The allergenicity of “hypoallergenic” dogs

It’s a primitive social urge in humans to interact with dogs. So much so that many people found to be clinically sensitive to dogs will own them anyway. In this context, it is not surprising that the search for dogs that elicit a minimal allergic response would claim so much energy, but are there such things as “hypoallergenic” dogs? Vredegoor et al. look at that question in this month’s issue (J Allergy Clin Immunol 2012;130:904-909.e7).

The authors examine levels of the primary dog allergen, Can f 1, in samples from dog fur and skin, and settled and airborne dust from “hypoallergenic” dogs (Labradoodles, Poodles, Spanish water dogs, and Airedale terriers), normal allergenic dogs (Labrador retrievers), and a variety of breeds and mixed breeds that made up the control group. Their results are paradoxical and even ironic.

Poodles and Labradoodles had the highest levels of Can f 1 in their coat and skin; Labrador retrievers had the lowest. Hair and dander shedding was highest from Airedale terriers. Vredegoor et al. report that environmental levels of Can f 1 were not significantly different between “hypoallergenic” dogs and their allergenic counterparts, though homes with covered floors had overall lower environmental levels than homes with exposed floors. The authors note that other identified canine allergens, such as Can f 2 and 3, were not screened due to lack of available methods for analyzing large sample sizes. 

The authors also collected information from owners by administering questionnaires. Dog-allergic owners reported much fewer symptoms with the breeds thought to be hypoallergenic and did not report having different house-cleaning practices than non-allergic owners. It was noted that recent swimming by the dogs had an overall effect of lowering allergen levels and Vredegoor et al. speculated that this could contribute to the lower levels found in Labrador retrievers, which are frequent swimmers.

Vredegoor et al. conclude that there is no evidence that supports the label “hypoallergenic” with respect to dogs, so we asked the authors to comment on a possible explanation for the number of dog-allergic owners who reported experiencing fewer symptoms with certain dogs: Senior author Esmeralda J.M. Seegers-Krop replies, “We believe the health effects can be a kind of placebo effect in these people. It has been seen in cat allergic people as well (they report not to be allergic to their own cat but only to other cats).”

Asthma therapies targeting Il-13

This month’s clinical review article by Ingram and Kraft (J Allergy Clin Immunol 2012;130: 829-842) presents exhaustive and timely coverage of a complex issue in asthma treatment, namely, the interface of IL-13 pathophysiology, asthma phenotypes, and IL-13 targeted therapies. The authors take the discussion to foundations of IL-4/IL-13 signaling in asthma before delving into the clinical and investigative implications associated with IL-13 dominance in atopic asthma. The review comprehensively covers current knowledge on the clinical and genetic heterogeneity of asthma, emerging phenotypes and subtypes, biomarker diagnostics, and systemic and targeted therapy responses in well-characterized asthma phenotypes.


Review highlights include:

• Cluster analysis of clinical asthma phenotypes by several research groups, including the consistent finding of eosinophilic, high TH2 cytokine profile asthma and non-eosinophilic, low TH2 cytokine profile asthma.

• Evidence confirming therapeutic efficacy of systemic and targeted therapies in eosinophilic, high TH2 asthma.

• Reports of the successful use of biomarkers in characterizing response to therapy, including recent research involving omalizumab, mepolizumab, and lebrikizumab for patients with severe and/or uncontrolled asthma characterized using clinical and biomarker indices.

• Specific evidence for applying FENO, induced sputum, IgE, and periostin to treatment decision making.

Ingram and Kraft note that traditional and targeted therapies are effective only for eosinophilic, TH2 high asthma patients, leaving a gap in our knowledge about how to effectively manage the low TH2 profile patients. They also remark that TH2 inflammation in asthma patients may be more effectively assessed through the use of combinations of inflammatory and molecular markers, rather than relying on observations of single biomarkers. They conclude by commenting that application of the molecular features of asthma phenotypes, in combination with clinical evidence, is being used to predict response to intervention. They follow by pointing out that the current knowledge base has defined a gap in managing asthma that does not present with a TH2 dominant signature.

