Publications by authors named "Muneo Inaba"

69 Publications

Treg and IL-1 receptor type 2-expressing CD4 T cell-deleted CD4 T cell fraction prevents the progression of age-related hearing loss in a mouse model.

J Neuroimmunol 2021 Aug 8;357:577628. Epub 2021 Jun 8.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, Osaka, Japan.

We investigated the association between cellular immunity and age-related hearing loss (ARHL) development using three CD4 T cell fractions, namely, naturally occurring regulatory T cells (Treg), interleukin 1 receptor type 2-expressing T cells (I1R2), and non-Treg non-I1R2 (nTnI) cells, which comprised Treg and I1R2-deleted CD4 T cells. Inoculation of the nTnI fraction into a ARHL murine model, not only prevented the development of ARHL and the degeneration of spiral ganglion neurons, but also suppressed serum nitric oxide, a source of oxidative stress. Further investigations on CD4 T cell fractions could provide novel insights into the prevention of aging, including presbycusis.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577628DOI Listing
August 2021

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells.

Arthritis Res Ther 2020 11 9;22(1):264. Epub 2020 Nov 9.

First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka, 573-1010, Japan.

Background: Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs.

Methods: We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production.

Results: We found that treatment with 1-10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.

Conclusions: Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.
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http://dx.doi.org/10.1186/s13075-020-02356-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654586PMC
November 2020

Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses.

Blood Adv 2020 08;4(15):3572-3585

First Department of Internal Medicine, Kansai Medical University, Shinmachi, Hirakata City, Osaka, Japan.

Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.
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http://dx.doi.org/10.1182/bloodadvances.2019001410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422102PMC
August 2020

Widespread time-dependent changes in tissue cytokine concentrations in brain regions during the acute phase of endotoxemia in mice.

Neurotoxicology 2020 01 16;76:67-74. Epub 2019 Oct 16.

Pathology Research Team, Faculty of Health Sciences, Kyorin University, 5-4-1 Shimorenjaku, Mitaka, Tokyo, 181-8612, Japan; Central Hospital, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan. Electronic address:

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction induced by the systemic response to infection in septic patients. In the present study, we modeled SAE by administering lipopolysaccharide (LPS) intraperitoneally to mice at a concentration of 3.0 mg/kg. We investigated regional preferences for cytokine-mediated brain reactions to endotoxemia and at what time point brain inflammation begins, as well as what cytokines are involved in acute brain reactions. Brains were divided into seven parts: cortex (CTX), olfactory system (Olf), hippocampus (Hip), striatum (Str), diencephalon (Die), brain stem (BS), and cerebellum (CBL). In each brain region, we determined the tissue concentrations of 11 cytokines: CCL2, CCL3, CCL11, CXCL1, CXCL2, CXCL9, CXCL10, G-CSF, IL-1β, IL-6, and TNF-α, in mice injected with LPS or saline, at 1, 4, and 24 h after injection using multiplex cytokine assays. Every brain region responded with the production of multiple cytokines to LPS-induced systemic inflammation during the acute phase (4-24 h) after LPS injection. IL-6, CCL2, CCL3, CXCL1, CXCL2, CXCL9, and TNF-α were "early cytokines" that increased only at 4 h but not at 24 h after LPS injection in most brain regions. CCL11, CXCL10, and G-CSF were "late cytokines" that were elevated up to 24 h after LPS injection in selected brain regions. The regions Olf, Hip, and Die were the most responsive to endotoxemia; these regions produced ten cytokines and continued to produce three "late cytokines" up to 24 h after LPS injection. Str was the least responsive to endotoxemia. The widespread nature of brain cytokine production explains the characteristics of SAE. Further studies on the roles of CCL11, CXCL10, and G-CSF may be especially important in terms of potential prevention of SAE between 4 and 24 h after the onset of sepsis.
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http://dx.doi.org/10.1016/j.neuro.2019.10.006DOI Listing
January 2020

The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells.

J Blood Med 2019 12;10:217-226. Epub 2019 Jul 12.

