記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Peptides  

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disorder in which vasopressin-secreting neurons degenerate over time due to the production of mutant proteins. We have demonstrated therapeutic effects of chemical chaperones in an FNDI mouse model, but the complexity and length of this evaluation were problematic. In this study, we established disease-specific mouse induced pluripotent stem cells (iPSCs) from FNDI-model mice and differentiated vasopressin neurons that produced mutant proteins. Fluorescence immunostaining showed that chemical chaperones appeared to protect vasopressin neurons generated from iPSCs derived from FNDI-model mice. Although KCL stimulation released vasopressin hormone from vasopressin neurons generated from FNDI-derived iPSCs, vasopressin hormone levels did not differ significantly between baseline and chaperone-added culture. Semi-quantification of vasopressin carrier protein and mutant protein volumes in vasopressin neurons confirmed that chaperones exerted a therapeutic effect. This research provides fundamental technology for creating in vitro disease models using human iPSCs and can be applied to therapeutic evaluation of various degenerative diseases that produce abnormal proteins.

DOI： 10.1016/j.peptides.2024.171151

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.resinv.2024.01.009.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JMIR Diabetes  

Background: In recent years, technologies promoting the digitization of self-monitoring of blood glucose (SMBG) records including app-cloud cooperation systems have emerged. Studies combining these technological interventions with support from remote health care professionals have reported improvements in glycemic control. Objective: To assess the use of an app-cloud cooperation system linked with SMBG devices in clinical settings, we evaluated its effects on outpatient management of diabetes without remote health care professional support. Methods: In this multicenter, open-label, and single-armed prospective study, 48 patients with diabetes (including type 1 and type 2) at 3 hospitals in Japan treated with insulin or glucagon-like peptide 1 receptor agonists and performing SMBG used the app-cloud cooperation system for 24 weeks. The SMBG data were automatically uploaded to the cloud via the app. The patients could check their data, and their attending physicians reviewed the data through the cloud prior to the patients’ regular visits. The primary outcome was changes in glycated hemoglobin (HbA1c) levels. Results: Although HbA1c levels did not significantly change in all patients, the frequency of daily SMBG following applying the system was significantly increased before induction at 12 (0.60 per day, 95% CI 0.19-1.00; P=.002) and 24 weeks (0.43 per day, 95% CI 0.02-0.84; P=.04). In the subset of 21 patients whose antidiabetic medication had not been adjusted during the intervention period, a decrease in HbA1c level was observed at 12 weeks (P=.02); however, this significant change disappeared at 24 weeks (P=.49). The Diabetes Treatment Satisfaction Questionnaire total score and “Q4: convenience” and “Q5: flexibility” scores significantly improved after using the system (all P<.05), and 72% (33/46) patients and 76% (35/46) physicians reported that the app-cloud cooperation system helped them adjust insulin doses. Conclusions: The digitization of SMBG records and sharing of the data by patients and attending physicians during face-to-face visits improved self-management in patients with diabetes.

DOI： 10.2196/48019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine Journal  

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in several organs including endocrine glands. Among endocrine irAEs, thyroid and pituitary irAEs are frequently observed, followed by primary adrenal insufficiency, insulin-dependent diabetes mellitus, and hypoparathyroidism. These conditions could lead to life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, several types of irAEs including thyroid and pituitary irAEs are reported to be associated with better overall survival. Therefore, it is important to understand and manage endocrine irAEs, which differ depending on the ICI regimen used. In this review, we describe the clinical features, potential biomarkers, management strategies, and possible mechanisms of thyroid and pituitary irAEs.

