Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

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Skin GVHD targets Lgr5+ HFSCs in association with impaired hair regeneration and wound healing. Topical ruxolitinib, unlike corticosteroids, protects Lgr5+ skin stem cells and maintains skin homeostasis in skin GVHD.

DOI： 10.1182/blood-2017-06-792614

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Immune checkpoint inhibitors (ICIs) are effective against many types of cancers. However, these drugs can trigger unintended immune attacks on normal tissues, leading to a range of side effects known as immune-related adverse events (irAEs). Involvement of the hematopoietic system in irAEs is rare, and a standard treatment has not yet been established. We herein report a 72-year-old man with non-small-cell lung cancer who developed aplastic anemia (AA) after ICI treatment. Eltrombopag improved the long-term blood count without causing severe infection. This case suggests that eltrombopag may be a viable treatment option for ICI-induced AA.

DOI： 10.2169/internalmedicine.5590-25

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Multiple myeloma (MM) is a hematological malignancy characterized by a poor prognosis. While certain probiotics have been shown to produce antitumor molecules that inhibit solid tumor progression, it remains unclear whether probiotic-derived compounds can exert similar effects on hematological tumors, such as MM. In this study, we screened the cell-free culture supernatants (CFCS) of 24 probiotic strains for antitumor effects against multiple myeloma (MM) cells and identified that the CFCS from Clostridium butyricum (C. butyricum) demonstrated the most significant reduction in MM cell viability. Further fractionation of this CFCS through reverse-phase and gel filtration chromatography revealed a high enrichment of butyrate in the antitumor fraction, as confirmed by gas chromatography-mass spectrometry. Butyrate reduced MM cell viability in a concentration-dependent manner. Butyrate was significantly more cytotoxic to RPMI-8226 cells than peripheral blood mononuclear cells (PBMCs) isolated from two non-cancerous individuals. In the xenograft model of RPMI-8226 cells, butyrate showed significant inhibition of tumor formation. Cell cycle analysis showed that butyrate induced G1 phase arrest and increased sub-G1 phase, suggesting DNA fragmentation. Western blot analysis demonstrated that butyrate treatment led to cleaved poly ADP-ribose polymerase (PARP) accumulation. Additionally, flow cytometry showed an increase in annexin V positive MM cells, indicating apoptosis. Butyrate also exhibited synergistic antitumor activity when combined with bortezomib, a proteasome inhibitor. These findings suggest that probiotic-derived molecules, including butyrate, may enhance the therapeutic effect of hematological malignancy, such as MM.

DOI： 10.1038/s41598-025-97038-8

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neulet.2025.138208

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BACKGROUND: Accumulating evidence has suggested that neuropeptides such as orexin, ghrelin, or oxytocin act centrally in the brain to regulate intestinal barrier function through the vagus nerve. It has been reported that the vagal cholinergic anti-inflammatory pathway was blocked by splenectomy. In the present study, we therefore examined the effect of splenectomy on neuropeptides-induced improvement of increased intestinal permeability. METHODS: Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min spectrophotometrically in rats. RESULTS: Splenectomy increased colonic permeability. The increased permeability by splenectomy was significantly blocked by vagal activation induced by carbachol or 2-deoxy-d-glucose which was prevented by atropine, suggesting vagal activation could prevent colonic hyperpermeability in splenectomized rats. In the splenectomized rats, intracisternal injection of orexin, ghrelin, oxytocin, or butyrate failed to inhibit increased colonic permeability while intracisternal glucagon-like peptide-1 (GLP-1) analogue, liraglutide, potently blocked the increased colonic permeability in a dose-dependent manner. The liraglutide-induced improvement of increased colonic permeability was blocked by atropine in splenectomized rats. Intracisternal injection of GLP-1 receptor antagonist attenuated 2-deoxy-d-glucose-induced improvement of colonic hyperpermeability in splenectomized rats. CONCLUSION: The present results suggested that the spleen is important in the improvement of intestinal barrier function by brain orexin, ghrelin or oxytocin, and butyrate. On the other hand, GLP-1 acts centrally in the brain to improve colonic hyperpermeability in a spleen-independent manner. All these results suggest that dual mechanisms (spleen dependent or independent) may exist for the brain-gut regulation in intestinal barrier function.