Kansai Medical University, First Department of Internal Medicine, Osaka, Japan.

Lenalidomide (LEN), an immunomodulatory drug (IMiD), is currently used for treatment of multiple myeloma (MM). LEN potentiates T cell and natural killer cell functions. However, the cellular and molecular mechanisms underlying the immunomodulatory effects of LEN remain unclear. We focused on the effects of LEN on human plasmacytoid dendritic cells (pDCs), which are the major source of interferon (IFN)-α in the blood and play a central role in innate immune responses. We found that bortezomib, a proteasome inhibitor used to treat MM, killed pDCs but that 0.1-3 μM LEN (covering clinical plasma concentration range) did not affect pDC survival or CD86 expression. Bortezomib inhibited pDC-derived IFN-α production in a dose-dependent fashion, but 0.1-3 µM LEN sustained pDC-derived IFN-α production when stimulated with an optimal concentration of CpG-ODN 2216 (3 μM). In pDCs stimulated with a low concentration of CpG-ODN (0.1 μM), LEN enhanced IFN-α production. These results indicated that LEN, when used at a clinically relevant concentration, can potentially enhance IFN-α production by pDCs. Collectively, our findings unveiled a novel target of LEN and extend the repertoire of the drug's known immunomodulatory effects. These effects may explain the low incidence of herpes zoster viral infection observed during LEN treatment compared with bortezomib treatment. LEN may function as an IMiD affecting a wide array of immune cells, including pDCs, leading to amplification of a positive immune axis able to eliminate MM cells.
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http://dx.doi.org/10.2147/JBM.S206459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635835PMC
July 2019

Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression.

Eur J Immunol 2019 11 11;49(11):2051-2062. Epub 2019 Jul 11.

First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.

DCs and epithelial cell-derived thymic stromal lymphopoietin (TSLP) have pivotal roles in allergic inflammation. TSLP stimulates myeloid DCs to express OX40-ligand (OX40L) and CCL17, which trigger and maintain Th2 cell responses. We have previously shown that statins, which are HMG-CoA reductase inhibitors, have the ability to suppress type I IFN production by plasmacytoid DCs. Here, we extended our previous work to examine the immunomodulatory effect of statins on allergic responses, particularly the TSLP-dependent Th2 pathway induced by myeloid DCs. We found that treatment of TSLP-stimulated DCs with either pitavastatin or simvastatin suppressed both the DC-mediated inflammatory Th2 cell differentiation and CRTH2 CD4 memory Th2 cell expansion and also repressed the expressions of OX40L and CCL17 by DCs. These inhibitory effects of statins were mimicked by treatment with either a geranylgeranyl-transferase inhibitor or Rho-kinase inhibitor and were counteracted by the addition of mevalonate, suggesting that statins induce geranylgeranylated Rho inactivation through a mevalonate-dependent pathway. We also found that statins inhibited the expressions of phosphorylated STA6 and NF-κB-p50 in TSLP-stimulated DCs. This study identified a specific ability of statins to control DC-mediated Th2 responses, suggesting their therapeutic potential for treating allergic diseases.
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http://dx.doi.org/10.1002/eji.201847992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899642PMC
November 2019

Activation of Dendritic Cells in Dry Eye Mouse Model.

Invest Ophthalmol Vis Sci 2018 07;59(8):3269-3277

Department of Ophthalmology, Nara Medical University, Nara, Japan.

Purpose: The immune system plays a major role in the pathogenesis of dry eye diseases (DED), and dendritic cells (DCs) are known to be important initiators of acquired immunity. Thus, the purpose of this study was to determine the contribution of DCs to the development of DED.

Methods: Mouse dry eye model was induced by subcutaneous injections of scopolamine and was euthanized at the baseline, and 2, 4, and 7 days postinjection. The activation of the DCs was determined by the mixed leukocyte reaction (MLR), and the number of activated CD86+ DCs in the lymph nodes was determined by flow cytometry. Upregulation of cytokines in the culture supernatant of MLR was determined by ELISA.

