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.  

Immunomodulation of allergic disease by nematode infection

The consistent observation that developing countries have very low frequencies of atopy and allergic diseases has been correlated with environmental exposure to helminth infection. The hygiene hypothesis has been proffered to account for these observations as it has to explain protective effects of living on traditional farms. Small numbers of pilot and proof-of-concept trials have been looking at the nematode-allergy connection as possible therapy for a number of diseases.

This month’s issue presents a review by Jouvin and Kinet (J Allergy Clin Immunol 2012;130:3-10) of this pioneering research and the preliminary results that suggest that certain helminths may be human symbionts rather than parasites.

Jouvin and Kinet begin with an overview of current research into nematode therapy for inflammatory bowel and autoimmune diseases, employing Trichurus suis ova (TSO), or pig whipworm, to treat patients with Crohn’s Disease (CD), ulcerative colitis (UC) and multiple sclerosis (MS). The trials were very small, from 4 subjects to 54 subjects, with safety and tolerability as the endpoints.  There were no AEs reported in the CD and UC trials, and mild GI distress and transient eosinophilia in the MS trial that resolved without subjects dropping out from the studies. Stool specimens collected were all negative for ova and parasites, except an isolated sample in the MS trial. These limited safety results were sufficient for FDA to approve an open-label efficacy study of TSO in MS.

Jouvin and Kinet review the basics of the hygiene hypothesis and discuss the epidemiological and animal evidence for immunomodulatory effects of helminths, as well as limited results of helminth treatment in Western countries. The authors also cover the logic supporting the choice of TSO, in particular because it is not a known human pathogen.

They summarize the safety findings of published research and note their own experience with TSO in the treatment of peanut or tree nut allergy, which was consistent with other reports of transient, mild GI side effects and eosinophilia. Secondary efficacy reports are also included, with some preliminary findings being promising: in a study of CD, 70% of subjects attained remission at the end of the study; in a UC trial, 43% in the treatment group had improved disease compared to 17% in the control group; and in an MS study, a  lower rate of appearance of new lesions imaged by MRI was observed during active treatment. The authors also present an interesting single case report on nematode treatment for autism.

Jouvin and Kinet discuss the potential of other nematodes as therapeutic agents then review the biochemistry of helminth extracts, noting that a phosphorylcholine glycoprotein, ES-62, has been isolated as an effector molecule. They comment that ES-62 prevent mast cell activation and modulate T_H17 responses. Also, ES-62 has been shown to require TLR4 for its activity.

The authors conclude that TSO as seen from very preliminary data is safe and well tolerated, and limited data suggests it ameliorates certain autoimmune diseases. They urge continued research on the mechanisms and optimal dosing to achieve immunomodulation. 

Back to beginnings of farming for answers to protection against allergies and atopy

On behalf of the GABRIEL Advanced Studies Group supported by the European Commission, Illi et al. (J Allergy Clin Immunol 2012;129:1470-1477) provide their results from a survey study designed to address the high variability in reported protective effects associated with farm environments on asthma and allergies (pp#). The study group survey was structured into two phases with questions in phase II targeting exposure to specific elements of the farm environment. Farms were placed in one of three categories depending on farm activities and husbandry: farms with no dairy cows or cattle, but other farm animals, and grain cultivation, farms with dairy cows and/or cattle, but no grain cultivation, and finally, farms with dairy cows and/or cattle, and grain cultivation. Survey queries covered exposure in utero to 3 years.

Illi et al. report that protective effects were highest and most broad for children raised on farms with both cows and cattle and agriculture activities. Exposure to cows, cows’ milk and straw had the greatest protective effect for asthma, exposure to fodder storage and manure were most protective on atopic dermatitis. Interestingly, the data collected could not sufficiently account for the protective effect against hay fever and atopic sensitization. Overall single exposure effect was greatest with cows’ milk, which greatly reduced the risk of asthma, hay fever and atopic sensitization. Exposure to straw had the strongest association with asthma protection, though the authors noted that the effects of individual constituents and contaminants in straw, such as manure, grass pollen, and microbial elements, could not be separated out.

Illi et al. comment that protective associations supported different physiological pathways, noting that cow exposure was associated with respiratory disease protection and cows’ milk association with atopic sensitization pointed to gut-mediated immune development.

The authors conclude that traditional farming environments like those established in humankind’s first non-nomadic lifestyle are the most beneficial from an immunologic natural history perspective. This can account for the variability in farm environment results since farming practices diverge greatly between the US and Central Europe. 

A new category of rhinitis based on localized atopy

This month, Rondón et al. (J Allergy Clin Immunol 2012;129:1460-1467) present an important classificatory revision centered on their identification of a new rhinitis phenotype: local allergic rhinitis (LAR). Building on their previous research, the authors characterize LAR as local specific IgE (sIgE), T_H2 local tissue response, and positive nasal allergen provocation test (NAPT) results in the absence of clinical indicators of systemic atopy, such as positive skin tests and serum specific-IgE. Patients with LAR are known to respond positively to nasal corticosteroids. In addition, they note that conjunctivitis and/or asthma can be comorbid with LAR.

