Publications by authors named "Isao Tawara"

68 Publications

Acquisition of JAK2 V617F to CALR-mutated clones accelerates disease progression and might enhance growth capacity.

Br J Haematol 2021 Jun 1. Epub 2021 Jun 1.

Department of Hematology and Oncology, Matsusaka Chuo General Hospital, Matsusaka, Mie, Japan.

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http://dx.doi.org/10.1111/bjh.17571DOI Listing
June 2021

[Successful treatment with cyclosporine in a patient with rituximab-refractory thrombocytopenic purpura].

Rinsho Ketsueki 2021 ;62(3):176-179

Department of Hematology and Oncology, Mie University Hospital.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening systemic thrombotic microangiopathy characterized by the presence of anti-ADAMTS13 antibodies (inhibitor). Here we report the case of a patient with refractory aTTP successfully treated with cyclosporine. A 69-year-old man presenting with hematuria and petechiae was referred to our hospital; he was disoriented and febrile. Laboratory results revealed Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure. Undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies (inhibitor) confirmed the diagnosis of aTTP. Despite performing plasma exchange and administering prednisolone and rituximab (375 mg/m), we were unable to restore his platelet counts to the normal level. Therefore, he was treated with cyclophosphamide (500 mg/bodyweight), vincristine (1.4 mg/m), bortezomib (1.3 mg/m), and cyclosporine (2.5 mg/kg). After the cyclosporine therapy, his platelet counts gradually normalized. Continuous cyclosporine maintenance therapy led to complete disappearance of the inhibitor. Therapeutic strategies for refractory aTTP have not yet been established. Further investigations are warranted to establish a therapeutic strategy for refractory aTTP.
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http://dx.doi.org/10.11406/rinketsu.62.176DOI Listing
April 2021

MPL exon 10 mutations other than canonical MPL W515L/K mutations identified by in-house MPL exon 10 direct sequencing in essential thrombocythemia.

Int J Hematol 2021 May 26;113(5):618-621. Epub 2021 Mar 26.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

MPL exon 10 mutations are one of the driver mutations in essential thrombocythemia (ET) or myelofibrosis (MF). We have established an in-house MPL mutation analysis system, covering the entire region of MPL exon 10 by direct sequencing. Since 2009, MPL exon 10 mutation analysis has been performed for diagnosis of myeloproliferative neoplasms (MPN) without JAK2 V617F or CALR exon 9 mutations. So far, 11 cases of MPL exon 10 mutation have been found in 51 patients with suspected MPN. In patients with ET, we detected five non-canonical MPL mutations including one novel mutation, MPL R514_P518delinsK, and one canonical MPL W515L mutation. Notably, three ET patients without canonical MPL mutations had thrombotic events. Meanwhile, in primary or secondary MF, only canonical MPL W515L/K mutations were found. Further cases need to be examined to elucidate the full MPL mutation profile in MPN. However, our data indicate that analysis of the whole of MPL exon 10 is warranted for the diagnosis of MPL mutations, especially in ET, and that the use of Japanese commercial laboratory tests that only detect canonical MPL W515L/K mutations may miss a significant percentage of MPL exon 10 mutations, which could delay the administration of anti-thrombotic therapy.
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http://dx.doi.org/10.1007/s12185-021-03134-6DOI Listing
May 2021

Early central nervous system relapse of monomorphic epitheliotropic intestinal T-cell lymphoma after cord blood transplantation.

Int J Hematol 2021 Jul 1;114(1):129-135. Epub 2021 Mar 1.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare subtype of intestinal T-cell lymphoma that occurs mostly in Asia. CHOP-like therapy is usually selected, but the prognosis is very poor. This report concerns a 43-year-old woman with newly diagnosed stage IVA MEITL. The patient obtained a partial response after 4 cycles of GDP (gemcitabine, dexamethasone, cisplatin) and achieved a complete response (CR) after cord blood transplantation (CBT) conditioned with total body irradiation, cyclophosphamide, and cytarabine. Seven months after transplantation, the patient experienced cognitive impairment. Magnetic resonance imaging of the brain showed a high-intensity lesion in the right cerebral peduncle and internal capsule. A cerebrospinal fluid examination confirmed central nervous system (CNS) relapse of MEITL. After 3 cycles of MPV (methotrexate, procarbazine, vincristine) followed by whole-brain radiotherapy, her cognitive impairment improved. Due to disease progression, she died 6 months after CNS relapse. Given the CNS relapse after achieving a CR with GDP and CBT in this patient, CNS prophylaxis during first-line therapy may be beneficial in the treatment of MEITL.
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http://dx.doi.org/10.1007/s12185-021-03107-9DOI Listing
July 2021

[Therapy-related acute promyelocytic leukemia with complex karyotype accompanied by cryptic PML/RARA on chromosome 15 by metaphase FISH].