DOI： 10.1111/nmo.14949

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Although lymphoma involving the adrenal gland is uncommon, it is associated with a high incidence of adrenal insufficiency, which may lead to adrenal crisis. The changes in adrenocortical function over the course of lymphoma treatment are not well described. We report three cases with lymphoma with bilateral adrenal enlargement who presented with adrenal insufficiency and had their adrenocortical function monitored during treatment. Case 1 was a 72-year-old man who presented with non-specific symptoms and was diagnosed with lymphoma involving the adrenal glands. Case 2 was a 71-year-old woman who was diagnosed with adrenal lesion of intravascular large B-cell lymphoma. Case 3 was an 84-year-old man diagnosed with primary adrenal lymphoma, presenting rapidly progressing bilateral adrenal tumors. All three were diagnosed with adrenal insufficiency at presentation. Rapid ACTH stimulation test was performed before and after chemotherapy and/or glucocorticoid replacement therapy, and adrenal insufficiency remained in all. Therefore, each required persistent glucocorticoid supplementation despite marked reduction in adrenal lesion. It is important to evaluate adrenocortical function and consider continuing glucocorticoid replacement therapy even after a significant treatment response in adrenal lymphomas.

DOI： 10.3389/fmed.2025.1632514

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Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

DOI： 10.1016/j.immuni.2024.05.018

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Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). While adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) upon injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, significantly reduced in a TGF--dependent manner. Administration of SB-431542, an inhibitor of TGF-β signaling, from day 14 to day 28 protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.

DOI： 10.1182/blood.2023023060

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Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.

DOI： 10.1172/JCI170125

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Graft-versus-host disease (GVHD) is the major obstacle to performing allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that intestinal stem cells are targeted in lower gastrointestinal GVHD. A leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-expressing gastric stem cells (GSCs) reside at the base of the gastric glands in mice. After experimental allo-HCT, Lgr5+ GSCs significantly decreased. Parietal cells, which underwent continuous renewal by GSCs, were injured in gastric GVHD, leading to failure of gastric acidification and aerobic bacterial overgrowth in the duodenum. Fate-mapping analysis demonstrated that administration of R-Spondin1 (R-Spo1) that binds to Lgr5 for 6 days in naïve mice significantly increased proliferating epithelial cells derived from Lgr5+ GSCs. R-Spo1 administered on days -3 to -1 and from days +1 to +3 of allo-HCT protected GSCs, leading to amelioration of gastric GVHD and restoration of gastric acidification, and suppression of aerobic bacterial overgrowth in the duodenum. In conclusion, Lgr5+ GSCs were targeted by gastric GVHD, resulting in disruption of the gastric homeostasis, whereas R-Spo1 protected Lgr5+ GSCs from GVHD and maintained homeostasis in the stomach.

DOI： 10.1182/bloodadvances.2023011034

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DOI： 10.1007/s12185-023-03560-8

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DOI： 10.1182/blood.2022015808

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Granulopoiesis in the bone marrow adjusts cellular output as demand for neutrophils changes. Reactive granulopoiesis is induced by profound neutropenia, but its mechanism remains to be clarified. We herein explored its mechanisms using mouse models of syngeneic hematopoietic stem cell transplantation (SCT) and 5-fluorouracil-induced neutropenia. After SCT, T cell production of IL-17A was up-regulated. Neutrophil recovery was significantly delayed in IL-17A-deficient or T cell-deficient RAG1-/- mice, and adoptive transfer of wild-type (WT) T cells facilitated neutrophil engraftment. Gut decontamination with oral antibiotics suppressed T cell production of IL-17A and impaired neutrophil recovery. Transplantation of fecal microbiota collected from neutropenic, not naive, mice promoted neutrophil recovery in these mice, suggesting that neutropenia-associated microbiota had a potential to stimulate reactive granulopoiesis. Our study uncovered a cross talk between gut microbiota and neutropenia after SCT and chemotherapy.