Results: Significantly increased superficial corneal punctate lesions and decreased number of goblet cells in the conjunctiva were observed in scopolamine-injected mice. The number of activated CD86+ DCs was significantly increased in the cervical lymph nodes but not in the inguinal lymph nodes of the dry eye mice. The stimulatory activity of the DCs derived from the cervical lymph nodes of dry eye mice was significantly higher than that of control mice, and upregulations of IL-17, IL-2, and IL-4 were observed in the culture supernatant of MLR. These results indicate that the DCs of the cervical lymph nodes were activated by the scopolamine injections.

Conclusions: Our results indicate that DCs in our dry eye model were sufficiently activated to stimulate the T cells that participate in the onset and progression of DED.
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http://dx.doi.org/10.1167/iovs.17-22550DOI Listing
July 2018

Induction of PIR-A/B DCs in the in vitro inflammatory condition and their immunoregulatory function.

J Gastroenterol 2018 Oct 5;53(10):1131-1141. Epub 2018 Mar 5.

Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka, 573-1191, Japan.

Background: Dendritic cells (DCs), primary antigen-presenting cells, are now well known as an immunoregulator of many aspects of immune responses including inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis. We have reported that PIR-A/B cDCs (conventional DCs) appeared in dextran sodium sulfate (DSS)-induced colitis and serve as a negative immunoregulator in an animal model of IBD. The immunoregulatory role of PIR-A/B cDCs was confirmed in both an in vitro culture system and an in vivo transfer experiment. Here, we have investigated the differentiation process of PIR-A/B cDCs in an in vitro inflammatory environment and examined their functions.

Methods: cDCs were isolated from the large intestinal lamina propria from C57BL/6 mice and cultured in an inflammatory environment (IL-1, IL-6, TNFα, and LPS). The appearance of PIR-A/B cDCs was determined after 24 h, and the in vitro-induced PIR-A/B cDCs were functionally and genetically examined.

Results: PIR-A/B cDCs were detected after a 24-h culture only in the inflammatory environment, and the cells acted as a negative immunoregulator when examined in an allogenic mixed leukocyte reaction (MLR). The message level of IL-27 was highly upregulated in PIR-A/B cDCs, while that of high mobility group box 1 protein (HMGB1) was downregulated in these cells. This was well in accordance with the fact that PIR-A/B cDCs showed a suppressive function against activated T cells. We found that PIR-A/B cDCs produced IL-27, as verified by an ELISA assay, and that the inhibitory effect by PIR-A/B cDCs was, at least partially, due to IL-27. Furthermore, CD85d cells, a human counterpart of mouse PIR-A/B cDCs, were found in the lamina propria of the colon of the patients with ulcerative colitis, but not in the similar part of the non-inflammatory area of colon specimens from patients with colon cancer.

Conclusions: PIR-A/B cDCs induced in an in vitro inflammatory environment model showed a suppressive function against activated T cells by producing an inhibitory cytokine.
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http://dx.doi.org/10.1007/s00535-018-1447-1DOI Listing
October 2018

Endotoxemia-induced cytokine-mediated responses of hippocampal astrocytes transmitted by cells of the brain-immune interface.

Sci Rep 2016 05 5;6:25457. Epub 2016 May 5.

Department of Pathology and Laboratory Medicine, Central Hospital, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392, Japan.

