Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English  

DOI： 10.1007/s12185-023-03560-8

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

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  

cisA2B3型はオモテ検査での抗A、抗Bの反応が弱く、血漿中に抗Bが認められる反応態度であるが、新生児におけるcisA2B3型の反応態度に関する報告は少ない。今回、cisA2B3型が疑われる新生児の血液型反応態度と成長に伴う血液型抗原量の変化について検討した。症例は日齢0日の新生児、ABO血液型検査はカラム凝集法にてオモテ検査のみ施行し、抗A:2+、抗B:0となった。母親が血清学的検査でcisA2B3型と疑われていたことから、児の血液型精査、母児のABO遺伝子タイピング、血液型抗原量を測定した。児の赤血球の抗B吸着解離試験よりB抗原が検出され、ABO遺伝子タイピングでは母児共にcisAB01/O01と判定された。血液型抗原量は母親と比較して児のA、B抗原量は低く、特にB抗原量が著しく低かった。1歳11ヵ月時に再検査したところ、児のB抗原量は出生時よりも増加し、血漿中から抗Bが検出された。新生児のcisAB型では通常の血液型検査では検出できないB抗原量であるため、血液型判定に際しcisAB型を疑う場合はABO遺伝子タイピングや血液型抗原量の測定が有用であることが示唆された。(著者抄録)

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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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Language：English   Publishing type：Research paper (scientific journal)  

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  

<背景>自己抗体保有患者は自己抗体の他に同種抗体を保有する頻度が多いため、共存する同種抗体の検出が重要となる。ポリエチレングリコール(PEG)吸着法は自己抗体吸着法として一般的に用いられているが、低力価の同種抗体も吸着されると指摘する報告がある。海外では低イオン強度溶液(low ionic strength solution;LISS)を用いた自己抗体吸着法(以下LISS吸着法)も短時間での自己抗体吸着において有用であるという報告があるが本邦では一般的ではない。今回我々はLISS吸着法が同種抗体の検出に有用であった3症例を経験したので報告する。<方法>自己抗体を保有する3患者においてLISS吸着法を行った。3ヵ月以内に輸血歴のない患者は自己赤血球を用い、輸血歴のある患者は患者とRh、Kidd、Diego同型の酵素処理した他家赤血球を用いて自己抗体の吸着を行い、上清で同種抗体の検索を行った。<結果>3例共にLISS吸着法にて同種抗体が検出された。<考察>LISS吸着法は自己抗体の吸着および、共存する同種抗体の検出において有用であると考えられた。(著者抄録)

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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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Language：English   Publishing type：Research paper (scientific journal)  

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  

<title>Key Points</title>
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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as alpha-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant a-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of a-defensins. Administration of R-Spo1 or recombinant a-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.

DOI： 10.1084/jem.20170418

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used. (Blood. 2017; 129(9): 1216-1225)

DOI： 10.1182/blood-2016-07-728337

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of a-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT.

DOI： 10.1182/blood-2014-12-615781

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