Rinsho Ketsueki 2020 ;61(11):1577-1583

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

A 53-year-old male presented with pancytopenia for 13 months. He had a past history of follicular lymphoma and hypopharyngeal cancer, which was treated via chemotherapy and radiotherapy. Bone marrow aspiration biopsy of the patient revealed a hypocellular marrow with 32% of hypergranular blasts without Auer bodies. There were also erythroid and megakaryocytic dysplasia in the bone marrow. Although the PML/RARA transcript was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR), the G-banding karyotype analysis showed a complex karyotype without t (15;17). The PML/RARA fusion signal was identified on chromosome 15 by metaphase FISH. The patient was diagnosed of therapy-related acute promyelocytic leukemia (t-APL) with cryptic PML/RARA. He successfully attained molecular complete remission with all-trans retinoic acid (ATRA) and two courses of arsenic trioxide (ATO). He was subsequently administered nivolumab without ATRA maintenance therapy because of a progressing metastasis of a hypopharyngeal cancer to the lung. The patient had a relapse of t-APL following nine courses of nivolumab, 8 months after ending consolidation therapy with ATO. Reinduction therapy with ATRA was not effective for the relapsed t-APL that was accompanied by del (5q) and monosomy 7. Little has been previously reported on t-APL with cryptic PML/RARA. Therefore, the clinical course of this patient may provide useful insights about the characteristics of t-APL with cryptic PML/RARA.
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http://dx.doi.org/10.11406/rinketsu.61.1577DOI Listing
February 2021

Tenascin-C in cardiac disease: a sophisticated controller of inflammation, repair, and fibrosis.

Am J Physiol Cell Physiol 2020 11 26;319(5):C781-C796. Epub 2020 Aug 26.

Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.

Tenascin-C (TNC) is a large extracellular matrix glycoprotein classified as a matricellular protein that is generally upregulated at high levels during physiological and pathological tissue remodeling and is involved in important biological signaling pathways. In the heart, TNC is transiently expressed at several important steps during embryonic development and is sparsely detected in normal adult heart but is re-expressed in a spatiotemporally restricted manner under pathological conditions associated with inflammation, such as myocardial infarction, hypertensive cardiac fibrosis, myocarditis, dilated cardiomyopathy, and Kawasaki disease. Despite its characteristic and spatiotemporally restricted expression, TNC knockout mice develop a grossly normal phenotype. However, various disease models using TNC null mice combined with in vitro experiments have revealed many important functions for TNC and multiple molecular cascades that control cellular responses in inflammation, tissue repair, and even myocardial regeneration. TNC has context-dependent diverse functions and, thus, may exert both harmful and beneficial effects in damaged hearts. However, TNC appears to deteriorate adverse ventricular remodeling by proinflammatory and profibrotic effects in most cases. Its specific expression also makes TNC a feasible diagnostic biomarker and target for molecular imaging to assess inflammation in the heart. Several preclinical studies have shown the utility of TNC as a biomarker for assessing the prognosis of patients and selecting appropriate therapy, particularly for inflammatory heart diseases.
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http://dx.doi.org/10.1152/ajpcell.00353.2020DOI Listing
November 2020

CD4 T cells support polyfunctionality of cytotoxic CD8 T cells with memory potential in immunological control of tumor.

Cancer Sci 2020 Jun 12;111(6):1958-1968. Epub 2020 May 12.

Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Japan.

Polyfunctionality/multifunctionality of effector T cells at the single cell level has been shown as an important parameter to predict the quality of T cell response and immunological control of infectious disease and malignancy. However, the fate of polyfunctional CD8 CTLs and the factors that control the polyfunctionality of T cells remain largely unknown. Here we show that the acquisition of polyfunctionality on the initial stimulation is a sensitive immune correlate of CTL survival and memory formation. CD8 T cells with high polyfunctionality, assessed with γ-interferon and tumor necrosis factor-α production and surface mobilization of the degranulation marker CD107a, showed enhanced Bcl-2 expression, low apoptosis, and increased CD127 KLRG1 memory precursor phenotype. Consistent with these observations, CD8 T cells were found to acquire high frequency of cells with polyfunctionality when stimulated in conditions known to enhance memory formation, such as the presence of CD4 T cells, interleukin (IL)-2, or IL-21. Utilizing T-cell receptor (TCR) transgenic mouse-derived CD8 T cells that express a TCR specific for a tumor-derived neoantigen, we showed that polyfunctional tumor-specific CTLs generated in the presence of CD4 T cells showed long persistence in vivo and induced enhanced tumor regression when adoptively transferred into mice with progressing tumor. Acquisition of polyfunctionality thus impacts CTL survival and memory formation associated with immunological control of tumor.
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http://dx.doi.org/10.1111/cas.14420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293103PMC
June 2020

[Successful treatment with a combination of elotuzumab, lenalidomide and dexamethasone of extramedullary disease in a patient with refractory multiple myeloma].

