Ustekinumab improves psoriasis without suppressing tumor antigen-specific cytotoxic T lymphocytes.

BACKGROUND: Ustekinumab is currently used for the treatment of psoriasis with remarkable efficiency. However, worries about the development of malignancies in ustekinumab-treated patients have not been completely resolved because of the major role of IL-12 and IL-23 in tumor immunity. In the present study, we tried to elucidate the effects of ustekinumab on antigen-specific tumor immunity. METHODS: After approval by the institutional ethical committee, a 56-year-old male volunteer with psoriasis was administered with 20 doses of WT1 peptide. WT1-specific cytotoxic T lymphocytes (CTLs) were evaluated by WT1 tetramer assay after mixed lymphocyte peptide culture. RESULTS: WT1 tetramer+ T cells with cytotoxic ability appeared in the blood after peptide administration and the frequency of WT1 tetramer+ T cells increased to more than 15 in 10(6) CD8+ T cells. Thirty months after stopping WT1 administration, the patient commenced treatment with ustekinumab for psoriasis at weeks 0 and 4, and every 12 weeks thereafter. Psoriasis plaques were almost cleared up and the response to ustekinumab has so far lasted for 30 months. The frequency of WT1 tetramer+ T cells has not changed since the initiation of ustekinumab treatment. The effects of ustekinumab on the antigen-presenting and CTL-inducing abilities of dendritic cells were explored in vitro, revealing limited effects on both immune functions. CONCLUSIONS: These in vivo/vitro findings imply that ustekinumab improves psoriasis without suppressing tumor antigen-specific CTLs and support the data of recent clinical trials showing no increased incidence of malignancies with ustekinumab treatment.

Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare, potentially life threatening, and aggressive form of psoriasis, which is characterized by sudden onset with repeated episodic skin inflammation leading to pustule formation. Familial GPP is known to be caused by recessively inherited mutations in the IL36RN gene, which encodes interleukin 36 receptor antagonist (IL-36Ra). In this article, we performed mutation analysis of the IL36RN gene in 14 Japanese patients with GPP, and identified mutations in two of these patients analyzed. One patient was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg), whereas the other carried compound heterozygous mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene. Expression studies using total RNA from the patients' skin revealed that the mutation c.115+6T>C resulted in skipping of exon 3, leading to a frameshift and a premature termination codon (p.Arg10Argfs*1). The protein structure analysis suggested that the missense mutation p.Thr123Arg caused misfolding and instability of IL-36Ra protein. In vitro studies in cultured cells showed impaired expression of the p.Thr123Arg mutant IL-36Ra protein, which failed to antagonize the IL-36 signaling pathway. Our data further underscore the critical role of IL36RN in pathogenesis of GPP.

Henoch Schönlein purpura associated with pulmonary adenocarcinoma.

INTRODUCTION: Henoch-Schönlein purpura is a common immunoglobulin A-mediated vasculitis syndrome in children. Henoch-Schönlein purpura can also affect adults and is probably related to malignancy. CASE PRESENTATION: We report the case of a 61-year-old Japanese man who presented for examination after an abnormal shadow was detected by chest radiography. He received a diagnosis of pulmonary adenocarcinoma, stage IV. Purpura on the legs, abdominal pain, diarrhea, hematuria and proteinuria developed at this time. Henoch-Schönlein purpura was diagnosed, base on the clinical symptoms and histological findings of biopsy specimens of the skin, which showed vasculitis with immunoglobulin A deposits. Our patient received chemotherapy with gemcitabine after successful steroid therapy for the Henoch-Schönlein purpura. CONCLUSION: Although hematological malignancies are well-known causes of vasculitides, cases of Henoch-Schönlein purpura associated with lung adenocarcinoma are rare. Our patient was treated with corticosteroid therapy, which cleared the purpura and cytotoxic chemotherapy for the non-small cell lung cancer. However, he died from heart failure due to cardiac tamponade.

Enhancement of photodynamic effect in normal rat keratinocytes by treatment with 1,25 dihydroxy vitamin D3.

BACKGROUND: To better understand the pathogenesis of photodynamic therapy (PDT)-induced apoptosis cytosolic calcium [Ca2+]i was measured using cultured fetal rat keratinocytes (FRSKs). Moreover, the influence of 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) with the action of increasing [Ca2+]i on the PDT effect was studied. METHODS: FRSKs were treated with a medium containing the photosensitizer, aluminum phthalocyanine tetrasulfonate (AlPcTs), and were then exposed to selective visible light derived from a halogen lamp. Electrophoresis of DNA extracted from the PDT-treated cells revealed DNA fragmentation, a sign of apoptosis in cultured FRSKs under the condition with or without 1,25(OH)2D3. RESULTS: PDT-treated FRSKs exhibited increased levels of [Ca2+]i; these levels were significantly elevated further by the treatment of cells with 1,25(OH)2D3. However, cells treated with ethylene glycol bis (b-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), a chelator of extracellular calcium, prior to PDT did not show any DNA fragmentation either in the presence or absence of 1,25(OH)2D3. CONCLUSION: PDT-induced apoptosis in FRSKs may be caused by the influx of extracellular calcium. Addition of 1,25(OH)2D3 clearly enhanced the DNA fragmentation in the cultured FRSKs, indicating the effect of increased [Ca2+]i. The combination therapy of AlPcTs-PDT with the administration of 1,25(OH)2D3 may contribute to the enhancement of the AlPcTs-PTD effect.