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Monday, January 31, 2011

The lung microbiome and asthma pathogenesis

In this issue, Huang et al. (J Allergy Clin Immunol 2011;127: 372-381.e3), reporting on behalf of the NHLBI’s Asthma Clinical Research Network [ACRN], report first-ever research findings associating the composition of airway flora with clinical features of asthma. They postulate that the airway supports a complex community of bacteria that may contribute to clinical features of asthma among asthmatics taking inhaled corticosteroids (ICS). The researchers use a microarra-based method that detects distinct 16S rRNA gene sequences permitting detection and identification of bacterial taxa without previous knowledge of their presence in the relevant sample. Huang et al. report that using this tool, taxa in the phylum Proteobacteria were the most abundant in the cohort of patients studied.

The study occurred in parallel with a clinical trial examining the effects of long-term clarithromycin therapy in subjects with sub-optimal asthma control. Bronchial brushings were obtained from 65 asthma subjects and 10 healthy subjects. The authors find that airway colonization is variable in both healthy and asthmatic subjects, but that asthmatic subjects had significantly greater bacterial diversity than controls. Further, subjects in the clarithromycin treatment group with the highest bacterial diversity pre-treatment, had the greatest improvement in airway hyperresponsiveness following treatment.

Huang et al. comment that finding an airway microbiota in asthma patients on ICS therapy may not be surprising, but in fact, is also consistent with the notion that disturbances in epithelial/mucosal-associated microbiomes are known to be associated with disease as is the case with intestinal inflammatory diseases. They suggest that colonization by specific bacteria may contribute to persistence of inflammation, disease presentation, and/or disease heterogeneity; in particular, they cite the example of bacteria in the family Comamonadaceae, which are known to have steroid degrading capacity, as potentially contributory to steroid-resistant asthma pathology. Further, Huang et al. propose that the effectiveness of macrolide therapy on reducing airway reactivity may be a combined effect of their anti-inflammatory and antibacterial properties.

The authors state that discerning whether increased bacterial burden and diversity is a function of having asthma or being on ICS therapy is an important research question in light of the widespread use of ICS in many airway diseases. Concluding, Huang et al. comment that their findings open new research paths on disease mechanisms in asthma.

We asked senior author Dr. Susan Lynch, PhD, from the University of California - San Francisco, to tell us a little more about the study:

JACI: Your findings have far-reaching implications for airway disease and systems biology research. In your opinion, what are the proximate priorities?

Dr. Lynch: Establishment of cross-disciplinary, integrated research efforts to define microbiota structure, function and host interplay in well defined cohorts of patients. Openness to the possibility that this field of research may dramatically change our long-held perceptions of chronic inflammatory disease genesis and progression.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.

Friday, January 7, 2011

Gene-environment protective effects are context-dependent in development of asthma

Recent genomic studies have begun to demonstrate that adaptive genotypes are only adaptive when expressed in their relevant context. In this month’s issue, Ege et al. and the European consortium, GABRIEL, present surprising findings from a gene-environment (G*E) interaction analysis for childhood asthma and the farming environment (J Allergy Clin Immunol 2011;127:138-144.e4).

Ege et al. report that previously identified common SNPs associated with asthma in urban populations did not interact with farming environment parameters. Previously identified interactions with farming related exposures were not confirmed despite adequate statistical power.

Among rarer SNPs, however, significant interactions were detected with farming related exposures such as
consumption of raw milk, and exposure to cow and/or straw. By this approach the authors identified new genes that differed from those reported as asthma-associated. SNPs in the GRM1 (metabotropic glutamate receptor 1) gene specifically and significantly interacted with farm exposures. The GRM1 is involved in immunological and neuronal synaptic function. The authors note that these results must be interpreted carefully as the SNPs are rare.

Ege et al. conclude that there may exist different phenotypes of asthma that are susceptible to either genetic or environmental effects, but rarely to both at the same time. They propose that genotypes which are protective for one exposed population do not carry an effect in an unexposed population.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.

Thursday, January 6, 2011

Advances in immunotherapy for allergies have increased safety and effectiveness

Casale and Stokes take a look at new technologies and experimental therapies developed to improve on the standard approach of subcutaneous injection of increasing concentrations of allergens (SCIT) in this month’s issue (J Allergy Clin Immunol 2011;127:8-15). They discuss omalizumab add-on therapy to conventional SCIT and report on studies in which omalizumab was administered concurrently and prior to initiation of SCIT. Omalizumab plus SCIT showed significant reduction in allergic rhinitis symptoms, and less use of rescue medication compared to SCIT alone. When omalizumab was given as pre-treatment to SCIT, both allergic rhinitis and allergic asthma subjects had fewer severe reactions and more subjects were able to achieve target maintenance dose than subjects receiving placebo plus SCIT.

The authors continue with recent efforts to mobilize mitigating Th1 responses through Toll-like receptor (TLR) agonists and CpG immunostimulatory responses. Combined allergen and TLR therapy is reported to provide significant improvements in rhinitis symptoms and medication use in both adults and children. They also discuss effectiveness associated with bonding immunostimulatory CpG sequences with ragweed allergen to influence T cell responses toward Th1 dominance and reduced eosinophilia; however, clinical impact was minimal. Engineering the allergen and CpG sequences, as well as CpG sequences alone, into virus-like particles provided significantly greater improvements in symptoms and immunologic markers.

Casale and Stokes cover the use of T-cell derived peptides in the treatment of allergies including cat allergy and bee venom allergy. They describe increased benefit and safety of SCIT therapy with newer preparations of Fel d 1 peptides, and early impressive results with Api m 1 and phospholipase A2.

Different routes of administration are also reviewed by the authors such as intranasal and intrabronchial, focusing on escalating oral and sublingual (SLIT) therapies. They report encouraging results from oral desensitization/tolerance studies for subjects with food allergies, which included decreased inflammation markers, decreased specific IgE, increased specific IgG, and achievement of tolerance in a majority of subjects. Results from SLIT therapy trials have been positive as well. SLIT clinical trials for grass and ragweed allergies have shown efficacy in subjects with seasonal allergic rhinitis, and there are positive results noted for other allergens in seasonal allergic rhinitis and allergic asthma.

In conclusion, the authors comment that adjunct omalizumab therapy clearly improves safety and TLR agonists are more effective for shifting to Th1 response. They are optimistic about the future of immunotherapy, although they feel that with the rapid evolution in new technology and increased knowledge of the immune system, how immunotherapy will be used in the future will be substantially different than what is occurring today.