Rinsho Ketsueki 2020 ;61(3):223-227

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

A 56-year-old man diagnosed with multiple myeloma was treated with CBD (cyclophosphamide, bortezomib, and dexamethasone; DEX), which was discontinued because of bortezomib-associated adverse events. Thereafter, he was treated with Ld (lenalidomide; LEN+DEX) followed by high-dose chemotherapy with autologous stem cell rescue, resulting in a complete response. Ld as maintenance therapy was discontinued because of immune thrombocytopenia, resulting in disease progression. Although treatment was switched to Pd (pomalidomide+DEX), DLd (daratumumab+LEN+DEX), and IRd (ixazomib+LEN+DEX); the patient's M protein level continued to increase and the extramedullary disease expanded despite radiotherapy. He was treated with E-Ld (elotuzumab+LEN+DEX) after 3 cycles of short VAD (vincristine, doxorubicin, and DEX). The extramedullary disease disappeared after 8 cycles of E-Ld. To the best of our knowledge, this is the first report showing the effectiveness of E-Ld treatment for extramedullary disease of a heavily treated patient for multiple myeloma. We believe that the clinical course of this patient provides useful insights about the antimyeloma mechanism of elotuzumab.
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http://dx.doi.org/10.11406/rinketsu.61.223DOI Listing
May 2020

Genetic polymorphisms and vincristine-induced peripheral neuropathy in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy.

Int J Hematol 2020 May 28;111(5):686-691. Epub 2020 Jan 28.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Vincristine (VCR)-induced peripheral neuropathy (VIPN) is a common and life-long toxicity in lymphoma patients receiving current standard chemotherapy. The association between VIPN and genetic polymorphisms is largely unknown in adult lymphoma patients. To examine the possible relationship between known genetic polymorphisms in patients with pediatric acute lymphoblastic leukemia and incidence of VIPN in adult patients with B cell lymphoma, we examined CEP72 rs924607, ETAA1 rs17032980, MTNR1B rs12786200, CYP3A5 rs776746, rs7963521, and rs1045644 genetic polymorphisms in samples from 56 adult patients with B-cell lymphoma who received rituximab, cyclophosphamide, doxorubicin, VCR, and prednisone (R-CHOP) chemotherapy. Mutation analysis was performed by direct sequencing. The median age was 65 years (range 30-79). The median cumulative dose of VCR was 12 mg (range 2-16). VIPN was documented in 42 patients (75%), and 9 (16%) had grade 2-4 VIPN. Age, impaired glucose tolerance, number of cycles of R-CHOP, and VCR cumulative dose were not associated with incidence of VIPN. There was no association between the incidence of grade 2-4 or any grade VIPN and these six genetic polymorphisms. These results indicate that CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 genetic polymorphisms are not associated with VIPN in patients with B-cell lymphoma who received R-CHOP.
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http://dx.doi.org/10.1007/s12185-020-02832-xDOI Listing
May 2020

Achievement of long-term remission of disseminated histoplasmosis in an AIDS patient.

Med Mycol Case Rep 2020 Mar 19;27:25-28. Epub 2019 Dec 19.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.

Histoplasmosis, a fungal infection caused by , is poor prognosis once it disseminated, especially in immunocompromised patients. A 50-year-old Japanese-Brazilian male with multiple cervical lymphadenopathies was diagnosed as disseminated histoplasmosis and acquired immunodeficiency syndrome (AIDS). Anti-fungal therapy was initiated followed by anti-retroviral therapy (ART). He achieved long-term remission by treatment with voriconazole. Here we report a case of an AIDS patient with disseminated histoplasmosis who achieved long-term survival in non-endemic area.
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http://dx.doi.org/10.1016/j.mmcr.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938860PMC
March 2020

Concomitant febuxostat enhances methotrexate-induced hepatotoxicity by inhibiting breast cancer resistance protein.

Sci Rep 2019 12 30;9(1):20359. Epub 2019 Dec 30.

Department of Pharmacy, Osaka University Hospital, Suita, Osaka, 565-0871, Japan.