A collaborative model for drug development for rare diseases

This month’s issue holds an article by Fiorentino et al. putting forward a model for rare disease drug development and the first realization of this model (J Allergy Clin Immunol 2012;130:613-616). Fiorentino and colleagues at the FDA in CDER’s Division of Gastroenterology and Inborn Error Products chose the rare disease eosinophilic esophagitis (EoE) as the focus of their efforts to establish this new paradigm.

Noting the rise in prevalence and incidence of EoE, the authors discuss the knowledge gaps that create obstacles to effective clinical interventions. They use this information to construct their model of “rational” drug development, which includes defining the disease in clinical, research and sociocultural terms, evaluating the natural history of the disease using the definitions identified, and reliably assessing clinical and patient-reported outcomes.

Fiorentino et al. describe their efforts to date implementing this model. They tapped critical research groups, such as The International Gastrointestinal Eosinophil Researchers (TIGERs), North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) to open discussions on disease definition and urge the inclusion of disease and patient advocacy groups in this early process. Advocacy groups are identified as critical to the success of the model because they bring strong interest in the long-term success of research into the disease.

Early progress is reported for the determination of a functional disease definition and appropriate terminology. The authors note that findings from graduate student research supported by the EoE project demonstrate that inconsistent and vague terminology is impeding research efforts. Additionally, they comment that research is underway to understand the relationship between positive clinical outcomes and the esophageal mucosal eosinophilia that is diagnostic for EoE. They point out that there is a pressing need to define and characterize the EoE patient population in order to develop appropriate patient-reported outcome measures.

An editorial in this issue by Rothenberg et al. presents additional perspectives and considerations (pp#). Dr. Rothenberg notes that an upcoming meeting (Sept. 19) provides an opportunity for more information and exchange of opinion about the subject. For further information: https://www.signup4.net/public/ap.aspx?EID=20123759E&OID=50

A large cohort analysis of allergic outcomes from peanut and tree nut consumption during pregnancy

Current research has challenged the conventional wisdom of dietary avoidance of food allergens during pregnancy. A recent study from the UK found that avoidance of peanuts, specifically, during pregnancy did not confer significant protection from peanut allergy to the infant. Accordingly, the UK removed that recommendation. In the US, avoidance is only recommended for children at risk by heredity.

In this issue, Maslova et al. (J Allergy Clin Immunol 2012;130:724-732) from Center for Fetal Programming, Statens Serum Institut, present important results from an analysis of a very large Danish birth cohort (n=61,908). The authors look at development of asthma, wheeze, and allergic rhinitis – not food allergy – in children whose mothers consumed peanuts and tree nuts during pregnancy as compared to children whose mothers avoided these foods.

At 18 months, children whose mothers ate peanuts more than once a week were less likely to have parent-reported asthma, while children whose mothers ate tree nuts were less likely to report asthma, wheeze and recurrent wheeze. At 7 years, children of mothers who ate peanuts and/or tree nuts were less likely to have a registered diagnosis of asthma. These results all reached statistical significance. The association of tree nut consumption during pregnancy with decreased likelihood of self-reported allergic rhinitis during the first 7 years of life was borderline statistically significant.

Maslova et al conclude by suggesting that their results do not support avoidance or decreased consumption of peanuts and tree nuts during pregnancy. 

Secretory phenotype of mast cells localized in nasal polyps from chronic rhinosinusitis subjects

Takabayashi et al. present novel findings in this issue on the distribution and protease secretion of mast cells (MC) found in nasal polyps from subjects with chronic rhinosinusitis (CRSwNP) (J Allergy Clin Immunol 2012; 130:410-420.e5). The authors compared MC from the epithelium, glands, and submucosa of CRSwNP with uncinate biopsy tissue (UT) from subjects with CRS without nasal polyps (CRSsNP) and control subjects.

They found mast cells numbers were highly increased in NP epithelium and glands, in particular, as compared to UT from CRSsNP and control subjects. Further, the MC populations in NP were distinguishable on the basis of their protease profile. Mast cells from the NP epithelium were tryptase-carboxypeptidase A3 (CPA3)-positive/chymase-negative, while MC from NP glands were tryptase-CPA3-chymase-positive.