Systemic inflammation shifts the brain microenvironment towards a proinflammatory state. However, how peripheral inflammation mediates changes in the brain remains to be clarified. We aimed to identify hippocampal cells and cytokines that respond to endotoxemia. Mice were intraperitoneally injected with lipopolysaccharide (LPS) or saline, and examined 1, 4, and 24 h after injection. Tissue cytokine concentrations in the spleens and hippocampi were determined by multiplex assays. Another group of mice were studied immunohistologically. Fourteen cytokines showed an increased concentration in the spleen, and 10 showed an increase in the hippocampus after LPS injection. Cytokines increased at 4 h (CCL2, CXCL1, CXCL2, and interleukin-6) were expressed by leptomeningeal stromal cells, choroid plexus stromal cells, choroid plexus epithelial cells, and hippocampal vascular endothelial cells, all of which were located at the brain-immune interface. Receptors for these cytokines were expressed by astrocytic endfeet. Cytokines increased at 24 h (CCL11, CXCL10, and granulocyte-colony stimulating factor) were expressed by astrocytes. Cells of the brain-immune interface therefore respond to endotoxemia with cytokine signals earlier than hippocampal parenchymal cells. In the parenchyma, astrocytes play a key role in responding to signals by using endfeet located in close apposition to the interface cells via cytokine receptors.
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http://dx.doi.org/10.1038/srep25457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857737PMC
May 2016

Fetal thymus graft enables recovery from age-related hearing loss and expansion of CD4-Positive T cells expressing IL-1 receptor type 2 and regulatory T Cells.

Immun Ageing 2015 15;12:26. Epub 2015 Dec 15.

First Department of Medicine, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka Japan.

Background: Accumulating evidence has indicated the relationship between the systemic immune system and the central nervous system including the inner ear.

Results: We have shown that age-related developments of T-cell dysfunction, hearing loss, and degeneration of cochlear spiral ganglion (SG) neurons observed in 6-month-old mice were recovered in 12 months old mice which previously given fetal thymus transplants twice. We have also demonstrated that CD4(+) T cells expressing interleukin 1 receptor type 2 (IL-1R2) and naturally occurring regulatory T cells (nTregs), which expanded in aged 12-month-old mice, were reduced in the thymus-grafted mice of the same age.

Conclusion: It is conceivable that the rejuvenation of systemic immune function by fetal thymus grafts contributes not only to the activation of cellular immunity but also to the decrease of IL-1R2(+) CD4(+) T cells or nTregs, which cells accelerate both age-related hearing loss (AHL) and neurodegeneration of the cochlear neurons. Further studies on the interactions among IL-1R2 expression on CD4(+) T cells, Tregs, and neuronal cells and also on the relationships between fetal thymus grafting and the rejuvenation of systemic immunity should be designed in order to advance towards therapeutic effects on neurosenescence, including AHL.
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http://dx.doi.org/10.1186/s12979-015-0053-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678479PMC
December 2015

Increased recruitment of bone marrow-derived cells into the brain associated with altered brain cytokine profile in senescence-accelerated mice.

Brain Struct Funct 2016 Apr 11;221(3):1513-31. Epub 2015 Jan 11.

Department of Pathology, Aichi Human Service Center, Institute for Developmental Research, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan.

Bone marrow-derived cells enter the brain in a non-inflammatory condition through the attachments of choroid plexus and differentiate into ramified myeloid cells. Neurodegenerative conditions may be associated with altered immune-brain interaction. The senescence-accelerated mouse prone 10 (SAMP10) undergoes earlier onset neurodegeneration than C57BL/6 (B6) strain. We hypothesized that the dynamics of immune cells migrating from the bone marrow to the brain is perturbed in SAMP10 mice. We created 4 groups of radiation chimeras by intra-bone marrow-bone marrow transplantation using 2-month-old (2 mo) and 10 mo SAMP10 and B6 mice as recipients with GFP transgenic B6 mice as donors, and analyzed histologically 4 months later. In the [B6 → 10 mo SAMP10] chimeras, more ramified marrow-derived cells populated a larger number of discrete brain regions than the other chimeras, especially in the diencephalon. Multiplex cytokine assays of the diencephalon prepared from non-treated 3 mo and 12 mo SAMP10 and B6 mice revealed that 12 mo SAMP10 mice exhibited higher tissue concentrations of CXCL1, CCL11, G-CSF, CXCL10 and IL-6 than the other groups. Immunohistologically, choroid plexus epithelium and ependyma produced CXCL1, while astrocytic processes in the attachments of choroid plexus expressed CCL11 and G-CSF. The median eminence produced CXCL10, hypothalamic neurons G-CSF and tanycytes CCL11 and G-CSF. These brain cytokine profile changes in 12 mo SAMP10 mice were likely to contribute to acceleration of the dynamics of marrow-derived cells to the diencephalon. Further studies on the functions of ramified marrow-derived myeloid cells would enhance our understanding of the brain-bone marrow interaction.
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http://dx.doi.org/10.1007/s00429-014-0987-2DOI Listing
April 2016

Platelet-derived RANK ligand enhances CCL17 secretion from dendritic cells mediated by thymic stromal lymphopoietin.

