross-inhibition of IgE reactivity between L. perenne and P. notatum. CONCLUSIONS: Pollen allergens of the subtropical P. notatum, including Pas n 1, show clinically relevant IgE cross-reactivity with pollen allergens of L. perenne but also species-specific IgE reactivity.

Latex allergy: a model for therapy.

Allergy to natural rubber latex products emerged as an important clinical condition following an increase in the use of latex gloves for barrier protection in the early 1980s. In addition to latex glove users, other high-risk groups with different latex exposure include spina bifida patients and others with multiple surgical procedures. Subjects with fruit and vegetable allergy are also at risk due to cross-reactive allergens. Following the significant advances in the identification and characterization of common aeroallergens, latex allergy was well placed to become an excellent model of therapy. Awareness of latex allergy and modes of sensitization enabled epidemiological studies to inform allergen avoidance initiatives, substantially reducing inadvertent exposure in major hospitals in Western countries. Spina bifida is often identified in utero or soon after birth, allowing vigorous latex allergen avoidance with enhanced efficacy of primary prevention. However, changing demographics of latex allergy and technological revolution in countries such as China and India are predicted to unleash a second wave of latex allergy reemphasizing the incentive for improved manufacturing procedures for latex products. The desirable high tensile strength and elasticity of natural rubber latex have made the commercial identification of good alternatives very difficult but this would also be attractive for primary prevention. In addition, an effective specific immunotherapy regimen would be valuable for selected high-risk atopic individuals. Current subcutaneous and sublingual immunotherapy schedules have been tested for treatment of latex allergy with evidence of efficacy but the risks of adverse events are high. For such potent allergens as latex, hypoallergenic but T cell-reactive preparations are required for clinical use. Identification of allergenic components of latex products, with generation of monoclonal antibodies and recombinant allergens, allowed sequence determination and mapping of T cell and B cell epitopes. Together, these reagents and data facilitated improved diagnostics and investigation of novel-specific therapeutics. Potential hypoallergenic latex preparations identified include modified non-IgE-reactive allergen molecules and short T cell epitope peptides. The co-administration of adjunct therapies such as anti-IgE or corticosteroids and of appropriate adjuvants for induction of regulatory T cell response offers promise for clinically effective, safe latex-specific vaccines.

Bahia grass pollen specific IgE is common in seasonal rhinitis patients but has limited cross-reactivity with Ryegrass.

BACKGROUND: Perennial Ryegrass is a major cause of rhinitis in spring and early summer. Bahia grass, Paspalum notatum, flowers late into summer and could account for allergic rhinitis at this time. We determined the frequency of serum immunoglobulin (Ig)E reactivity with Bahia grass in Ryegrass pollen allergic patients and investigated IgE cross-reactivity between Bahia and Ryegrass. METHODS: Serum from 33 Ryegrass pollen allergic patients and 12 nonatopic donors were tested for IgE reactivity with Bahia and Ryegrass pollen extracts (PE) by enzyme-linked immunosorbent assay (ELISA), western blotting and inhibition ELISA. Allergen-specific antibodies from a pool of sera from allergic donors were affinity purified and tested for IgE cross-reactivity. RESULTS: Seventy-eight per cent of the sera had IgE reactivity with Bahia grass, but more weakly than with Ryegrass. Antibodies eluted from the major Ryegrass pollen allergens, Lol p 1 and Lol p 5, showed IgE reactivity with allergens of Ryegrass and Canary but not Bahia or Bermuda grasses. Timothy, Canary and Ryegrass inhibited IgE reactivity with Ryegrass and Bahia grass, whereas Bahia, Johnson and Bermuda grass did not inhibit IgE reactivity with Ryegrass. CONCLUSIONS: The majority of Ryegrass allergic patients also showed serum IgE reactivity with Bahia grass PE. However, Bahia grass and Ryegrass had only limited IgE cross-reactivity indicating that Bahia grass should be considered in diagnosis and treatment of patients with hay fever late in the grass pollen season.

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven.

BACKGROUND: IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses. OBJECTIVES: To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy. METHODS: Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced. RESULTS: The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts. CONCLUSION: In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.

Characterization of the human T cell response to rye grass pollen allergens Lol p 1 and Lol p 5.

BACKGROUND: Knowledge of dominant T cell epitopes of major allergens recognized by allergic individuals is required to improve efficacy and safety of allergen immunotherapy. Rye grass pollen (RGP) is the most important source of seasonal aeroallergens in temperate climates and Lol p 1 and Lol p 5 are the two major IgE-reactive allergens. This study aimed to characterize the T cell response to these allergens using a large panel of RGP-sensitive individuals. METHODS: Short-term RGP-specific T cell lines (TCL) were generated from 38 RGP-sensitive subjects and stimulated with Lol p 1 and/or Lol p 5 allergens and synthetic 20-mer peptides. Proliferative responses were determined by 3H-thymidine uptake and IL-5 and IFN-gamma in culture supernatants analysed by ELISA. RESULTS: Of 17 subjects tested for reactivity to both allergens 16 (94%) responded to Lol p 1 and/or Lol p 5, establishing these as major T cell-reactive allergens. Sites of T cell reactivity were spread throughout the allergen molecules but regions of high reactivity were found. For Lol p 1 these spanned residues 19-38, 109-128, 154-173, 190-209, and for Lol p 5 37-56, 100-119, 145-164, 154-173, 190-209, 217-236 and 226-245. IL-5 and IFN-gamma were produced by T cells cultured with proliferation-inducing peptides. CONCLUSIONS: T cell responses to RGP major allergens have been extensively characterized, providing fundamental information for developing T cell-targeted immunotherapy for RGP allergy.

A novel grass pollen allergen mimotope identified by phage display peptide library inhibits allergen-human IgE antibody interaction.

The aim of this study was to investigate the molecular basis of human IgE-allergen interaction by screening a phage-displayed peptide library with an allergen-specific human IgE-mimicking monoclonal antibody (mAb). A mAb that reacted with major grass pollen allergens was successfully identified and shown to inhibit human IgE-allergen interaction. Biopanning of a phage-displayed random peptide library with this mAb yielded a 12 amino acid long mimotope. A synthetic peptide based on this 12-mer mimotope inhibited mAb and human IgE binding to grass pollen extracts. Our results indicate that such synthetic peptide mimotopes of allergens have potential as novel therapeutic agents.

T-cell receptor contact and MHC binding residues of a major rye grass pollen allergen T-cell epitope.

BACKGROUND: T cells are pivotal in the elicitation of allergic diseases. Analogues of T-cell epitope peptides with a modification at a T-cell receptor (TCR) contact site can alter selected T-cell effector functions. Thus the ability to modulate allergen-specific T-cell responses towards TH1 -like by stimulation with peptide analogues may downregulate allergic inflammation. OBJECTIVES: The purpose of this study was to characterize the minimal epitope recognized by cloned T cells of a dominant Lol p 5 epitope, p105-116, and identify the critical residues involved in TCR and MHC contact. METHODS: Using peptides with progressive truncation of N- and C-terminal residues in T-cell proliferation assays, we identified the core epitope recognized by cloned CD4(+) T cells. An additional series of peptides with single amino acid substitutions were used in T-cell proliferation and live-cell MHC binding assays. Taken together, these results allowed identification of MHC binding and TCR contact residues of p105-116. RESULTS: The core epitope of p105-116 was identified as residues 107-114. Within this core epitope, 3 residues were found to be important for MHC binding, positions 107, 110, and 112, whereas those at positions 108, 109, 110, 111, and 113 were putative TCR contact residues. CONCLUSIONS: The identification of the TCR and MHC contact residues of a dominant Lol p 5 T-cell epitope and analogues of this peptide capable of modulating T-cell responses will allow the evaluation of these peptides' potential as immunotherapeutic agents for rye grass pollen allergic disease.