DOI： 10.1507/endocrj.EJ23-0524

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine Journal  

Anti-thyroglobulin antibodies (TgAb) and/or anti-thyroid peroxidase antibodies (TPOAb) positivity at baseline is a risk marker for thyroid immune-related adverse events (thyroid-irAEs) in anti-programmed cell death-1 antibody (PD-1-Ab) treatment; however, it is unknown if TgAb and TPOAb titers are associated with clinical characteristics of thyroid-irAEs. Among 586 patients treated with PD-1-Ab at Nagoya University Hospital between 2 November 2015 and 30 September 2021, 57 patients developed thyroid-irAEs (thyrotoxicosis [n = 38]; hypothyroidism without prior thyrotoxicosis {isolated hypothyroidism} [n = 19]) in whom thyroid function, and TgAb and TPOAb titers were determined at baseline and at the onset. The changes in TgAb (median, 54.8 vs. 0.2 IU/mL; p = 0.002) and TPOAb titers (31.6 vs. 0 IU/mL; p = 0.032) from baseline to onset of developing thyroid-irAEs were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism. Higher TgAb and TPOAb titers, and the TgAb titer at baseline were associated with an earlier onset of thyrotoxicosis and higher peak free thyroxine levels, respectively. Twenty-eight patients who developed hypothyroidism after thyrotoxicosis had higher TgAb (54.5 vs. 10.7 IU/mL; p = 0.011) and TPOAb titers at baseline (46.1 vs. 9.0 IU/mL; p < 0.001) and greater changes in TgAb (61.7 vs. 7.8 IU/mL; p = 0.025) and TPOAb titers (52.8 vs. –0.8 IU/mL; p < 0.001) than patients who did not develop hypothyroidism. The TgAb titer at baseline and changes in the TgAb and TPOAb titers were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism, suggesting that the magnitude of the thyroid autoimmune response reflects the clinical types of thyroid-irAEs.

DOI： 10.1507/endocrj.EJ23-0480

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Primary Care Diabetes  

Aims: In our previously reported randomized controlled trial in patients with noninsulin-treated type 2 diabetes, the use of flash glucose monitoring (FGM) improved glycated hemoglobin (HbA1c), and the improvement was sustained after the cessation of glucose monitoring. In this post-hoc analysis, we examined data from our trial to identify the factors that influenced FGM efficacy. Methods: We analyzed data for 48 of 49 participants of the FGM group who completed the trial to clarify the changes in various parameters and factors related to HbA1c improvement with the use of FGM. Results: Analyses of the FGM data during the 12-week FGM provision period showed that the weekly mean blood glucose levels considerably decreased as early as at 1 week compared with the baseline values, and this decline continued for 12 weeks. An enhancement in the Diabetes Treatment Satisfaction Questionnaire regarding “willingness to continue the current treatment” score was significantly associated with the improvement in HbA1c at 12 (p = 0.009) and 24 weeks (p = 0.012). Conclusions: Glycemic control was improved soon after FGM initiation, accompanied by improved satisfaction with continuation of the current treatment in patients with noninsulin-treated type 2 diabetes.

DOI： 10.1016/j.pcd.2023.09.009

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Journal of clinical endocrinology and metabolism  

CONTEXT: Positive antithyroglobulin (TgAb) and/or antithyroid peroxidase antibodies (TPOAb) at baseline indicate a high risk of thyroid immune-related adverse events (irAEs) induced by antiprogrammed cell death-1 antibodies (anti-PD-1-Ab). However, whether the positivity patterns of both antibodies are associated with the risk of thyroid irAEs is unknown. OBJECTIVE: The aim of the present study was to clarify the association of the pattern of TgAb and TPOAb positivity at baseline with the risk of thyroid irAEs induced by anti-PD-1-Ab. METHODS: Patients (n = 516) were evaluated for TgAb and TPOAb at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after initiating anti-PD-1-Ab. RESULTS: Fifty-one (9.9%) patients developed thyroid irAEs (thyrotoxicosis in 34, hypothyroidism without prior thyrotoxicosis in 17). Twenty-five patients subsequently developed hypothyroidism following thyrotoxicosis. The cumulative incidence of thyroid irAEs differed among 4 groups classified by the presence of TgAb/TPOAb at baseline (group 1: TgAb-(-)/TPOAb-(-), 4.6% [19/415]; group 2: TgAb-(-)/TPOAb-(+), 15.8% [9/57]; group 3: TgAb-(+)/TPOAb-(-), 42.1% [8/19]; group 4: TgAb-(+)/TPOAb-(+), 60.0% [15/25]) as follows: groups 1 vs 2-4 (P ≤ .001) and groups 2 vs 3 (P = .008) and 4 (P < .001). There were different incidences of thyrotoxicosis (groups 1-4, 3.1%, 5.3%, 31.6%, 48.0%, respectively; P < .001) in groups 1 vs 3 and 4, and groups 2 vs 3 and 4, and of hypothyroidism (groups 1-4: 2.9%, 15.8%, 31.6%, 60.0%, respectively; P < .001) in groups 1 vs 2 to 4, and groups 2 vs 4. CONCLUSION: The risk of thyroid irAEs was affected by the pattern of TgAb and TPOAb positivity at baseline; there were high risks of thyrotoxicosis in patients with TgAb-(+) and of hypothyroidism in patients with TgAb-(+) and those with TPOAb-(+).

