Does sublingual immunotherapy work with multiallergen mixes?
It is generally accepted—in the United States, at least—that effective subcutaneous injection immunotherapy can be accomplished with mixes of multiple non–cross-reacting allergen extracts. To date, no study of sublingual immunotherapy (SLIT) with more than 2 differing allergen extracts has been reported. In this issue of the Journal, Amar et al (p 150) address this question. Fifty-three subjects with grass pollen–induced allergic rhinitis received 10 months of SLIT consisting of monotherapy with timothy grass (30 μg of Phl p 5 daily), the same dose of timothy grass plus 9 nonrelated pollen extracts, or placebo. A very poor pollen season obscured the clinical response. However, those receiving timothy grass monotherapy showed significant differences from placebo for titrated skin prick test and nasal challenge results, specific IgG4 antibody levels, and timothy grass–stimulated release of IFN-γ from PBMCs, all indicating a relevant positive response. Those receiving the same dose of timothy grass combined with 9 other extracts had results that differed from those with placebo only for titrated skin prick test results and then less than those with monotherapy. Although lacking statistical power to directly compare the 2 active groups, this study suggests caution in administering multiallergen SLIT until further studies have been conducted.
MIF-DNA vaccination prevents and improves atopic dermatitis in murine models
Atopic dermatitis (AD) is a common chronic inflammatory skin disease. The relapsing and remitting course of AD places a psychologic, social, and financial burden on patients and their families. New treatment options are needed to prevent the progression of AD to more severe forms of the disease. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has been implicated in the pathogenesis of AD. Hamasaka et al (p 90) developed an MIF-DNA vaccine that breaks immunologic tolerance by introducing oligonucleotides encoding a foreign TH cell epitope into the murine MIF cDNA sequence. The therapeutic aim of cytokine vaccine therapy is to induce high titers of circulating polyclonal autoantibodies to neutralize the pathologic levels of a particular cytokine. The advantages of this therapy include the potential to maintain high antibody titers, long-term efficacy, and low cost. The authors showed that MIF-DNA vaccination prevented the occurrence of the AD skin phenotype in AD model mice. Furthermore, the MIF-DNA vaccine also improved symptoms of pre-existing AD (see Figure). It was demonstrated that the therapeutic effect of MIF-DNA vaccination could be adoptively transferred by serum IgG that contained MIF autoantibodies. The MIF-DNA vaccine approach offers the additional advantage of requiring only a periodic booster injection, and it might allow for the potential resolution of immunopathology in those with refractory inflammatory disease.
Therapeutic effect of MIF-DNA vaccination in pre-existing atopic dermatitis.
IL-27—an important inflammatory mediator in chronic eczema?
IL-27 is a novel member of the IL-6/IL-12 family that plays a role in the early regulation of TH1 differentiation and exerts, in the murine system, inhibitory effects on immune responses. Wittmann et al (p 81) analyzed the potential role of IL-27 in epidermal inflammatory skin responses in human subjects. They show that both subunits of IL-27 are expressed in chronic lesions of eczematous skin, which is similar to what is seen with other so-called TH1-associated cytokines. In functional experiments the authors demonstrate for the first time that human keratinocytes directly respond to IL-27 with an upregulation of the TH1 lymphocyte–attracting chemokine CXCL10 (see Figure) and with MHC class I upregulation. Interestingly, IL-27 acts as a strong priming signal on keratinocytes able to amplify chemokine production and surface molecule expression when used before a second signal, such as TNF-α. Importantly, the effects of IL-27 cannot be mimicked by IL-6, IL-12, or IL-23. The findings of this study provide new evidence that IL-27 is able to act in an inflammatory, disease-maintaining manner in the epidermal compartment of patients with eczema. IL-27 or IL-27–induced CXCL10 can thus be considered target molecules in the development of treatment strategies for chronic phases of eczematous skin diseases.
IL-27 induces the chemokine CXCL10 in keratinocytes (A), thus attracting T lymphocytes (B).