Rondón et al. effectively argue that the current allergic versus non-allergic rhinitis (AR and NAR, respectively) distinction is not sufficient in light of the findings of localized atopy. They suggest that patients diagnosed with idiopathic rhinitis or non-allergic rhinitis with eosinophilia may in fact have LAR, which would decisively impact clinical management as patients with true idiopathic or non-allergic (vasomotor) rhinitis would not respond to therapy like LAR patients would.

The authors propose a revised rhinitis classification (Table 1, pp#) that splits allergic rhinitis into systemic and local atopy subcategories. They estimate prevalence from European data to be between 47-62% of patients reporting seasonal or perennial allergy symptoms. Their and other early results have shown that house dust mite, grass, and olive pollen are common triggers, though they note that comprehensive findings are needed to refine NAPT specificity.

Rondón et al. review the published pathophysiology evidence as well as the reported clinical presentation. They clearly identify the gaps that future research should fill, such as clinical management overlap between AR and LAR, the need for more practical NAPT testing procedures, the relationship between LAR and atopic march, and mechanisms of localized allergic responses. The authors comment that patients with LAR receiving subcutaneous immunotherapy have increased tolerance upon repeat NAPT and also develop positive skin tests and detectable serum specific-IgE. 

The iatrogenic effect of successful ICS therapy on the progress of asthma research

This month’s issue features an editorial by Jeffrey Drazen, MD (J Allergy Clin Immunol 2012;129:1200-1201). Dr. Drazen presents the intriguing argument that our success in treating asthma with inhaled corticosteroids (ICS) has hampered significantly our ability to discern the complex, heterogeneous pathophysiology of the disease.

He briefly reviews for the reader the lengthy history of medicine’s attempts to understand and classify asthma, with reference to the JACI's 2011-2012 Asthma: Current Status and Future Directions series, which featured contributions from leaders in the field of asthma on topics such as asthma’s natural history and clinical presentation, gaps in diagnosis and treatment response, and new targets for therapy based on asthma genotypes. Dr. Drazen commends the efforts that have been made over the years, but notes that for all the research that’s been done, little true progress in early detection and prevention has resulted.

His argument is predicated on the observation that ICS efficacy for treating the inflammatory component of asthma is not specific to a single pathway and, thus, doesn’t inform the mechanisms of asthma biology. Notable work on anti-cytokine therapies for asthma is discussed, with the observation that its success has been less than expected. Drazen comments that these trials have demonstrated sensitive subgroups, but there are limited diagnostics available to identify them.

With a nod to a point raised in Stephen Holgate’s article in the JACI series (J Allergy Clin Immunol 2011;128:495-505), Dr. Drazen supports the idea that the immune dysfunction theory of asthma may need to be discarded in favor of focus on structural abnormality fundamental to the epithelium.

Drazen concludes by deflecting the idea that ICS therapy is the perfect treatment precisely because asthma is so heterogenous. He insists that understanding the specifics of asthma pathology and targeting those elements directly is the patient-centered mandate.

Three injections and counting...

Senti et al. have “injected” new hope into allergy immunotherapy (IT) with this month's report of the results of their research into intralymphatic administration of cat dander allergen for treatment of cat allergy (J Allergy Clin Immunol 2012;129:1290-1296). 

Conventional IT has a low appeal for most allergy sufferers because of the lengthy time requirement to achieve desensitization/tolerance. This is true for subcutaneous as well as sublingual IT. Although this treatment duration can be shortened by higher doses of allergen per treatment, the authors point out that this significantly increases risk of systemic reaction.

Senti et al. generated a unique delivery platform for the cat allergen, Fel d 1, using an HIV-derived translocation peptide combined with part of a human invariant chain that permitted targeting of the vaccine to the MHC class II pathway, avoiding phagocytosis and subsequent degradation. They report that the modular vehicle, MAT-Fel d 1, induced less in vitro degranulation of basophils and of mast cells in skin tests, suggesting that the vaccine may be safer than administration of unmodified allergen.

Subjects in the study received three inguinal intralymphatic injections of sequentially increased doses of MAT-Fel d 1 or placebo under ultrasound guidance. Subjects received injections once every 4 weeks. At 5 weeks after the 3^rd injection, subjects in the treatment group had 5-fold increased levels of IgG₄ compared to controls. This was positively correlated to increased titers of IL-10. The authors report nasal tolerance increased in the treatment group by a factor of 74 compared to the control group. Senti et al. also report increased tolerance of skin prick testing and intradermal testing.  At day 300 follow up, the treatment group reported continued nasal and ocular tolerance.

In conclusion, Senti et al. emphasize the rapid achievement of increased tolerance with a greater safety profile of their modular vaccine, MAT-Fel d 1. They note the need for larger studies permitting increased statistical power as well as efficacy assessment by symptom and medication reduction. 

[Update 5/2/12] We asked Dr. Senti and senior author Thomas Kündig to comment on the next steps in their research. They note, "[We] are currently planning a dose escalation and phase IIb study for further clinical development. Also, MAT molecules containing major bee venom allergen Api m 1, and dust mite allergens and birch allergens have been generated and work well in mice."