DOI： 10.1210/clinem/dgad231

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Stem Cell Reports  

Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

DOI： 10.1016/j.stemcr.2023.05.002

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Hyperglycemia impairs immune response; however, it remains unknown whether the anti-tumor effects of anti-programmed cell death-1 antibody (PD-1-Ab) treatment are changed in hyperglycemic conditions. We analyzed the effect of PD-1-Ab on tumor growth in streptozotocin-induced diabetic mice (STZ-mice) subcutaneously inoculated with MC38 (a colon carcinoma cell line). Furthermore, we assessed the expression of chemokines by polymerase chain reaction (PCR) array in tumor-draining lymph nodes (dLNs) of these mice and MC38 cells cultured in different glucose concentrations. The suppressive effect of PD-1-Ab on tumor growth was attenuated. This was accompanied by fewer tumor-infiltrating CD8+ T cells, and STZ-mice had fewer tumor-infiltrating CD11c+ dendritic cells (DCs) than normoglycemic mice. mRNA expression levels of CXCL9, a chemokine recruiting CD8+ T cells, were lower in dLNs of STZ-mice than in normoglycemic mice after PD-1-Ab treatment, and its protein was expressed in DCs. In MC38 cells cultured with 25 mM glucose, mRNA expression of CCL7, a chemokine recruiting DCs, was decreased compared to cells cultured with 5 mM glucose. These results suggest that the STZ-induced hyperglycemia impairs the effect of PD-1-Ab treatment on MC38 tumor growth, and is accompanied by reduced infiltration of DCs and CD8+ T cells and decreased expression of CCL7 and CXCL9.

DOI： 10.1038/s41598-023-33049-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Immunology  

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

DOI： 10.3389/fimmu.2023.1165004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of endocrinology and metabolism  

Objective: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. Materials and methods: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. Results: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (-4.7 ± 2.0 kg, P < 0.001) and 2 weeks (-5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x - 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. Conclusion: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process.

DOI： 10.20945/2359-3997000000532

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.stemcr.2023.02.006

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Neuroendocrinology  

Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin-releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy-associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.

DOI： 10.1111/jne.13223

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内分泌学会  

DOI： 10.1507/endocrj.EJ22-0339

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

DOI： 10.1038/s41598-022-22405-8

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Journal of clinical endocrinology and metabolism  

BACKGROUND: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. METHODS: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. RESULTS: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. CONCLUSION: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

DOI： 10.1210/clinem/dgac467

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nutrients  

Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

DOI： 10.3390/nu14183835

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2337/db21-0953

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Best Practice and Research: Clinical Endocrinology and Metabolism  

Immune-related adverse events (irAEs) are caused by immune checkpoint inhibitors in several organs including the endocrine glands. Thyroid dysfunction (thyroid irAEs) is often observed among endocrine irAEs and is induced by blockade of programmed cell death 1 (PD-1), programmed death ligand 1, or PD-1 plus cytotoxic T-lymphocyte antigen 4. Endocrinologically, destructive thyroiditis or hypothyroidism is observed in most cases, whereas hyperthyroidism (Graves' disease) is rare. Most patients who develop destructive thyroiditis or hypothyroidism subsequently require thyroid hormone replacement therapy. Thyroid irAE development is associated with prolonged survival in patients with non-small cell lung carcinoma. The incidence of thyroid irAEs is higher in patients who are positive versus negative for anti-thyroid antibodies at baseline, suggesting that these antibodies can predict thyroid irAE development. Cytotoxic T cells, especially CD4 T cells, are reportedly involved in the development of destructive thyroiditis. In this review, we describe the clinical features, potential biomarkers, and mechanism of thyroid irAEs.