Severe asthma: Different patterns of smooth muscle remodeling
Severe asthma is heterogeneous and often difficult to treat. Kaminska et al (p 45) have described 2 different subtypes of patients with severe asthma: those with chronic persistent airflow obstruction, as documented over a 1-year period, and those without. The authors examined potential differences in clinical factors, sputum inflammatory markers, and features of airway remodeling by means of morphometric analysis of biopsy specimens and by using high-resolution computed tomographic scanning. They found that those with persistent airflow obstruction had an earlier age of onset and longer disease duration but also had increased airway smooth muscle and possibly submucosal fibrosis, with ongoing neutrophilic and eosinophilic inflammation (see Figure). However, no differences were found in high-resolution computed tomographic airway measurements. This article raises several interesting questions with respect to severe asthma and remodeling. That significant inflammation persists in association with increased remodeling and seemingly “fixed” obstruction (despite the best available treatment) suggests that smooth muscle remodeling might be reversible if inflammation could be appropriately controlled. Moreover, it remains to be elucidated whether the 2 groups described are pathophysiologically and genetically distinct asthma subtypes or whether they belong to a continuum of disease severity and progression. Finally, the authors might have identified a more specific target group for bronchial thermoplasty, an investigational treatment directed at reducing airway smooth muscle mass in asthma.
Smooth muscle in an airway wall biopsy of a severe asthmatic.
Virus-like particles decorated with immune receptors of choice modulate the function of allergen-specific T lymphocytes
T lymphocytes play a central role in the pathogenesis of allergic diseases. They contribute to the (early) sensitization phase, as well as to late-phase reactions, in target organs. T-cell responses are orchestrated by the delicate balance between HLA/peptide complexes (Signal 1) and costimulatory or inhibitory molecules (Signal 2) on antigen-presenting cells. The numerous activating and inhibitory molecules expressed on natural antigen-presenting cells make their net effect not easy to predict and direct. Therefore reductionist antigen-presenting systems were clearly warranted. Leb et al (p 121) show that the production of HLA class II–restricted immunosomes (ie, virus-like particles [VLPs] decorated with HLA class II molecules plus allergen peptide) is feasible. Although VLPs decorated with HLA-DR1/allergen peptide (from Artemisia vulgaris) plus costimulator CD80 induce vigorous activation of allergen-specific T cells, omission of costimulatory molecules generates VLPs with anergizing potential. Moreover, depending on the costimulator expressed on VLPs, allergen-specific T cells can be instructed to secrete different cytokine profiles (see Figure). Significantly, coexpression of CD58, the ligand for CD2, induced IL-10/IFN-γ–secreting T cells, a phenotype that is reminiscent of regulatory T cells. A special advantage of the VLP platform is its modular nature, allowing accommodation of immunoregulatory molecules of choice adjacent to HLA/allergenic peptide complexes, thus opening new avenues for clinical application.
VLPs instruct allergen-specific T cells to secrete different cytokine profiles. Cytokine profiles of T-cell receptor transgenic allergen-specific peripheral blood T cells from a mugwort pollen–allergic individual on incubation with VLPs expressing the indicated combinations of immune receptors.
Cord blood cytokine responses predict the severity of respiratory syncytial virus infection
Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections in children under the age of 12 months and the most common cause of wheezing respiratory infections requiring hospitalization in this age group. A positive association between RSV infection and asthma or wheezing has been found, but it is not known whether the tendency for asthma is already present before the RSV infection. In a prospective setting Juntti et al (p 52) were able to show that infants hospitalized for RSV infection before the age of 6 months had different LPS-stimulated cytokine response profiles at birth in comparison with children with no respiratory infections. The innate immunity cytokines IL-6 and IL-8 were found to correlate with each other in factorial analysis, and this combination was found to predict hospitalization for RSV infection. Cytokine combinations formed in the factorial analysis did not predict the susceptibility to RSV infection in general. The authors suggest that a predisposition to exaggerated innate immune responses might be a factor affecting both the severity of RSV infection in infancy and the postinfectious development of asthma.
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