DOI： 10.1073/pnas.2211230119

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Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency. This results in significant reductions in GVHD whilst promoting potent GVL effects (relapse in recipients receiving glucocorticoids, vehicle or PT-Cy was 12%, 56% and 100% respectively). Intriguingly, patients with acute myeloid leukemia not in remission that received unmanipulated haplo-SCT and peri-transplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%: 95% CI, 18%-47%) with high overall survival at 3 years (58%: 95% CI, 38-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

DOI： 10.1172/jci.insight.153551

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Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). We previously reported the efficacy of the Hokkaido Ultrasonography (US)-based scoring system (HokUS-10) for US findings. To establish easier-to-use criteria, we retrospectively evaluated US findings from 441 patients, including 30 patients with SOS using the HokUS-10 scoring system. Using logistic regression analysis, we established the novel diagnostic criteria HokUS-6. In the presence of ascites, US diagnosis was made in the presence of two of the following 6 parameters: moderate amount of ascites, the appearance of a paraumbilical vein blood flow signal, gallbladder wall thickening, portal vein dilatation, portal vein velocity decrease, and hepatic artery resistive index increase. The AUC, sensitivity, and specificity of HokUS-6 were 0.974 (95% confidence interval 0.962-0.990), 95.2%, and 96.9%, respectively. The scores were significantly higher in patients with severe SOS than in those with non-severe SOS (p = 0.013). Furthermore, the scores before HSCT were significantly higher in patients who developed SOS than in controls (p = 0.001). The HokUS-6 is an easy and useful way to diagnose and identify the risk of SOS.

DOI： 10.1007/s12185-021-03137-3

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Language：Japanese   Publisher：(一社)日本内科学会  

54歳男性。右鼠径リンパ節腫脹を主訴とした。27歳時に急性前骨髄球性白血病に対しHLA適合の兄から骨髄移植を受けていた。53歳時に右大腿外側部にケロイド様皮疹が出現し、皮膚生検の診断はanaplastic lymphoma kinase(ALK)陰性の未分化大細胞リンパ腫(ALCL)であった。電子線治療で皮膚病変は消失したが、7ヵ月後にFDG-PETで全身のリンパ節病変(鎖骨上窩、傍大動脈、右鼠径部)を認めた。再発病変を疑い、右鼠径リンパ節を生検したところ、右大腿皮膚生検同様の組織所見を認め、ALK陰性ALCLと診断した。末梢血をドナー細胞、頬粘膜をレシピエント細胞としてキメリズム解析を行い、ドナー由来のALCLと診断した。ALCLに対しCHOP療法(cyclophosphamide、doxorubicin、vincristine、prednisolone)を行ったが、病変の増大を認め、brentuximab vedotin(BV)単剤による治療に変更した。経過は良好で、現在まで完全奏効を維持している。

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PURPOSE: Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a fatal complication after hematopoietic stem cell transplantation. We previously reported the usefulness of an ultrasonographical (US) scoring system, the Hokkaido US-based scoring system consisting of ten parameters (HokUS-10): (1) hepatomegaly in the left lobe and (2) right lobe, (3) dilatation of the main portal vein (PV), (4) hepatofugal flow in the main PV, (5) decreased velocity of the PV, (6) dilatation of the para-umbilical vein (PUV), (7) appearance of blood flow signal in the PUV, (8) gallbladder (GB) wall thickening, (9) ascites, and (10) increased resistive index of the hepatic artery, for the diagnosis of SOS/VOD. However, the reliability of this system among operators remains elusive. Therefore, we prospectively evaluated the reliability of HokUS-10. METHODS: Twenty-four healthy volunteers and 40 patients with liver dysfunction were enrolled. Inter- and intra-operator reliabilities were analyzed using three sonographers. RESULTS: The median concordance rate of HokUS-10 among three sonographers and intra-operator in 24 volunteers was 92% (95% CI: 73-98%) and 98% (95% CI: 92-100%), respectively. In all 64 cases, in terms of the reliability between two sonographers for three representative US parameters (amount of ascites, GB wall thickening, and appearance of PUV blood flow signal), the median concordance rate was more than 98% (95% CI: 86-106%). CONCLUSION: The inter- and intra-reliabilities of HokUS-10 were excellent. Thus, US might be a reliable tool for SOS/VOD diagnosis.

DOI： 10.1007/s10396-020-01071-1

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Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.