The authors note clear expansion in MC numbers that they suggest could be the result of increased migration and accumulation as well as proliferation. Since mast cell tryptase can activate protease-activated receptor (PAR) 2, which facilitates allergic inflammation, and mast cell chymase can activate PAR-1 signaling and is a potent glandular secretagogue, the results of Takabayashi et al suggest that mast cells localized in submucosal glands may be well positioned to drive important features of the inflammatory response associated with chronic rhinosinusitis and nasal polyp formation.

Association between traditional farming and childhood wheeze from the GABRIEL Advanced Study Group

The European GABRIEL Advanced Studies project has provided a large body of data and samples for investigating effects of traditional farm environments on childhood asthma and atopy. Research on the GABRIELA cohort has demonstrated that traditional farming environments like those found in Europe have a protective effect on childhood atopy and, less consistently, childhood asthma. Yet, recent findings show that microbial diversity in farming environments appears to play a stronger role for asthma than for atopy. This month’s issue holds another important report on the impact of farm life on different childhood wheeze phenotypes by Fuchs et al. (J Allergy Clin Immunol 2012;130:382-388.e6).

Fuchs et al note that there are different wheeze phenotypes that correlate to different clinical outcomes, and that comorbid atopy complicates the search for wheeze-specific farm effects. To address this, the authors partition the study population into atopic and non-atopic children. In addition to analyzing the farm effect on atopy, they further investigate the effect on different wheeze phenotypes (transient, current, persistent, late-onset), airway inflammation and lung function for atopic and non-atopic children, separately.

They report that farm environment has a significant beneficial effect on all wheeze phenotypes. This protective effect was independent of atopic sensitization. This was different for lung mechanics as measured by lung function and on airway inflammation, on which farming had no appreciable overall effect. However, farm-exposed atopic children had less severe lung function impairment and lower exhaled nitric oxide (FeNO) than non-exposed atopic children.

Fuchs et al. speculate that farming’s protective effects are mediated through antiviral activities of the innate immune system that minimize respiratory infections. Future steps in their research to better elucidate underlying mechanisms will be analyses in prospective setups and studies further including the analysis of innate and adaptive immune mechanisms related to defense against viral infections and the role of the microbiome in upper and lower airways herein.

Anti-IL17 mAb shows promising results in psoriasis treatment

Exciting – and surprising – results from a clinical trial for psoriasis are presented in this month’s issue by Krueger et al (J Allergy Clin Immunol 2012;130:145-154.e9). The authors report on a randomized trial of a new humanized IgG₄ monoclonal antibody, ixekizumab. It would be fair to say the results from their phase I trial are near astonishing.

Based on published evidence that psoriasis is a T_H17-mediated disease, the authors postulate that IL-17 acts as a “gatekeeping” cytokine in the pathogenesis of psoriasis, noting that much of the evidence from animal studies points to IL-22. They point out that IL-22 in humans is produced from a different T cell subset, T_H22 cells, unlike mice where T_H17 cell produce both.

Their speculation paid off. Krueger et al. report dose-dependent, significant improvement in both pathophysiology and clinical presentation of psoriasis subjects after only 2 weeks of ixekizumab treatment. Skin biopsies from subjects demonstrated rapid improvements in keratinocyte proliferation, hyperplasia, epidermal thickness, T cell and dendritic cell infiltration of the dermis and significantly suppressed expression of innate immunity peptides. After 6 weeks of treatment, the authors report that subjects’ skin appeared normal. Interestingly, 100% of subjects in the 150mg dosing group no longer presented clinically with psoriasis at 6 weeks of therapy. Krueger et al. comment that the effectiveness of ixekizumab at 2 and 6 weeks was surprising since other antibody therapies typically require 12 weeks to demonstrate efficacy. They also note that the adverse effects profile is agreeable and the drug well-tolerated.

Noting that many genes associated with psoriasis are co-regulated by IL-17 and TNF-α, Krueger et al. show that IL-17 blockade with ixekizumab is far more effective in suppressing the co-regulated genes than TNF-α blockade by etanercept. They suggest that their evidence shows that IL-17 is a pivotal cytokine in the pathology of psoriasis, affecting many effector functions of other T cell subsets.