Combined IL-2 Immunocomplex and Anti-IL-5 mAb Treatment Expands Foxp3+ Treg Cells in the Absence of Eosinophilia and Ameliorates Experimental Colitis

Interleukin (IL)-2 is expressed during T cell activation and induces the proliferation and differentiation of T cells. CD4+Foxp3+ regulatory T cells (Tregs) constitutively express the high affinity IL-2 receptor (CD25/IL-2Rα) and rapidly respond to IL-2 to elaborate numerous suppressive mechanisms that limit immune-mediated pathologies. Accumulating evidence supports the concept that an aberrant balance between Tregs and Teff contribute to the pathology of intestinal inflammation and that the IL-2/Treg axis is a potential pathway to exploit for the treatment of inflammatory bowel disease (IBD). Here, we show that treatment of mice with IL-2/IL-2 antibody (JES6-1) immunocomplex during DSS-induced colitis induced Foxp3+ Treg expansion, but also potently stimulated GATA3+ type 2 innate lymphoid cell (ILC2) proliferation and high-level expression of IL-5. Furthermore, IL-2/JES6-1 treatment resulted in massive eosinophil accumulation and activation in the inflamed colon, and afforded only modest protection from colitis. In light of these findings, we observed that combined IL-2/JES6-1 and anti-IL-5 mAb treatment was most effective at ameliorating DSS-induced colitis compared to either treatment alone and that this regimen allowed for Foxp3+ Treg expansion without concomitant eosinophilia. Collectively, our findings provide insight into how blockade of IL-5 may aid in optimizing IL-2 immunotherapy for the treatment of intestinal inflammation

肝硬変患者の肝性腹水・浮腫に対するTolvaptan の治療反応性の検討

京都府立医科大学附属北部医療センター消化器内科京都府立医科大学消化器内科学Department of Molecular Gastroenterology and Hepatology, North Medical Center Kyoto Prefectural University of MedicineDepartment of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of MedicineTolvaptan は肝性腹水の治療に非常に有用な薬剤だが、日常臨床ではしばしば無効例を経験する。本研究ではTolvaptan への反応性について、治療前後の腹水、肝予備能、血液生化学的検査の変化を検討したところ、Tolvaptan への反応性は、腎機能、肝予備能に規定されることがわかった。またTolvaptan 無効例でもアルブミン補充や腹水濾過再静注(CART) を併用することで、治療効果の改善を認めた。本研究は少数例の検討であり、今後症例の集積が必要である

低用量アスピリンによる十二指腸輪状潰瘍の一例

京都府立医科大学附属北部医療センター　消化器内科京都府立医科大学消化器内科学Department of Gastroenterology and Hepatology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine症例は74歳男性。主訴は腹痛と嘔吐。造影CTにて十二指腸下行脚の壁肥厚と狭窄を認め、上部消化管内視鏡検査では同部位に輪状潰瘍及び高度狭窄を認めた。冠動脈疾患と脳梗塞の既往から低用量アスピリン(LDA)を内服していたためLDA潰瘍と診断した。薬物治療としてボノプラザンの投与を開始し、十二指腸狭窄に対してバルーン拡張術を施行したところ、輪状潰瘍は治癒し現在も再発を認めていない。(著者抄録

難治性肝膿瘍に対する抗菌薬動注療法

京都府立医科大学附属北部医療センター　消化器内科福知山市民病院　放射線科福知山市民病院　消化器内科京都府立医科大学附属北部医療センター　放射線科京都府立医科大学　消化器内科Department of Gastroenterology and Hepatology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Radiology, Fukuchiyama City HospitalDepartment of Gastroenterology and Hepatology, Fukuchiyama City HospitalDepartment of Radiology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine症例は36歳男性。主訴は発熱。肝右葉に多発する内部蜂巣状の膿瘍を認めた。経静脈的抗菌療法により炎症は沈静せず膿瘍は増大した。蜂窩織炎成分主体の病変性状によりドレナージ療法は困難と考え、大腿動脈経由に設置した肝動脈リザーバーを用いて抗菌薬動注療法を開始した。17日目に膿瘍の著明な縮小と炎症反応の鎮静化、28日目に膿瘍は消失した。本例のように従来治療が困難な肝膿瘍に対しては、抗菌薬の肝動注療法が有効である可能性があり、治療法の一つとして考慮する価値がある

大腸Cold Snare Polypectomyにおける手技の工夫とその切除検体の臨床病理学的検討

京都府立医科大学附属北部医療センター　消化器内科京都府立医科大学附属北部医療センター　病理診断科市立福知山市民病院消化器内科京都府立医科大学消化器内科学Department of Gastroentarology and Hepatology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Pathology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Gastroentarology and Hepatology, Fukuchiyama City HospitalDepartment of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science近年、Cold Snare Polypectomy(CSP) は、その簡便性、安全性から急速に普及しており、当院でも2014年よりCSPを導入している。CSP導入当初の臨床病理学的解析では、病変の完全一括切除率は67％であった。一方、本検討では、3本編細径スネアの導入を含めた手技の工夫により完全一括切除率は94％まで向上を認めた。本研究は少数例の検討であり、今後前向き試験による検討が必要である