Platelets 2015 27;26(5):425-31. Epub 2014 May 27.

First Department of Internal Medicine, Kansai Medical University , Osaka , Japan.

Dendritic cells (DCs) play an integral role in cellular cascade that initiate and maintain Th2 responses in allergy. In this study, we examined the interaction between platelets and DCs to determine the role of platelets in the intervention of immune responses through modulation of DC functions. Blood-purified myeloid DCs, which had been stimulated with thymic stromal lymphopoietin (TSLP-DCs), formed aggregates with activated platelets. TSLP-DC maturation was induced after the interaction with TRAP6-activated platelets as indicated by an increase in the expression of CD86, CD40, and CD83. In addition, production of a Th2 cell-attracting chemokine, CCL17, was clearly upregulated by coculture of TSLP-DCs with TRAP6-activated platelets. We further found that an expression of RANK ligand (RANKL) on platelets was upregulated by the TRAP6 activation, and that, using the neutralizing antibody against RANKL, the platelet-derived RANKL induces the activation of TSLP-DCs. Thus, activated platelets can intervene in adaptive immune responses through induction of functional modulation of TSLP-DCs. Platelets have the ability to enhance the DC-mediated Th2 response and may contribute to the allergic inflammation. In conclusion, our study provides new insights in platelet functions and the possible mechanism of allergic responses that stem from DCs.
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http://dx.doi.org/10.3109/09537104.2014.920081DOI Listing
March 2016

IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.

Allergol Int 2014 Sep 25;63(3):443-55. Epub 2014 May 25.

First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

Background: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses.

Methods: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP-treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis.

Results: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase.

Conclusions: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.
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http://dx.doi.org/10.2332/allergolint.13-OA-0672DOI Listing
September 2014

IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand.

Allergol Int 2014 27;63(3):443-455. Epub 2015 Feb 27.

First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

Background: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses.

Methods: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis.

Results: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase.

Conclusions: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.
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http://dx.doi.org/10.2332/allergolint.13-OA-0672DOI Listing
February 2015

Immunoregulatory function of PIR-A/B+ DCs in the inflammatory responses of dextran sodium sulfate-induced colitis.

J Gastroenterol 2014 Oct 29;49(10):1367-77. Epub 2013 Sep 29.

Division of Gastroenterology and Hepatology, Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8506, Japan,

Background: Dendritic cells (DCs) may play an important role in forms of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. DCs are generally recognized as initiators of acquired immunity and also serve as regulators of both innate and acquired immunity. We used the animal model of colitis induced by dextran sodium sulfate (DSS), and examined whether DCs prepared from the colon show immunoregulatory roles in the termination of DSS-induced colitis.

Methods: C57BL/6 mice exposed to DSS for 5 days developed acute colitis. DCs were isolated from the large intestinal lamina propria, and then analyzed for phenotypical, functional, and genetic data.

Results: Only PIR-A/B(low) conventional DCs (cDCs) were detected in the steady state. However, after the treatment of DSS, PIR-A/B(high) cDCs appeared and gradually increased from day 5 to day 7, at which time the DSS-induced colitis was terminated. Then, allogeneic mixed leukocyte reaction (MLR) was performed. The stimulatory activity of PIR-A/B(high) cDCs obtained on day 7 was very low, and the addition of PIR-A/B(high) cDCs suppressed the T cell proliferation in MLR, indicating the immunoregulatory role of PIR-A/B(high) cDCs. The immunoregulatory role of PIR-A/B(high) cDCs was confirmed by the in vivo transfer experiment, showing their therapeutic effect on DSS-induced colitis. The message level of TGFβi was significantly higher in PIR-A/B(high) cDCs, while that of IFN-γ was highly upregulated in PIR-A/B(low) cDCs, being well in accordance with the fact that PIR-A/B(high) cDCs showed a suppressive function against activated T cells.