Methotrexate (MTX) is an antifolate agent used for the treatment of various malignancies and is eliminated by breast cancer resistance protein (BCRP). Because febuxostat (FBX) is known to inhibit BCRP activity, FBX might exacerbate MTX-related adverse effects. In this study, we examined the drug-drug interaction between FBX and MTX in BCRP-expressing membrane vesicles. Moreover, we retrospectively investigated the impact of FBX on MTX-related adverse effects in 38 patients (144 cycles) receiving high-dose MTX therapy (HDMTX). The Food and Drug Administration Adverse Event Reporting System (FAERS) database and human hepatocellular carcinoma cell line HepG2 cells were used to evaluate the effects of FBX on MTX-induced hepatotoxicity. In the membrane vesicle study, FBX significantly inhibited BCRP-mediated transport of MTX. Concomitant FBX significantly increased the incidence of hepatotoxicity, but not of nephrotoxicity and hematological toxicity in patients receiving HDMTX. FAERS database analyses revealed that the reporting odds ratio of FBX for MTX-induced hepatotoxicity was 4.16 (95% CI: 2.89-5.98). Co-incubated FBX significantly decreased the cell viability and increased cytotoxicity in MTX-treated HepG2 cells. These findings suggest that concomitant FBX enhances MTX-induced hepatotoxicity by inhibiting hepatic BCRP. These findings provide important information for the safe management of HDMTX therapy in clinical settings.
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http://dx.doi.org/10.1038/s41598-019-56900-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937279PMC
December 2019

Life-Threatening Tongue and Retropharyngeal Hemorrhage in a Patient with Hemophilia A with Inhibitors.

Am J Case Rep 2019 Jul 15;20:1022-1026. Epub 2019 Jul 15.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

BACKGROUND Massive tongue hemorrhage in patients with hemophilia is a medical emergency because it can lead to airway obstruction. However, managing bleeding in patients with inhibitors is more difficult than in patients without inhibitors. We report a case of life-threatening massive tongue and retropharyngeal hematoma in a patient with hemophilia A who had inhibitors. CASE REPORT The patient was a 71-year-old man with severe hemophilia A with high-responding inhibitors. He was admitted to our hospital with dysarthria and dysphagia secondary to a massive tongue hematoma. Although bypassing therapy was started immediately after admission, he rapidly developed an airway obstruction and cardiopulmonary arrest secondary to suffocation. Cardiopulmonary resuscitation and surgical cricothyrotomy were performed, which restored his pulse and breathing. On day 5 of hospitalization, he underwent tracheotomy under inhibitor-neutralizing therapy, and we began emicizumab on day 19 of hospitalization to prevent further bleeding events. He recovered and was transferred to another hospital for rehabilitation on day 64 of hospitalization. CONCLUSIONS Because tongue hematomas progress dramatically within a few days, prompt airway maintenance by tracheotomy under appropriate hemostatic therapy must be considered. Furthermore, emicizumab induction after primary hemostasis prevents further bleeding. We suggest that initiating emicizumab therapy is a good choice to prevent further bleeding after critical bleeding events if the patient has not received the drug previously.
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http://dx.doi.org/10.12659/AJCR.916151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647615PMC
July 2019

Infiltrating CCR2 monocytes and their progenies, fibrocytes, contribute to colon fibrosis by inhibiting collagen degradation through the production of TIMP-1.

Sci Rep 2019 06 12;9(1):8568. Epub 2019 Jun 12.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.

Intestinal fibrosis is a serious complication in inflammatory bowel disease (IBD). Despite the remarkable success of recent anti-inflammatory therapies for IBD, incidence of intestinal fibrosis and need for bowel resection have not significantly changed. To clarify the contribution of haematopoietic-derived cells in intestinal fibrosis, we prepared bone marrow (BM) chimeric mice (chimeras), which were reconstituted with BM cells derived from enhanced green fluorescent protein (EGFP)-transgenic mice or CC chemokine receptor 2 (CCR2)-deficient mice. After 2 months of transplantation, BM chimeras were treated with azoxymethane/dextran sodium sulphate. During chronic inflammation, CCR2 BM-derived monocyte and fibrocyte infiltration into the colon and CC chemokine ligand 2 production increased, leading to colon fibrosis in EGFP BM chimeras. In CCR2-deficient BM chimeras, monocyte and fibrocyte numbers in the colonic lamina propria significantly decreased, and colon fibrosis was attenuated. In colon tissue, mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 but not of collagen I, transforming growth factor-β1 or matrix metalloproteinases was significantly different between the two chimeras. CCR2 monocytes and fibrocytes showed high Timp1 mRNA expression. Our results suggest that infiltrating CCR2 monocytes and their progenies, fibrocytes, promote colon fibrosis by inhibiting collagen degradation through TIMP-1 production.
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http://dx.doi.org/10.1038/s41598-019-45012-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562037PMC
June 2019

A population of CD20CD27CD43CD38 B1 cells in PNH are missing GPI-anchored proteins and harbor mutations.

Blood 2019 07 21;134(1):89-92. Epub 2019 May 21.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan; and.