DOI： 10.1016/j.beem.2022.101660

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/clinem/dgab829

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrinology (United States)  

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

DOI： 10.1210/endocr/bqac004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrinology and Metabolism  

Background: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. Methods: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. Results: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P= 0.022; 11/14 vs. 7/26, P= 0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. Conclusion: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

DOI： 10.3803/EnM.2021.1282

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Diabetologia  

DOI： 10.1007/s00125-021-05610-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Pharmacological Sciences  

We investigated whether peripheral combination treatment of a sodium–glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.

DOI： 10.1016/j.jphs.2021.08.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Diabetologia  

Aims/hypothesis: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. Methods: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. Results: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan–Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. Conclusions/interpretation: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s00125-021-05516-1

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

DOI： 10.1038/s41598-021-98590-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

DOI： 10.1038/s41598-021-92386-7

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PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Science translational medicine  

DOI： 10.1126/scitranslmed.abb7495

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience  

DOI： 10.1016/j.neuroscience.2021.02.009

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Peptides  

DOI： 10.1016/j.peptides.2021.170517

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PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/jitc-2021-002493

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内分泌学会  

<p>The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8–18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.</p>

DOI： 10.1507/endocrj.EJ20-0769

PubMed

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrinology and Metabolism  

DOI： 10.3803/EnM.2021.1007

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PLoS ONE  

DOI： 10.1371/journal.pone.0248065

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pituitary  

DOI： 10.1007/s11102-021-01135-6

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine Journal  

<p>Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.</p>

DOI： 10.1507/endocrj.EJ20-0436

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

DOI： 10.1038/s41598-020-76839-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：iScience  

DOI： 10.1016/j.isci.2020.101648

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bmjdrc-2019-001115

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neurochemistry International  

DOI： 10.1016/j.neuint.2020.104733

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1507/endocrj.EJ19-0569

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41416-020-0736-7

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cell Reports  

DOI： 10.1016/j.celrep.2019.12.009

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal for ImmunoTherapy of Cancer  

DOI： 10.1136/jitc-2020-000779

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0228004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1507/endocrj.EJ19-0224

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.isci.2019.09.032

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Stem Cell Research  

DOI： 10.1016/j.scr.2019.101572

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/en.2019-00105.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1507/endocrj.EJ18-0545

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.13800

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neulet.2018.06.013

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/path.5046

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1507/endocrj.EJ17-0399

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/js.2017-00432

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neulet.2017.06.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2017.05.019

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ebiom.2017.01.007

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>  免疫チェックポイント阻害薬で認められる免疫関連有害事象（immune-related adverse events; irAEs）は全身の臓器で認められ，大腸炎，肝炎，間質性肺炎，皮膚炎，神経・筋障害，内分泌障害などが報告されている．死亡に至る重篤例もあることから適切な対応が重要である．irAEsとして障害される内分泌器官は下垂体，甲状腺，副腎皮質，膵，副甲状腺が挙げられ，それぞれ異なる対応を要する．下垂体障害の頻度は細胞傷害性T細胞抗原（cytotoxic T-lymphocyte-associated antigen; CTLA）-4に対する抗体であるイピリムマブで4-10％程度，programmed cell death（PD）-1に対する抗体で1％未満と報告されている．下垂体前葉機能障害および下垂体腫大を呈する症例は臨床的に下垂体炎と考えられる．内分泌学的には副腎皮質刺激ホルモン（ACTH）の障害が最も高頻度で認められ，診断が遅れると副腎クリーゼとなり得る重篤な副作用である．これまでに報告された抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎の症例を検討した結果，両者の臨床的特徴には相違点があることが解ってきた．本講演では，抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎について臨床的特徴をそれぞれ解説し，両者の相違点について考察する．</p>