DOI： 10.1126/scitranslmed.aaw0720

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AIM:  To measure histological villous atrophy and to clarify the diagnostic accuracy of endoscopic villous atrophy in gastrointestinal graft-versus-host disease. METHODS:  Data for patients who underwent upper and/or lower endoscopic examinations after hematopoietic stem cell transplantation were retrospectively collected. In study 1, group A included 56 patients in whom GI-GVHD was histologically confirmed and group B included 60 patients in whom GI-GVHD was not histologically confirmed. Group C included 59 patients before HSCT. The lengths of villi and crypts in the duodenum and terminal ileum were histologically measured. In study 2, the diagnostic accuracies of villous atrophy of the duodenum and of the terminal ileum using magnifying endoscopy were evaluated. RESULTS:  In study 1, the lengths of villi and the villi/crypt (V/C) ratios of the duodenum and terminal ileum in group A were significantly smaller than those in the other groups (p < 0.05). V/C ratio was moderately correlated with clinical severity, histological grades, and endoscopic grades in the terminal ileum. In study 2, the diagnostic accuracies of magnified images for villous atrophy were 83.8% in the duodenum and 94.9% in the terminal ileum. CONCLUSION:  Magnifying endoscopy enables evaluation of villous atrophy and is useful for optical biopsy of GVHD.

DOI： 10.1007/s00277-020-03966-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41409-019-0733-8

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Other Link： http://www.nature.com/articles/s41409-019-0733-8

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00277-020-03937-3

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Other Link： http://link.springer.com/article/10.1007/s00277-020-03937-3/fulltext.html

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Nivolumab is effective in the treatment of classical Hodgkin lymphoma that relapsed after allogeneic hematopoietic stem cell transplantation (SCT) with the risk of graft-versus-host disease; however, the optimal time and dose of nivolumab administration remain to be investigated. Nivolumab binding to PD-1 masks flowcytometric detection of PD-1 by the anti-PD-1 monoclonal antibody EH12.1. Using this method, we monitored nivolumab binding on T cells after nivolumab treatment in a patient with classical Hodgkin lymphoma relapsed after allogeneic SCT. Nivolumab was effective while prolonged nivolumab binding was evident, but restoration of PD-1 staining predicted tumor relapse. Flowcytometric monitoring of nivolumab binding on T cells could be a promising biomarker for predicting tumor relapse and determining the timing of nivolumab administration.

DOI： 10.1007/s12185-019-02737-4

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Language：Japanese   Publisher：(一社)日本輸血・細胞治療学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本輸血・細胞治療学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J04824&link_issn=&doc_id=20200312340007&doc_link_id=%2Fcc5trcel%2F2020%2F006601%2F007%2F0031-0035%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcc5trcel%2F2020%2F006601%2F007%2F0031-0035%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Asia-Pacific Blood and Marrow Transplantation Group  

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various kinds of hematological malignancies and disorders. Recently, HLA-haploidentical stem cell transplantation with post-transplantation cyclophosphamide (PTCy-haplo HSCT) has been widely performed due to its safety and favorable immune recovery. However, graft rejection remains an obstacle to PTCy-haplo HSCT. Donor specific antibody (DSA) is considered to be a major factor of graft rejection of haplo HSCT. We herein present a case of graft rejection after PTCy haplo-HSCT due to DSA induced by pretransplant platelet transfusion after donor selection. The patient was dependent on platelet transfusion and had not received cytotoxic chemotherapy because he was diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable. We retrospectively confirmed the level of DSA just before the first transplantation and found that it was dramatically elevated, which was enough to cause graft rejection. We successfully performed cord blood transplantation of the HLA that was not the target of DSA, as salvage transplantation without any desensitization. This case illustrates that we have to confirm the presence of DSA immediately before the haplo-HSCT, particularly in high risk patients who are dependent on platelet transfusion and have no cytotoxic chemotherapy before HSCT.

DOI： 10.31547/bct-2020-004

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Language：Japanese   Publisher：日本染色体遺伝子検査学会  

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

<title>Abstract</title>Chronic graft-versus-host disease (GVHD) profoundly affects the quality of life of long-term survivors of allogeneic hematopoietic stem cell transplantation (SCT). The eyes are frequently involved, and dry eye syndrome is the most common manifestation of ocular chronic GVHD. We explored the role of heat shock protein 47 (HSP47) in ocular GVHD and developed a novel antifibrotic topical therapy using vitamin A–coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47 (VA-lip HSP47). In a mouse model of chronic GVHD, infiltration of HSP47+ fibroblasts and massive fibrosis surrounding the lacrimal ducts were observed after allogeneic SCT, leading to impaired tear secretion. After ocular instillation, VA-lip HSP47 was distributed to the lacrimal glands, knocked down HSP47 expression in fibroblasts, reduced collagen deposition, and restored tear secretion after allogeneic SCT. Ocular instillation of VA-lip HSP47 also ameliorated established lacrimal gland fibrosis and dry eye syndrome. VA-lip HSP47 eye drops are a promising prophylactic and therapeutic option against dry eye syndrome in chronic GVHD.