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http://dx.doi.org/10.1182/blood.2019001343DOI Listing
July 2019

Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance.

J Clin Invest 2019 03 11;129(3):1278-1294. Epub 2019 Feb 11.

Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.

Immune checkpoint inhibitors and adoptive transfer of gene-engineered T cells have emerged as novel therapeutic modalities for hard-to-treat solid tumors; however, many patients are refractory to these immunotherapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. By comparing the tumor microenvironment of checkpoint inhibition-sensitive and -resistant murine solid tumors, we observed that the resistant tumors had low immunogenicity. We identified antigen presentation by CD11b+F4/80+ tumor-associated macrophages (TAMs) as a key factor correlated with immune resistance. In the resistant tumors, TAMs remained inactive and did not exert antigen-presenting activity. Targeted delivery of a long peptide antigen to TAMs by using a nano-sized hydrogel (nanogel) in the presence of a TLR agonist activated TAMs, induced their antigen-presenting activity, and thereby transformed the resistant tumors into tumors sensitive to adaptive immune responses such as adoptive transfer of tumor-specific T cell receptor-engineered T cells. These results indicate that the status and function of TAMs have a significant impact on tumor immune sensitivity and that manipulation of TAM functions would be an effective approach for improving the efficacy of immunotherapies.
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http://dx.doi.org/10.1172/JCI97642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391090PMC
March 2019

Expression of CD25 fluctuates in the leukemia-initiating cell population of CD25-positive AML.

PLoS One 2018 14;13(12):e0209295. Epub 2018 Dec 14.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

CD25 is expressed on leukemic cells in 10-20% cases of acute myeloid leukemia (AML), and its expression is associated with poor prognosis. We reevaluated the relationship between CD25 expression and the leukemia-initiating cell (LIC) properties of AML using a patient-derived xenograft model. We divided lineage marker-negative (Lin-) CD34+CD38- or Lin-CD34+ cells from CD25-positive AML into CD25-positive and -negative populations, and then transplanted each population into NOD.Cg-PrkdcscidIl2rgtm1Wjl/Sz mice. Leukemic engraftment was observed with both CD25-positive and -negative populations from three of nine CD25-positive AML patients. In two of those three patients, CD25-positive and -negative Lin-CD34+ cells engrafted at the primary transplantation led to leukemic engraftment at the secondary transplantation, in which engrafted cells contained both CD25-positive and -negative Lin-CD34+ AML cells. In an in vitro culture system, expression of CD25 was considerably induced in the CD25-negative population of Lin-CD34+ cells from two cases of CD25-positive AML. In one case, CD25-positive Lin-CD34+ cells gave rise to CD25-negative as well as -positive CD34+ cells. These observations suggest that there exist CD25-positive and -negative populations that can reconstitute CD25-positive AML in a patient-derived xenograft model, and that CD25 expression fluctuates in the LICs of AML.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209295PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294374PMC
May 2019

Murine Models of Steroid Refractory Graft-versus-Host Disease.

Sci Rep 2018 08 20;8(1):12475. Epub 2018 Aug 20.

Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.

Corticosteroids are the first line therapy for acute graft-versus-host disease (GVHD). However, the outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack of effective treatments. The development of therapies for SR-GVHD is limited by an incomplete understanding of its pathophysiology partly because of the absence of clinically relevant animal models of SR-GVHD. Here we addressed the need for a SR-GVHD animal model by developing both MHC matched multiple minor histocompatibility antigens (miHAs) mismatched and MHC mismatched haploidentical murine models of SR-GVHD. We demonstrate that animals can develop SR-GVHD regardless of whether steroids are initiated early or late post allogeneic bone marrow transplantation (allo-BMT). In general, we observed increased GVHD specific histopathological damage of target organs in SR-GVHD animals relative to steroid responsive animals. Interestingly, we found no significant differences in donor T cell characteristics between steroid refractory and responsive animals suggesting that donor T cell independent mechanisms may play more prominent roles in the pathogenesis of SR-GVHD than was considered previously.
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http://dx.doi.org/10.1038/s41598-018-30814-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102256PMC
August 2018

Renal papillary tip extract stimulates BNP production and excretion from cardiomyocytes.

PLoS One 2018 7;13(5):e0197078. Epub 2018 May 7.

Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Background: Brain natriuretic peptide (BNP) is an important biomarker for patients with cardiovascular diseases, including heart failure, hypertension and cardiac hypertrophy. It is also known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease; however, the mechanism remains unclear.

