Noriaki Aoi

Case of de novo psoriasis possibly triggered by nivolumab.

Dear Editor, Nivolumab is a fully humanized anti-programmed cell death protein 1 (PD-1) monoclonal immunoglobulin G4 antibody that was the first anti-PD-1 agent on the market. The side-effects associated with nivolumab include fatigue, rash, thyroid dysfunction and colitis, some of which may be related to the drug’s immunoregulatory mechanisms. Here, we report the first case of a patient with amelanotic malignant melanoma who developed de novo psoriasis vulgaris after receiving nivolumab treatment. An 89-year-old man started to receive nivolumab treatment (2 mg/kg every 3 weeks) for recurrent metastatic melanoma (stage rT3-N1-M1) that had originated as an amelanotic malignant melanoma of the nasal cavity. The pruritic, scaling and erythematous plaques on his back developed approximately 2 weeks after the first nivolumab treatment and they worsened after the second treatment, at which point he was referred to our department for further evaluation (Fig. 1a). Histopathology examination of the lesion showed uniform elongation of the rete ridges and thinning of the suprapapillary plate with intermittent parakeratosis (Fig. 1b,c), hyperkeratosis, loss of the granular layer and neutrophil aggregation in the stratum corneum (i.e. Munro’s microabscess) on high-magnification view of hematoxylin–eosin staining (Fig. 1d). The patient never had psoriasis or any other severe skin disease previously. Thus, de novo psoriasis presumably triggered by nivolumab therapy was diagnosed. The psoriatic lesions and itchiness were well controlled by calcipotriol/betamethasone dipropionate combination ointment. The patient developed vitiligo at the site of his psoriatic lesions approximately 3 months after initiating nivolumab therapy (Fig. 1e), and it spread to other parts of his body later. Ultimately, he became cachexic, and at 6 months after initiating nivolumab therapy, he died of melanoma-related disseminated intravascular coagulation. The PD-1 pathway contributes to suppressing T-helper (Th)1 and Th17 cell populations, and the PD-1 blockade may augment Th1 and Th17 cells. Psoriasis is a possible autoimmune disease that has been associated with the presence of discrete populations of Th17 cells in the dermis. Thus, a psoriatic eruption in patients receiving nivolumab treatment may be a consequence of the PD-1 blockade. Three cases of nivolumab therapy-related psoriasis-like eruption or exacerbation have been previously reported. Ohtsuka et al. reported a patient who received nivolumab for primary oral mucosal melanoma and developed a psoriasiform eruption that mimicked psoriasis with unclear borders or crusts. Two other reported cases developed exacerbations of pre-existing psoriasis during nivolumab therapy. The patient’s human leukocyte antigen (HLA) profile included HLAA24, -A26, -B40, -B54, -Cw1 and -Cw3. A higher prevalence of HLA-A24, -B52 and -Cw1 has been reported in Japanese patients. Thus, HLA might have been a predisposing factor. We encountered a case of de novo psoriasis that eventually developed concurrent vitiligo in the same area, which later spread to the patient’s entire body. Arakawa et al. showed that patients with psoriasis harbor epidermal CD8 T cells which specifically recognizes melanocyte-specific autoantigens in the context of major histocompatibility complex class I. Thus, the PD-1 blockage may lead to expand such T cells that recognize melanocytes as well as melanoma cells.

Sublingual Immunotherapy Induces Regulatory Function of IL-10-Expressing CD4+CD25+Foxp3+ T Cells of Cervical Lymph Nodes in Murine Allergic Rhinitis Model

Sublingual immunotherapy (SLIT) has been considered to be a painless and efficacious therapeutic treatment of allergic rhinitis which is known as type I allergy of nasal mucosa. Nevertheless, its mechanisms need to be further investigated. In this study, we constructed an effective murine model of sublingual immunotherapy in allergic rhinitis, in which mice were sublingually administered with ovalbumin (OVA) followed by intraperitoneal sensitization and nasal challenge of OVA. Sublingually treated mice showed significantly decreased specific IgE responses as well as suppressed Th2 immune responses. Sublingual administration of OVA did not alter the frequency of CD4+CD25+ regulatory T cells (Tregs), but led to upregulation of Foxp3- and IL-10-specific mRNAs in the Tregs of cervical lymph nodes (CLN), which strongly suppressed Th2 cytokine production from CD4+CD25− effector T cells in vitro. Furthermore, sublingual administration of plasmids encoding the lymphoid chemokines CCL19 and CCL21-Ser DNA together with OVA suppressed allergic responses. These results suggest that IL-10-expressing CD4+CD25+Foxp3+ Tregs in CLN are involved in the suppression of allergic responses and that CCL19/CCL21 may contribute to it in mice that received SLIT.

Japanese traditional medicine, Senn-kinn-naidaku-sann up-regulates Toll-like receptor 4 and reduces murine allergic rhinitis.

OBJECTIVE To determine the mechanisms by which a traditional herbal medicine, Senkinnaidakusan (SKNS), controls Th2 responses, we examined the production of IL-12 by murine macrophages treated with SKNS. RESULTS Treatment with SKNS significantly increased TLR4 mRNA in macrophages. Furthermore, pre-treatment with SKNS enhanced the production of IL-12 by macrophages stimulated with LPS. When SKNS was orally administered to C3H/HeN mice at the induction phase after OVA sensitization, the serum levels of OVA-specific immunoglobulin (Ig)E and IgG1 decreased, Interleukin (IL)-4 production by spleen T cells in response to OVA was significantly suppressed, while interferon (IFN)-gamma production was increased. After nasal challenge of OVA, eosinophilic infiltration in the nasal mucosa and the number of sneezes were significantly inhibited in SKNS-treated mice compared with control mice. Besides, expression of IL-5 in the nasal mucosa was also inhibited. Using another strain of mice, C3H/HeJ (TLR4 negative), there was no difference in OVA-specific Igs or splenic cytokine production between the SKNS treatment and non-treatment groups. The eosinophilic infiltration in the nasal mucosa, the number of sneezes and IL-5 expression in the nasal mucosa were also not effected even after SKNS treatment. CONCLUSION These results suggest that oral administration of SKNS inhibits Th2 responses by enhancement of IL-12 release from macrophages via up-regulation of TLR4 expression.

Short review on sublingual immunotherapy for patients with allergic rhinitis: from bench to bedside.

Sublingual immunotherapy has been considered to be a painless and effective therapeutic treatment for allergic rhinitis, and is known as type 1 allergy of the nasal mucosa. So far, its mechanism of action has been elucidated employing peripheral blood serum and lymphocytes in an antigen-specific fashion. Because of the limitations in sampling human materials, there is still controversy among many reports between clinical efficacy and laboratory data. Therefore, its mechanism of action needs to be investigated further by using promising animal models such as rodents and monkeys. Bearing this in mind, in our present study, we successfully constructed an effective murine model for sublingual immunotherapy in allergic rhinitis in which mice were administered ovalbumin (OVA) sublingually followed by intraperitoneal sensitization and nasal challenge.