DOI： 10.2177/jsci.40.264a

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2017/1543149

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2177/jsci.40.90

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s11102-016-0780-8

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0164544

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.expneurol.2016.08.007

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>  免疫チェックポイント阻害剤はT細胞の活性化を負に制御する分子に対するモノクローナル抗体で，細胞傷害性T細胞抗原（CTLA）4に対する抗体であるイピリムマブ（Ipi）とprogrammed cell death-1に対する抗体であるニボルマブが本邦でも近年使用開始された．これらの薬剤は，優れた抗腫瘍効果の一方で，自己免疫機序が想定される重篤な副作用を発症させ，特に，肝炎，腸炎，皮膚炎，内分泌障害が好発する．内分泌副作用として，下垂体炎，甲状腺機能異常症，副腎炎，1型糖尿病などが報告されており，薬剤によりその発症頻度は異なる．特に我々は，従来まれな疾患と考えられてきた下垂体炎が，Ipi使用者において約10％もの頻度で発症することに着目し，抗マウスCTLA4抗体をSJLマウスに連続投与することで下垂体に炎症細胞浸潤を呈する抗CTLA4抗体誘発下垂体炎マウスモデルを作成した．本マウスにおける病態解析を進め，抗CTLA4抗体は下垂体に発現するCTLA4に直接結合し，補体活性化を介したII型アレルギー反応により下垂体に炎症を誘発する可能性を報告した．さらに，Ipiにより下垂体炎を発症した患者血清中に抗下垂体抗体が存在することを明らかにし，臨床における抗下垂体抗体の診断的有用性を示した．本講演では抗CTLA4抗体による下垂体炎の発症メカニズムおよび実際の症例を紹介するとともに，現在名古屋大学で行っている臨床研究についても紹介したい．</p>

DOI： 10.2177/jsci.39.350b

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1681/ASN.2014121196

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/jc.2014-4209

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ijc.28973

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1507/endocrj.EJ14-0369

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ki.2014.119

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/jc.2014-1049

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1126/scitranslmed.3008002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/jc.2013-2411

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/jc.2013-1912

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1089/thy.2012.0554

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/en.2012-1452

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1210/en.2012-1236

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12020-011-9549-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/glia.21114

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1681/ASN.2010040438

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2826.2009.01894.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1089/thy.2006.0121

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担当ページ：38(11), p1753   記述言語：日本語

担当ページ：10月4週号　p45-46   記述言語：日本語 著書種別：教科書・概説・概論

担当ページ：第150巻・特別号(2), S144-S148   記述言語：日本語

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担当ページ：276(8), 782-785   記述言語：日本語 著書種別：学術書

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担当ページ：705-711   記述言語：日本語 著書種別：学術書

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記述言語：日本語 著書種別：学術書

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記述言語：日本語

開催年月日： 2024年5月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

国名：日本国  

開催年月日： 2024年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：東京   国名：日本国  

開催年月日： 2024年3月

記述言語：英語  

開催地：Dubai   国名：アラブ首長国連邦  

開催年月日： 2024年3月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：Dubai   国名：アラブ首長国連邦  

開催年月日： 2024年2月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：名古屋   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：岡山   国名：日本国  

開催年月日： 2023年8月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

国名：日本国  

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：札幌   国名：日本国  

開催年月日： 2023年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：名古屋   国名：日本国  

開催年月日： 2023年6月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：名古屋   国名：日本国  

開催年月日： 2022年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：東京   国名：日本国  

開催年月日： 2022年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：大阪   国名：日本国  

開催年月日： 2022年9月 - 2022年10月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：横浜   国名：日本国  