Methods And Results: We developed a BNP reporter mouse and occasionally found that this promoter was activated specifically in the papillary tip of the kidneys, and its activation was not accompanied by BNP mRNA expression. No evidence was found to support the existence of BNP isoforms or other nucleotide expression apart from BNP and tdTomato. The pBNP-tdTomato-positive cells were interstitial cells and were not proliferative. Unexpectedly, both the expression and secretion of BNP increased in primary cultured neonatal cardiomyocytes after their treatment with an extract of the renal papillary tip. Intraperitoneal injection of the extract of the papillary tips reduced blood pressure from 210 mmHg to 165 mmHg, the decrease being accompanied by an increase in serum BNP and urinary cGMP production in stroke-prone spontaneously hypertensive (SHR-SP) rats. Furthermore the induction of BNP by the papillary extract from rats with heart failure due to myocardial infarction was increased in cardiomyocytes.

Conclusions: These results suggested that the papillary tip express a substance that can stimulate BNP production and secretion from cardiomyocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937764PMC
August 2018

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers.

Oncotarget 2018 Mar 16;9(19):14909-14921. Epub 2018 Feb 16.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.

The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased ( = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration ( = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.
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http://dx.doi.org/10.18632/oncotarget.24504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871086PMC
March 2018

[Atypical hemolytic uremic syndrome with C3 p.I1157T missense mutation successfully treated with eculizumab].

Rinsho Ketsueki 2018;59(2):178-181

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

A 23-year-old man from Mie Prefecture, Japan, with past and family history of hematuria was diagnosed with influenza A and admitted to our hospital on the following day because of hemoglobinuria. He was diagnosed with thrombotic microangiopathy and was suspected of having atypical hemolytic uremic syndrome (aHUS). C3 p.I1157T missense mutation, which we had previously reported in eight aHUS patients from six families in Mie Prefecture, was identified. The laboratory findings and symptoms of our patient promptly improved after administering eculizumab. Little information is available on abnormalities of the complement system in aHUS or on mutation-specific outcomes of eculizumab therapy. Eculizumab was effective for treating our aHUS patient with C3 p.I1157T missense mutation.
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http://dx.doi.org/10.11406/rinketsu.59.178DOI Listing
February 2019

Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS.

Blood 2017 11 31;130(18):1985-1994. Epub 2017 Aug 31.

Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.

Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.
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http://dx.doi.org/10.1182/blood-2017-06-791202DOI Listing
November 2017

CXCL12-CXCR4 Axis Is Required for Contact-Mediated Human B Lymphoid and Plasmacytoid Dendritic Cell Differentiation but Not T Lymphoid Generation.

J Immunol 2017 10 25;199(7):2343-2355. Epub 2017 Aug 25.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.

We investigated the involvement of CXCL12-CXCR4 interactions in human lymphohematopoiesis by coculture with telomerized human stromal cells. CXCR4 expression was low in CD34CD38CD45RACD10CD7CD19 immature hematopoietic stem/precursor cells (HSPCs) but higher in CD34CD38CD45RACD10CD7CD19 early lymphoid precursors and even higher in CD34CD38CD45RACD10CD7CD19 pro-B cells. Inhibition of the effect of stromal cell-produced CXCL12 by an anti-CXCR4-blocking Ab suppressed the generation of CD45RACD10CD7CD19 early T lymphoid precursors (ETPs) and CD45RACD10CD7CD19 B lymphoid precursors on stromal cells, but it did not affect the generation of ETPs in conditioned medium of stromal cell cultures. Replating assays showed that contact with stromal cells was critical for HSPC-derived CD45RACD10CD7CD19 B lineage-biased precursors to differentiate into CD19 pro-B cells, which was suppressed by the anti-CXCR4 Ab. Conversely, HSPC-derived ETPs possessed T and B lymphoid and monocytic differentiation potential; stromal cell contact was not required for their growth but rather promoted B lymphoid differentiation. The anti-CXCR4 Ab did not affect the growth of ETPs in conditioned medium, but it suppressed their B lymphoid differentiation on stromal cells. CD14CD11cHLA-DRCD123CD303 plasmacytoid dendritic cells developed from HSPCs and ETPs exclusively in contact with stromal cells, which was suppressed by the anti-CXCR4 Ab. These data indicate that CXCL12 plays an essential role in stromal cell contact-mediated B lymphoid and plasmacytoid dendritic cell differentiation from immature hematopoietic and early T lymphoid precursors with a multilineage differentiation potential, but it does not participate in contact-independent generation of early T lymphoid precursors.
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http://dx.doi.org/10.4049/jimmunol.1700054DOI Listing
October 2017

Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation.

Oncotarget 2017 May;8(19):30766-30780

Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.