DOI： 10.1182/bloodadvances.2018028431

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Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Transfusion Medicine and Cell Therapy  

DOI： 10.3925/jjtc.65.98

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Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell-derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell-derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.

DOI： 10.1182/bloodadvances.2018020008

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Language：Japanese   Publisher：(一社)日本輸血・細胞治療学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/jci.insight.121886

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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The R-Spondin (R-Spo) family regulates WNT signaling and stimulates the proliferation and differentiation of intestinal stem cells (ISCs). R-Spo plays a critical role in maintaining intestinal homeostasis, but endogenous producers of R-Spo in the intestine remain to be investigated. We found that R-Spo3 was the major R-Spo family member produced in the intestine and it was predominantly produced by CD45-CD90+CD31+ lymphatic endothelial cells (LECs) in the lamina propria of the intestinal mucosa. Transcriptome analysis demonstrated that LECs highly expressed R-Spo receptor, Lgr5, suggesting an autocrine stimulatory loop in LECs. LECs were significantly reduced in number, and their R-Spo3 production was impaired in intestinal graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. The impaired production of R-Spo3 in the intestine may be a novel mechanism of delayed tissue repair and defective mucosal defense in intestinal GVHD. We demonstrate a novel role of intestinal LECs in producing R-Spondin3 to maintain intestinal homeostasis.

DOI： 10.1038/s41598-018-29100-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

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HSP47+ myofibroblasts are accumulated in the fibrotic lesions of chronic GVHD and promote fibrosis in a CSF-1R+ macrophage-dependent manner. Vitamin A–coupled liposomes containing HSP47 siRNA abrogate HSP47 expression in myofibroblasts and ameliorate fibrosis in chronic GVHD.

DOI： 10.1182/blood-2017-04-779934

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DOI： 10.1084/jem.20170418

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DOI： 10.1182/blood-2016-07-728337

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DOI： 10.1182/blood-2014-12-615781

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DOI： 10.1038/bmt.2011.53

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Language：Japanese   Publisher：The Japan Society of Transfusion Medicine and Cell Therapy  

&lt;p&gt;&lt;b&gt;Background: &lt;/b&gt;Spectra Optia&lt;sup&gt;®&lt;/sup&gt; is an apheresis system that enables peripheral blood stem cell collection (PBSCC) to be easily conducted due to its unique automated interface management system. We retrospectively analyzed the number for CD34-positive cells in collected products and the collection efficiency for CD34-positive cells between the Spectra Optia&lt;sup&gt;®&lt;/sup&gt; MNC mode (MNC group) and CMNC mode (CMNC group) for PBSCC.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods: &lt;/b&gt;We retrospectively analyzed 233 cases of PBSCC (autologous PBSCC: 103 cases, allogeneic PBSCC: 130 cases), which were performed in our institution between August 2013 and February 2018.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results: &lt;/b&gt;In autologous PBSCC, there was no significant difference in the number of CD34-positive cells in collected products or the collection efficiency for CD34-positive cells between the two groups. In allogeneic PBSCC, the number of CD34-positive cells in collected products and the collection efficiency for CD34-positive cells in the CMNC group were significantly higher than those in the MNC group. Peripheral blood platelet count and hemoglobin concentration were identified as the factors influencing the collection efficiency for CD34-positive cells.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusion: &lt;/b&gt;In autologous PBSCC, the number and collection efficiency for CD34-positive cells were not significantly different between the two modes, whereas in allogeneic PBSCC, the CMNC mode was more efficient for PBSCC than the MNC mode.&lt;/p&gt;

DOI： 10.3925/jjtc.64.742

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2016237547

Event date： 2022.12

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2016.10

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2016.2

Language：English   Presentation type：Oral presentation (general)  

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