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OBJECTIVE: The definition of severe uncontrolled asthma and the best phenotype-driven management are not fully established. Objective: We aimed to reach a consensus on the definition of severe uncontrolled asthma and give recommendations on optimal management with phenotype-targeted biological therapies.
METHODS: A modified Delphi technique was used. A scientific committee provided statements addressing the definition of severe uncontrolled asthma and controversial issues about its treatment with biologics. The questionnaire was evaluated in 2 rounds by expert allergists. With the results, the scientific committee developed recommendations and a practical algorithm.
RESULTS: A panel of 27 allergists reached agreement on 27 out of the 29 items provided (93.1%). A consensus definition of severe uncontrolled asthma was agreed. Prior to initiation of therapy, it is mandatory to establish the asthma phenotype and assess the presence of clinically important allergic sensitizations. Anti-IgE, anti-IL-5, anti-IL-5 receptor, and anti-IL-13/IL-4 receptor inhibitors are suitable options for patients with allergic asthma and a blood eosinophil level >300/μL (>150/μL in patients receiving oral corticosteroids). IL-5 and anti-IL-5 receptor inhibitors are recommended for patients with an eosinophilic phenotype and can also be used for patients with severe eosinophilic allergic asthma with no or a suboptimal response to omalizumab. Dupilumab is recommended for patients with moderate-severe asthma and a TH2-high phenotype. Only physicians with experience in the treatment of severe uncontrolled asthma should initiate biological treatment.
CONCLUSIONS: We provide consensus clinical recommendations that may be useful in the management of patients with severe uncontrolled asthma.

Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs).
Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs.
Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways.
The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.

Atopic dermatitis (AD), a common chronic pruritic inflammatory skin disease, impacts the quality of life of patients and caregivers and has become a global health problem. It is increasingly recognized as a disease not only of children but also of adults who may have a persistent or relapsing course from childhood or who develop new-onset adult disease. Besides well-established atopic comorbidities, associations with a number of nonatopic comorbidities have been reported. AD is characterized by both immune dysregulation and epidermal barrier dysfunction. The findings that nonlesional skin in AD has both terminal keratinocyte differentiation defects and immune abnormalities as well as multiple markers of immune and inflammatory activation in the circulation point to the systemic nature of the disease and have important translational implications. Although AD is predominantly associated with type 2 immune responses, activation of other cytokine pathways including TH1, TH22, and TH17/IL-23 has been reported, suggesting potential therapeutic targets and provide a rationale for treatment with novel biologics. Dupilumab, a fully human mAb targeting the IL-4 Rα subunit, blocks signaling of both IL-4 and IL-13 and is the first biologic to be approved for the treatment of moderate-to-severe AD in adult patients. Other biologics in current trials for AD are targeting the IL-31 receptor, IL-13, and the common p40 subunit of IL-12/IL-23.

Dengue viruses (DENVs) are re-emerging pathogens transmitted by mosquitoes mainly in tropical and subtropical regions. Each year, they are estimated to infect 390 million people globally. The major challenge confronting dengue vaccine development is the need to induce balanced, long lasting tetravalent immune responses against four co-circulating virus serotypes (DENV-I, -II, -III, -IV), because primary infection by any one of which may predispose infected individuals to more severe diseases during a heterotypic secondary infection. Another difficulty is to select representative strains in vaccine design to provide cross-protection against most circulating virus strains. In this study, aimed at developing a tetravalent subunit vaccine with a representative single protein, we designed two vaccines (named cE80(D4) and cE80(max)) based on the consensus sequences of the ectodomain of envelope protein of 3127 DENV strains, and then expressed them in the baculovirus expression system. Both vaccines were capable of eliciting specific antibodies against all four DENV serotypes, and the predominant IgG subtype elicited by the two vaccines was IgG1. Moreover, these vaccines activated both type I and type II antigen-specific helper T cells that secreted IFN-γ and IL-4, respectively. This proof-of-concept study has set foundation for further optimization of a single protein-based tetravalent DENV vaccine.

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Through consensus, establish a post-marketing scheme and the technical processes to evaluate Chinese medicine\'s immunotoxicity on a population, as well as its beneficial influences on the immune system. Provide regulations on the collection, storage and transportation of serum samples. This article applies to the post-marketing scientific evaluation of the immunotoxicity of parenterally administered, and for other ways of taking Chinese medicine.