Long-surviving memory CD8+ T cells generated by stimulation with appropriate tumor-associated antigens are the most aggressive and persistent tumoricidal effectors. In this event of memory CD8+ T cell development, the signal transducer and activator of transcription (STAT) proteins function as the crucial intracellular signaling molecules, but the regulatory mechanism of STATs in CD8+ T cells is not fully understood. In this study, we report for the first time, by using murine vaccination models, that signal-transducing adaptor protein-2 (STAP2) maintains the cytotoxicity of long-lived memory CD8+ T cells by controlling a STAT3/suppressor of cytokine signaling 3 (SOCS3) cascade. Following T cell activation, STAP2 expression was transiently reduced but was subsequently recovered and augmented. Analysis using small-interfering RNA (siRNA) demonstrated that restored STAP2 expression was associated with the activation of STAT3/SOCS3 signals and maintenance of cytotoxic T lymphocytes (CTLs) secondary responses by preventing their differentiation into terminal effector cells. Notably, this STAP2-dependent memory differentiation was observed in the spleen, but not in the lymph nodes (LNs). These findings indicate an essential role for STAP2 in the generation of a high-quality memory CD8+ CTLs periphery, and suggest the therapeutic potential of STAP2 in cancer patients.
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http://dx.doi.org/10.18632/oncotarget.15403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458166PMC
May 2017

MYD88, CD79B, and CARD11 gene mutations in CD5-positive diffuse large B-cell lymphoma.

Cancer 2017 04 4;123(7):1166-1173. Epub 2016 Dec 4.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

Background: CD5-positive (CD5 ) diffuse large B-cell lymphoma (DLBCL) is characterized by frequent central nervous system recurrence and a predominant activated B-cell-like nature. Primary DLBCL in sanctuary sites (DLBCL-SS) also demonstrates these features, and >70% of patients harbor myeloid differentiation primary response 88 (MYD88) (L265P) and CD79B mutations. The objective of the current study was to elucidate a possible relationship between CD5 DLBCL and DLBCL-SS.

Methods: MYD88, CD79B, CD79A, and caspase recruitment domain family member 11 (CARD11) mutations were examined in samples from 40 patients with CD5 DLBCL. Mutation analysis was performed by direct sequencing.

Results: MYD88 and CD79B mutations were detected in 33% (13 patients) and 38% (15 patients), respectively, of the 40 patients with CD5 DLBCL. Ten patients had these 2 gene mutations, and 1 had a CD79A mutation. One of 2 patients with testicular involvement had both MYD88 and CD79B mutations. The other patient had a MYD88 mutation alone. None of the 31 patients examined was found to have a CARD11 mutation. MYD88 and CD79B mutations were found to be associated with localized disease (P = .038 and P = .003, respectively). Primary extranodal lymphoma was associated with higher frequencies of mutations in MYD88 or both MYD88 and CD79B (P = .008 and P = .014, respectively). There was no significant difference in overall survival based on MYD88 and CD79B mutation status.

Conclusions: The incidence of MYD88 and CD79B mutations in patients with CD5 DLBCL is lower than that in patients with DLBCL-SS, suggesting that CD5 DLBCL is not the same disease as DLBCL-SS in terms of gene mutation status. CARD11 mutations are rare in patients with CD5 DLBCL. Cancer 2017;123:1166-1173. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30404DOI Listing
April 2017

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects.

JCI Insight 2016 07 7;1(10):e86331. Epub 2016 Jul 7.

Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.
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http://dx.doi.org/10.1172/jci.insight.86331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033881PMC
July 2016

ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease.

Sci Transl Med 2015 Oct;7(308):308ra160

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We previously identified high plasma soluble suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and death. sST2 sequesters interleukin-33 (IL-33), limiting its availability to T cells expressing membrane-bound ST2 (mST2) [T helper 2 (TH2) cells and ST2(+)FoxP3(+) regulatory T cells]. We report that blockade of sST2 in the peritransplant period with a neutralizing monoclonal antibody (anti-ST2 mAb) reduced GVHD severity and mortality. We identified intestinal stromal cells and T cells as major sources of sST2 during GVHD. ST2 blockade decreased systemic interferon-γ, IL-17, and IL-23 but increased IL-10 and IL-33 plasma levels. ST2 blockade also reduced sST2 production by IL-17-producing T cells while maintaining protective mST2-expressing T cells, increasing the frequency of intestinal myeloid-derived suppressor cells, and decreasing the frequency of intestinal CD103 dendritic cells. Finally, ST2 blockade preserved graft-versus-leukemia activity in a model of green fluorescent protein (GFP)-positive MLL-AF9 acute myeloid leukemia. Our findings suggest that ST2 is a therapeutic target for severe GVHD and that the ST2/IL-33 pathway could be investigated in other T cell-mediated immune disorders with loss of tolerance.
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http://dx.doi.org/10.1126/scitranslmed.aab0166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699312PMC
October 2015

Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans.

Blood 2015 Jan 26;125(5):815-9. Epub 2014 Nov 26.

