Allergen immunotherapy is the only curative treatment for IgE-mediated allergic diseases in contrast to symptomatic treatment such as anti-histamine agents. Subcutaneous immunotherapy (SCIT) has been introduced in Japan for treatment of allergic rhinitis and/or asthma caused by pollens and/or house dust mites (HDM) in early 1960s, and the clinical efficacy has been well-known. However, the major drawbacks of SCIT are necessity of repeated painful injections as well as the risk of severe systemic adverse reactions. Sublingual immunotherapy (SLIT) was developed to resolve these issues. In Japan, Japanese cedar (JC) pollen SLIT-drop was developed initially for treatment of JC pollinosis, and approved for patients of 12 years of age and older in 2014. For adolescent and adult patients with HDM-allergic rhinitis, HDM SLIT-tablet was launched in 2015 and subsequently approved to be also available for pediatric patients (<12 years of age) in 2018. Moreover, JC pollen SLIT-tablet for JC pollinosis was approved in 2018 for all patients with no age limit. Here, we also describe that the formulation technologies of SLIT tablets and distribution of allergens after sublingual administration as well as the development of SLIT drop/tablets.

Th2 cells are well known to play important roles in allergic diseases including allergic rhinitis (AR). Meanwhile, the factors that induce and sustain the pathogenesis of AR remain unclear. The recent development of sublingual immunotherapy (SLIT) is expected to allow changes to the underlying pathogenesis of AR. However, the phenotype of the pathogenic Th2 cells (Tpath2) cells in house dust mite-induced AR (HDM-AR) and the relation between Tpath2 and SLIT efficacy have not been clarified. Therefore we analyzed the cytokine production and frequency of HDM-reactive T-cell subsets in peripheral blood mononuclear cells (PBMCs) using flow cytometry in 89 HDM-AR patients (placebo; n = 43 and HDM 300 IR; n = 46) who participated in a placebo-controlled study of SLIT with HDM tablets. All patients provided samples both before treatment as a baseline and at the end of the 52-week study. HDM-reactive IL-5⁺IL-13⁺CD27⁻CD161⁺CD4⁺ cells and ST2⁺CD45RO⁺CD4⁺ cells were observed in the PBMCs from each patient with HDM-AR; these cells significantly decreased after SLIT in the group treated with active tablets. HDM-reactive ST2⁺CD45RO⁺CD4⁺ cells were significantly lower in active-responders. In conclusion, HDM-reactive ST2⁺CD45RO⁺CD4⁺ cells or those combined with IL-5⁺IL-13⁺CD27⁻CD161⁺CD4⁺ cells may be useful as markers indicating the successful treatment of SLIT. These cells may play a crucial role in the pathogenesis of HDM-AR as Tpath2.

Subcutaneous immunotherapy (SCIT) is a causative treatment for allergic diseases. More recently, it has become clear that regulatory T (Treg) cells are increased by SCIT. Treg cells are generally divided into two main groups: 1) CD25⁺ Foxp3⁺ CD4⁺ T cells (Foxp3⁺ Treg cells) and 2) IL-10-producing Foxp3⁻ CD4⁺ T cells (Tr1 cells). We demonstrated that the number of Tr1 cells in peripheral blood mononuclear cells in SCIT-treated pollinosis patients were significantly higher than that in non-SCIT-treated patients, but Foxp3⁺ Treg cells were not. Consistent with the results of human peripheral blood, Tr1 cells were increased in the lungs of asthmatic mice by SCIT, but Foxp3⁺ Treg cells were not. Moreover, in vitro-induced Tr1 cells were responded to the antigen to produce a large amount of IL-10 in in vitro and in vivo. Adoptive transfer of the induced Tr1 cells significantly suppressed the development of asthma. In any species of human and mouse, the increase in Tr1 cells rather than Foxp3⁺ Treg cells could be important for the effects of SCIT. The increased Tr1 cells by SCIT functionally suppressed allergic asthma probably via production of IL-10 in response to the specific antigen. Therefore, analyses of the induction mechanisms of Tr1 cells and search for compounds which induce Tr1 cells are thought to lead to development of more efficient SCIT.

From the era of subcutaneous immunotherapy (SCIT) in 1960s, allergen immunotherapy (AIT) has been established as a highly effective and curable treatment for allergic diseases. Furthermore, the recent appearance of sublingual immunotherapy (SLIT) in which the complicated administration procedure in SCIT was improved has been causing paradigm shifts in the treatment of allergic rhinitis. During the long history of AIT, the mechanisms by which this therapy leads its strong efficacy have been investigated but not fully clarified yet. The production of blocking antibodies that interrupt allergen-IgE binding, normalization of Th1/Th2 balance, and introduction of regulatory T cells are the major candidate mechanisms, though there are several conflicting reports. In our recent clinical study of SLIT against Japanese cedar pollinosis, we also tried to elucidate its mechanisms. Especially by comparing high-responder and non-responder patients using integrated analysis with multiple data, not by comparing with a placebo control group using individual data, we have successfully identified several target molecules and cascades of SLIT. Herein, we would like to describe the potential mechanisms by which AIT exhibits its strong efficacy with referring our recent novel findings.

Drug metabolism is an important determinant to control pharmacokinetics, drug response and drug toxicity. Large variabilities are observed in expression or activity of drug-metabolizing enzymes such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Therefore, understanding of the causes for the variation of drug metabolism potencies is essential for efficient drug development and promotion of safe use of medicines. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, and by epigenetic regulation such as DNA methylation and histone acetylation. In addition to such regulatory mechanisms, recent studies revealed that microRNAs (miRNAs) significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. miRNAs are endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs. More recently, it has been clarified that the presence of pseudogenes or single nucleotide polymorphisms as well as RNA editing event affect miRNA-dependent regulation. It is unwavering fact that miRNAs significantly contribute to inter- and intra-individual differences in the expression of drug-metabolizing enzymes. In this review, we introduce current knowledge of miRNA-mediated regulation of drug metabolism.

Calcimimetics allosterically activate the calcium receptor (CaR) and inhibit the secretion of parathyroid hormone (PTH). Cinacalcet hydrochloride (cinacalcet) has been approved as the first calcimimetic drug for the treatment of secondary hyperparathyroidism (SHPT) in patients with hemodialysis. Cinacalcet improved the achievement of target serum PTH and Ca levels and helped drastically reduce the number of parathyroidectomies. However, cinacalcet has side effects involving the gastrointestinal tract, such as nausea and vomiting, which makes it difficult to increase the dose and may result in reduced compliance. Evocalcet has been developed to improve defects of cinacalcet for management of SHPT. Evocalcet acts as an allosteric modulator of CaR, just like cinacalcet. However, its metabolic pathway is different from that of cinacalcet. The metabolism of evocalcet by cytochrome P450 is very low, so evocalcet has higher bioavailability. As a result, its pharmacologically effective dose for the inhibition of PTH secretion is lower than that of cinacalcet. Evocalcet had less of an effect on the gastrointestinal tract than cinacalcet because of the reduced dose required. In a clinical trial with a randomized, double-blind, head-to-head comparison study, it was also confirmed that the incidence of gastrointestinal-related adverse events was lower in the evocalcet group than in the cinacalcet group. Evocalcet may thus be a potent option for the management of SHPT.