Polysorbate 80 (PS80 or Tween-80) is often used as an additive to promote the rapid solubilization of pharmaceuticals in aqueous solutions. We investigated whether coinjection of a minimal amount of PS80 had a modulatory effect on the immunotherapeutic effects of Cry (Cryptomeria)-consensus peptide, a novel peptide developed for the therapeutic management of Japanese cedar pollinosis, using a Cry j 1-sensitized mouse model with experimental allergic rhinitis. Subcutaneous challenge with Cry-consensus peptide plus 50 microg/ml of PS80 did not affect the antigen-specific proliferation of splenocytes, but decreased the potency of Cry-consensus peptide to inhibit antigen-specific interleukin (IL)-5 production by the cells significantly in comparison with challenge with Cry-consensus peptide alone. However, there was no significant difference between the effect of Cry-consensus peptide administration on interferon (IFN)-gamma production in the presence and absence of PS80, indicating that PS80 interfered with the T helper 1 (Th1)-dominant T helper balance induced by Cry-consensus peptide challenge. Moreover, the increase in the level of antigen-specific immunoglobulin G2a (IgG2a) induced by Cry-consensus peptide challenge was inhibited slightly but unambiguously by PS80 coinjection. These in vitro experiments indicated that PS80 induces Th2-type differentiation of T helper cells through preferential inhibition of IFN-gamma expression relative to IL-5 expression in splenocytes in a concentration-dependent manner. In naïve mice, sensitization by Cry-consensus peptide with PS80 induced antigen-specific IL-5 production more potently than sensitization by Cry-consensus peptide alone, and when PS80 was added to bone marrow-derived dendritic cells, the endocytosis of fluorescence-labelled Cry-consensus peptide was dramatically inhibited in a concentration-dependent manner. Therefore, we conclude that PS80 has an immunomodulatory effect on the antigen-specific response resulting in a shift towards Th2 predominance with respect to the antigen recognition stage. Taken together, our findings suggest that PS80 might decrease the efficacy of Cry-consensus peptide through modulation of the efficiency of antigen endocytosis and/or of the direction of successive T helper cell differentiation.

Formulation of vaccines has for the most part relied on simple adjuvants which are able to enhance the immune response to the immunogen. Cytokines are an attractive alternative to conventional preparations, and have been tested in a number of different systems. However, experience has indicated that there are a number of guidelines that must be followed. The dose of cytokine administered is critical for optimal effect. Too little will have no effect, and too much will have undesirable side effects. For instance, at high doses IL-2 can induce autoimmune disease and interferon gamma can have a suppressive effect. Cytokines may also have to be administered at the same site or even to the same cell as the antigen for optimal effect. Conjugation or molecular chimerization of antigens and cytokines can achieve this effect efficiently. Formulation of cytokine with antigen may overcome any detrimental effect that the antigen may have. Should the antigen have any suppressive epitopes or have a direct effect on essential intracellular mechanisms, cytokines may be used to overcome these effects. In some cases, Th1 or Th2 cytokines have been used to enhance a protective Th1 or Th2 response. However, the paradigm does not always hold, and Th1 cytokines can enhance Th2 responses, or have no overall effect on phenotype. Further, in some host species, there is evidence that there may be no Th1/Th2 dichotomy. The most important aspect of using cytokines as adjuvants is in ensuring that there is a balanced response.

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a chronic myelogenous leukemia-like syndrome and mount impaired responses to certain viral and bacterial infections. To gain a mechanistic understanding of the contributions of ICSBP to humoral and cellular immunity, we characterized the responses of control and ICSBP-/- mice to infection with influenza A (flu) and Leishmania major (L. major). Mice of both genotypes survived infections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response. In sera of ICSBP-/- mice, however, IgG1 antibodies dominated over IgG2a antibodies, a pattern indicative of a Th2-driven response. The dominance of IgG1 and IgE over IgG2a was detected in the sera of uninfected mice as well. A seeming Th2 bias of ICSBP-deficient mice was also uncovered in their inability to control infection with L. major, where resistance is known to be dependent on IL-12 and IFN-gamma as components of a Th1 response. Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide. Compromised Th1 differentiation in ICSBP-/- mice could not be attributed to hyporesponsiveness of CD4(+) T cells to interleukin (IL)-12; however, the ability of uninfected and infected ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.