Department of Internal Medicine, Division of Hematology-Oncology, Blood and Marrow Transplantation Program, and.

We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced proinflammatory cytokine levels in plasma and from PBMCs and decreased ex vivo responses of PBMCs to proinflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells to nonspecific stimuli. However, the numbers of regulatory T cells (Tregs) were increased, which revealed greater demethylation of the Foxp3 T regulatory-specific demethylation region. Vorinostat-treated patients showed increased expression of CD45RA and CD31 on Tregs, and these Tregs demonstrated greater suppression on a per cell basis. Consistent with preclinical findings, HDAC inhibition also increased signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase. Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT.
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http://dx.doi.org/10.1182/blood-2014-10-605238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311228PMC
January 2015

Interleukin-17 induces an atypical M2-like macrophage subpopulation that regulates intestinal inflammation.

PLoS One 2014 25;9(9):e108494. Epub 2014 Sep 25.

Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Interleukin 17 (IL-17) is a pleiotropic cytokine that acts on both immune and non-immune cells and is generally implicated in inflammatory and autoimmune diseases. Although IL-17 as well as their source, mainly but not limited to Th17 cells, is also abundant in the inflamed intestine, the role of IL-17 in inflammatory bowel disease remains controversial. In the present study, by using IL-17 knockout (KO) mice, we investigated the role of IL-17 in colitis, with special focus on the macrophage subpopulations. Here we show that IL-17KO mice had increased susceptibility to DSS-induced colitis which was associated with decrease in expression of mRNAs implicated in M2 and/or wound healing macrophages, such as IL-10, IL-1 receptor antagonist, arginase 1, cyclooxygenase 2, and indoleamine 2,3-dioxygenase. Lamina propria leukocytes from inflamed colon of IL-17KO mice contained fewer CD11b+Ly6C+MHC Class II+ macrophages, which were derived, at least partly, from blood monocytes, as compared to those of WT mice. FACS-purified CD11b+ cells from WT mice, which were more abundant in Ly6C+MHC Class II+ cells, expressed increased levels of genes associated M2/wound healing macrophages and also M1/proinflammatory macrophages. Depletion of this population by topical administration of clodronate-liposome in the colon of WT mice resulted in the exacerbation of colitis. These results demonstrate that IL-17 confers protection against the development of severe colitis through the induction of an atypical M2-like macrophage subpopulation. Our findings reveal a previously unappreciated mechanism by which IL-17 exerts a protective function in colitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177893PMC
December 2015

Splenectomy increases the number of circulating hematopoietic stem/progenitor cells in patients with hepatitis C virus-associated liver cirrhosis.

Hepatol Res 2014 Dec 25;44(14):E376-E385. Epub 2014 Mar 25.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

Aim: The spleen is not believed to contribute to hematopoiesis in healthy adults. However, several reports have demonstrated that the spleen in adults contains a large number of hematopoietic stem/progenitor cells (HSC). Although splenectomy increases platelet and leukocyte counts, the effects of splenectomy on circulating HSC have not been elucidated. In this study, we evaluated the association between the number of circulating HSC and splenectomy in patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC).

Methods: In 48 patients with various stages of HCV-associated chronic liver disease and seven patients with LC who underwent splenectomy, and 10 healthy volunteers, we determined the numbers of circulating CD34 cells and colony-forming unit culture by flow cytometry and methylcellulose culture, respectively. Plasma stromal cell-derived factor-1α (SDF-1α) concentrations were measured using an enzyme-linked immunosorbent assay.

Results: The numbers of circulating CD34 cells and colony-forming unit culture decreased but the plasma SDF-1α concentration increased with the progression of liver disease. There was an inverse correlation between the number of circulating HSC and the plasma SDF-1α concentration. The numbers of circulating HSC and platelets were determined before and after splenectomy in seven patients with LC. In these patients, the numbers of circulating HSC and platelets increased significantly after splenectomy and the enhancing effect persisted for a long time.

Conclusion: Our data suggest that the spleen plays an important role in modulating HSC dynamics in patients with HCV-associated chronic liver disease. Our results also imply that splenectomy may improve liver function in patients with LC.
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http://dx.doi.org/10.1111/hepr.12319DOI Listing
December 2014

Monocytes infiltrate the pancreas via the MCP-1/CCR2 pathway and differentiate into stellate cells.

PLoS One 2014 8;9(1):e84889. Epub 2014 Jan 8.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)(+)CD45(-) cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP(+)CD45(-) cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and α-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP(+) PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6C(high) monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP(+)F4/80(+)CCR2(+) monocytic cells and EGFP(+) PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP(+) bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP(+) PaSCs in injured mice. We propose that CCR2(+) monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084889PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885670PMC
September 2014
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