アニサキス症による好酸球性肉芽腫を合併した早期胃癌の一例

京都府立医科大学附属北部医療センター　消化器内科京都府立医科大学　消化器内科京都府立医科大学附属北部医療センター　外科Department of Gastroenterology, North Medical Center,Kyoto Prefectural University of MedicineMolecular Gastro enterology and Hepatology, Kyoto Prefectural University of MedicineDepartment of Surgery, North Medical Center,Kyoto Prefectural University of Medicine症例は80代、男性。市民検診での胃透視で前庭部に異常所見を指摘され、精査加療目的に当院受診となった。上部消化管内視鏡検査では胃幽門部に30mm大の3型腫瘍を認めた。生検結果はadenocarcinoma tub2-porであった。胸腹部造影CT検査では所属リンパ節腫大・遠隔転移は認めず、術前診断:cT2N0M0 cStage Iとして手術加療を行った。最終病理診断はadenocarcinoma(por1>tub2>tub1)pT1b(SM2 0.7mm)Ly0V1aN0であり、腫瘍直下の筋層内に2mmの壊死を伴う肉芽腫を認めた。肉芽腫内には好酸球浸潤を認め、遺伝子解析の結果Anisakis simplexが検出された。その後術後経過良好で、現在再発なく、当院外科外来で経過観察されている。(著者抄録

Impact of particulate microplastics generated from polyethylene terephthalate on gut pathology and immune microenvironments

Summary: Environmental microplastics have emerged as a critical issue in maintaining the planetary ecosystem. In this study, we generated particulate microplastics from polyethylene terephthalate (PM-PET) and investigated their impact in the gut by using mouse models and implementing histological examinations, as well as multi-omics analysis for colonic immune cells and microbiota. As a result, histological approaches showed that chronic and physiological low dose exposure of PM-PET did not affect intestinal pathology and mucin barriers, respectively. Moreover, immunohistochemical analysis demonstrated that the numbers of T cells, B cells, macrophages, and granulocytes were not affected by the exposure to PM-PET. However, RNA-seq analysis revealed that PM-PET had a substantial impact on the transcriptome in gut immune cells and their metabolisms, while 16s rRNA metagenomic analysis showed that the composition of microbiota was modestly affected. These results suggest an unexpected role played by the PM-PET in affecting gut immune homeostasis without detectable inflammation

Contribution of Mesenteric Lymph Nodes and GALT to the Intestinal Foxp3+ Regulatory T-Cell CompartmentSummary

Background & Aims: Foxp3+ regulatory T cells (Tregs) in the intestine promote immune tolerance to enteric antigens. Previous studies have shown that C-C chemokine receptor 7 (CCR7)-dependent migration of intestinal dendritic cells to the mesenteric lymph nodes (mLN) is involved in peripheral Foxp3+ Treg accumulation in the intestine and the establishment of oral tolerance. However, the relative contribution of this CCR7+ dendritic cellâmLNâTreg axis to the total intestinal Foxp3+ Treg pool during the steady-state remains unclear. In this study, the contribution of CCR7, as well as the mLN and gut-associated lymphoid tissue (GALT), to the intestinal Foxp3+ Treg compartment in the small intestine (SI) and large intestine (LI) was assessed. Methods: Intestinal Foxp3+ Tregs were quantitated in Ccr7-/- mice and in mice devoid of secondary lymphoid organsâincluding mLN and GALTâowing to a deficiency in lymphotoxin (LT) signaling. Specific analyses of Foxp3+Helios+ thymically derived (t)Tregs and Foxp3+Helios- peripherally derived (p)Tregs in the SI and LI, as well as the role for the mLN in supporting Foxp3+ pTreg development using the B6.Cg-Tg(TcraTcrb)425Cbn/J/ovalbumin (OVA) feeding system, were performed. Results: Foxp3+ Tregs were enriched in the intestine relative to the mLN, independent of CCR7. In the absence of the mLN and GALT, normal frequency and numbers of Foxp3+ Tregs were observed in LTα-deficient (Lta-/-) mice. However, Foxp3+Helios- pTregs were decreased in the SI of Lta-/- mice, corresponding with defective Foxp3+ pTreg expansion to OVA. In the LI, however, the proportion of Foxp3+Helios- pTregs and Foxp3+ pTreg induction to OVA was comparable between Lta-/- and Lta+/+ mice, which coincided with preferential expression of Treg-inducing/immunoregulatory cytokines. Conclusions: The overall size of the intestinal Foxp3+Treg pool is not impacted significantly by CCR7, mLN, or GALT during the steady-state. However, mLN/GALT appear to contribute to the Foxp3+ pTreg compartment in the SI, particularly in response to soluble oral antigen. These findings highlight important differences in the regulation of intestinal Tregs between the SI and LI, and suggest that enteric antigens may use mLN/GALT to induce Foxp3+ pTreg in the SI, while directly promoting Foxp3+ pTregs in the LI. Keywords: Regulatory T Cell, Foxp3, Intestin

Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration

International audienceGut microbiota and their metabolites are instrumental in regulating intestinal homeostasis. However, early-life microbiota associated influences on intestinal development remain incompletely understood. Here we demonstrate that co-housing of germ-free (GF) mice with specific-pathogen free (SPF) mice at weaning (exGF) results in altered intestinal gene expression. Our results reveal that one highly differentially expressed gene, erythroid differentiation regulator-1 (Erdr1), is induced during development in SPF but not GF or exGF mice and localizes to Lgr5+ stem cells and transit amplifying (TA) cells. Erdr1 functions to induce Wnt signaling in epithelial cells, increase Lgr5+ stem cell expansion, and promote intestinal organoid growth. Additionally, Erdr1 accelerates scratch-wound closure in vitro, increases Lgr5+ intestinal stem cell regeneration following radiation-induced injury in vivo, and enhances recovery from dextran sodium sulfate (DSS)-induced colonic damage. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage