Mark Larche

Fel d 1–derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: A randomized, placebo-controlled study

BACKGROUNDnAllergic rhinoconjunctivitis is an increasingly common source of morbidity, with sensitivity to cats accounting for 10% to 15% of disease burden. Allergy to cats is also a major risk factor for the development of asthma.nnnOBJECTIVESnWe sought to probe the persistence of the treatment effect of a novel F el d 1-derived peptide antigen desensitization (Cat-PAD) 1 year after the start of treatment in subjects with cat allergy-induced rhinoconjunctivitis after standardized allergen challenge.nnnMETHODSnIn a randomized, double-blind, placebo-controlled, parallel-group clinical trial, subjects attended an environmental exposure chamber in which they were exposed to cat allergen before and after treatment with 2 different regimens of Cat-PAD over a 3-month period. Clinical efficacy was assessed as a change in total rhinoconjunctivitis symptom scores 18 to 22 weeks and 50 to 54 weeks after the start of treatment.nnnRESULTSnTreatment with Cat-PAD showed greater efficacy with 4 administrations of a 6-nmol dose 4 weeks apart than with 8 administrations of a 3-nmol dose 2 weeks apart. The treatment effect of 6 nmol persisted 1 year after the start of treatment and was significantly different from that of 3 nmol (P = .0342) and placebo (P = .0104). The treatment effect was apparent on both nasal and ocular symptoms at 1 year.nnnCONCLUSIONSnA short course of Cat-PAD improves the ocular and nasal components of rhinoconjunctivitis symptoms in subjects with cat allergy, with the treatment effect persisting 1 year after the start of treatment.

Fel d 1‐derived synthetic peptide immuno‐regulatory epitopes show a long‐term treatment effect in cat allergic subjects

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.

OX40L blockade and allergen‐induced airway responses in subjects with mild asthma

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.

New Directions in Immunotherapy

Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for initiating and adhering to treatment.

The effect of rituximab on vaccine responses in patients with immune thrombocytopenia

B-cell depletion may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). We investigated the effects of rituximab on antibody and cellular responses to Streptococcus pneumoniae polysaccharide and Haemophilus influenzae type b (Hib) vaccines in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n = 17) or placebo (n = 7). Among 20 evaluable patients, 3 of 14 (21%) in the rituximab group and 4 of 6 (67%) in the placebo group achieved a fourfold increase in anti-pneumococcal antibodies (P = .12). For anti-Hib antibodies, 4 of 14 (29%) and 5 of 6 (83%), respectively, achieved a fourfold increase (P < .05). Fewer patients in the rituximab group demonstrated Hib killing (2 of 14 [14%], 5 of 6 [83%], P < .05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, preplasma cell blasts and interferon-γ-secreting T cells were reduced in rituximab-treated patients. Antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with depleted B-cell pools. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in ITP patients.

T Cell Epitope-Based Allergy Vaccines

Specific immunotherapy (SIT) with extracts containing intact allergen molecules is clinically efficacious, but associated with frequent adverse events related to the allergic sensitization of the patient. As a result, treatment is initiated in an incremental dose fashion which ultimately achieves a plateau (maintenance dose) that may be continued for several years. Reduction of allergic adverse events may allow safer and more rapid treatment Thus, many groups have developed and evaluated strategies to reduce allergenicity whilst maintaining immunogenicity, the latter being required to achieve specific modulation of the immune response. Peptide immunotherapy can be used to target T and/or B cells in an antigen-specific manner. To date, only approaches that target T cells have been clinically evaluated. Short, synthetic peptides representing immunodominant T cell epitopes of major allergens are able to modulate allergen-specific T cell responses in the absence of IgE cross linking and activation of effector cells. Here we review clinical and mechanistic studies associated with peptide immunotherapy targeting allergy to cats or to bee venom.xa0

Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement

One of the major concerns in the practice of allergy is related to the safety of procedures for the diagnosis and treatment of allergic disease. Management (diagnosis and treatment) of hypersensitivity disorders involves often intentional exposure to potentially allergenic substances (during skin testing), deliberate induction in the office of allergic symptoms to offending compounds (provocation tests) or intentional application of potentially dangerous substances (allergy vaccine) to sensitized patients. These situations may be associated with a significant risk of unwanted, excessive or even dangerous reactions, which in many instances cannot be completely avoided. However, adverse reactions can be minimized or even avoided if a physician is fully aware of potential risk and is prepared to appropriately handle the situation.Information on the risk of diagnostic and therapeutic procedures in allergic diseases has been accumulated in the medical literature for decades; however, except for allergen specific immunotherapy, it has never been presented in a systematic fashion. Up to now no single document addressed the risk of the most commonly used medical procedures in the allergy office nor attempted to present general requirements necessary to assure the safety of these procedures.Following review of available literature a group of allergy experts within the World Allergy Organization (WAO), representing various continents and areas of allergy expertise, presents this report on risk associated with diagnostic and therapeutic procedures in allergology and proposes a consensus on safety requirements for performing procedures in allergy offices. Optimal safety measures including appropriate location, type and required time of supervision, availability of safety equipment, access to specialized emergency services, etc. for various procedures have been recommended.This document should be useful for allergists with already established practices and experience as well as to other specialists taking care of patients with allergies.

Amelioration of ovalbumin-induced allergic airway disease following Der p 1 peptide immunotherapy is not associated with induction of IL-35

In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of TH2 cells and decreased interleukin (IL)-17+ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3+ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease.

T cell‐mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells

Inhaled peptide challenge has been shown to induce T cell‐mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4+ T cells and increased levels of thymus and activation‐regulated chemokine (TARC; CCL17). Epithelial‐derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH2 responses via CCL17 production.

Peptide and Recombinant Immunotherapy

Because of the need to standardize allergen immunotherapy and the desire to reduce allergic adverse events during therapy, a transition to recombinant/synthetic hypoallergenic approaches is inevitable. Evidence supports the notion that effective therapy can be delivered using a limited panel of allergens or even epitopes, weakening the argument that all allergens must be present for optimal efficacy. Moreover, standardized products will allow direct comparisons between studies and, for the first time, immunotherapy studies will be truly blinded, allowing an accurate assessment of the actual treatment effect that can be achieved with this form of intervention.