開催年月日： 2022年7月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：松江   国名：日本国  

開催年月日： 2022年6月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：つくば、Web  

開催年月日： 2022年6月

記述言語：日本語  

開催地：大分、Web  

開催年月日： 2022年6月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：大分、Web  

開催年月日： 2022年2月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：Web  

開催年月日： 2022年2月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：京都、Web  

開催年月日： 2021年12月

開催地：横浜  

開催年月日： 2021年11月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：大阪＋Web  

開催年月日： 2021年11月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：東京  

開催年月日： 2021年11月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：東京  

開催年月日： 2021年11月

記述言語：日本語  

開催地：Web  

開催年月日： 2021年10月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：奈良  

開催年月日： 2021年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：奈良   国名：日本国  

開催年月日： 2021年10月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：横浜  

開催年月日： 2021年4月

開催年月日： 2020年11月

記述言語：日本語  

開催年月日： 2020年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催年月日： 2020年10月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2020年10月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催年月日： 2020年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2019年12月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2019年12月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：大阪  

開催年月日： 2019年11月

記述言語：日本語  

開催地：高知  

開催年月日： 2019年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：名古屋  

開催年月日： 2019年10月

記述言語：英語   会議種別：口頭発表（招待・特別）  

開催地：Vienna  

開催年月日： 2019年5月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2019年5月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2018年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2018年5月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2018年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2017年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

<p>  免疫チェックポイント阻害薬で認められる免疫関連有害事象（immune-related adverse events; irAEs）は全身の臓器で認められ，大腸炎，肝炎，間質性肺炎，皮膚炎，神経・筋障害，内分泌障害などが報告されている．死亡に至る重篤例もあることから適切な対応が重要である．irAEsとして障害される内分泌器官は下垂体，甲状腺，副腎皮質，膵，副甲状腺が挙げられ，それぞれ異なる対応を要する．下垂体障害の頻度は細胞傷害性T細胞抗原（cytotoxic T-lymphocyte-associated antigen; CTLA）-4に対する抗体であるイピリムマブで4-10％程度，programmed cell death（PD）-1に対する抗体で1％未満と報告されている．下垂体前葉機能障害および下垂体腫大を呈する症例は臨床的に下垂体炎と考えられる．内分泌学的には副腎皮質刺激ホルモン（ACTH）の障害が最も高頻度で認められ，診断が遅れると副腎クリーゼとなり得る重篤な副作用である．これまでに報告された抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎の症例を検討した結果，両者の臨床的特徴には相違点があることが解ってきた．本講演では，抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎について臨床的特徴をそれぞれ解説し，両者の相違点について考察する．</p>

開催年月日： 2017年5月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催年月日： 2016年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

<p>  免疫チェックポイント阻害剤はT細胞の活性化を負に制御する分子に対するモノクローナル抗体で，細胞傷害性T細胞抗原（CTLA）4に対する抗体であるイピリムマブ（Ipi）とprogrammed cell death-1に対する抗体であるニボルマブが本邦でも近年使用開始された．これらの薬剤は，優れた抗腫瘍効果の一方で，自己免疫機序が想定される重篤な副作用を発症させ，特に，肝炎，腸炎，皮膚炎，内分泌障害が好発する．内分泌副作用として，下垂体炎，甲状腺機能異常症，副腎炎，1型糖尿病などが報告されており，薬剤によりその発症頻度は異なる．特に我々は，従来まれな疾患と考えられてきた下垂体炎が，Ipi使用者において約10％もの頻度で発症することに着目し，抗マウスCTLA4抗体をSJLマウスに連続投与することで下垂体に炎症細胞浸潤を呈する抗CTLA4抗体誘発下垂体炎マウスモデルを作成した．本マウスにおける病態解析を進め，抗CTLA4抗体は下垂体に発現するCTLA4に直接結合し，補体活性化を介したII型アレルギー反応により下垂体に炎症を誘発する可能性を報告した．さらに，Ipiにより下垂体炎を発症した患者血清中に抗下垂体抗体が存在することを明らかにし，臨床における抗下垂体抗体の診断的有用性を示した．本講演では抗CTLA4抗体による下垂体炎の発症メカニズムおよび実際の症例を紹介するとともに，現在名古屋大学で行っている臨床研究についても紹介したい．</p>