Conclusion: PIR-A/B(high) cDCs showed a suppressive function against activated T cells by producing inhibitory cytokines.
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http://dx.doi.org/10.1007/s00535-013-0879-xDOI Listing
October 2014

Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis.

J Rheumatol 2013 Jul 1;40(7):1074-81. Epub 2013 May 1.

First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

Objective: Biologic treatments including the humanized anti-interleukin 6 (anti-IL-6) receptor antibody tocilizumab (TCZ) provide therapeutic options for patients with rheumatoid arthritis (RA). We investigated useful biomarkers to predict the responsiveness to TCZ by measurement of serum proinflammatory cytokine concentrations.

Methods: Serum samples were collected from 61 patients with RA before biologic treatment and at 4 weeks after initial administration of either TCZ (n = 32) or infliximab (IFX; n = 29) and from 13 healthy serum donor controls. Disease Activity Score of 28 joints (DAS28) was determined at baseline and after treatment.

Results: Although IL-1β, IL-2, IL-6, IL-17A, IL-17F, interferon-α, and tumor necrosis factor-α (TNF-α) were all increased in sera from patients with RA compared with controls, only the IL-6 level was significantly correlated with DAS28 before treatment. The IL-6 level before treatment was positively correlated with DAS28 after TCZ treatment, and was significantly lower in TCZ-responsive patients (as judged by a post-treatment DAS28 < 3.2) than in TCZ-resistant patients (post-treatment DAS28 ≥ 3.2). DAS28 after TCZ was significantly lower than after administration of IFX in patients with low pretreatment IL-6 (< 51.5 pg/ml, the mean baseline value of IL-6 in all RA patients), but not in those with high pretreatment IL-6. These results indicate that low serum IL-6 is associated with a favorable response to TCZ.

Conclusion: Although both TNF-α and IL-6 are major targets of therapeutic intervention in RA, baseline serum IL-6 but not baseline TNF-α level is a potential biomarker reflecting disease activity. Measurement of serum IL-6 in RA before treatment may be useful to estimate residual disease activity after TCZ treatment and to predict responsiveness to TCZ treatment.
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http://dx.doi.org/10.3899/jrheum.121389DOI Listing
July 2013

Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus.

Brain Behav Immun 2013 Mar 25;29:82-97. Epub 2012 Dec 25.

Department of Stem Cell Disorders, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.

Although the immune system modulates higher functions of the brain under non-inflammatory conditions, how immune cells interact with brain parenchymal cells remains to be determined. Using bone marrow chimeric mice in which the recipients' immune system was reconstituted by marrow cells derived from GFP-transgenic mice by syngeneic intra-bone marrow-bone marrow transplantation (IBM-BMT) and by intravenous (IV)-BMT, we examined the distribution, density and differentiation of donor-derived marrow cells in the brain parenchyma 2 weeks and 1, 4 and 8 months after BMT. Marrow-derived cells started to populate discrete brain regions from 1 to 4 months after BMT, exhibited ramified morphology and expressed Iba-1. The ramified marrow-derived cells were distributed in more brain regions and for a longer time after IBM-BMT than IV-BMT. Most of these discrete regions were adjacent to the attachments of choroid plexus that comprised thinned brain parenchyma consisting of astroglial processes in the narrow channel between the ependyma and pia. These specific portions of astroglial processes expressed fractalkine. In the choroid plexus stroma, not only Iba-1+ myeloid cells but also non-myeloid CXCL12-expressing cells were of bone marrow-origin. Transcripts of fractalkine, CXCL12 and their related molecules such as CX3CR1, ADAM10 and CXCR4 were detected in the tissue consisting of the choroid plexus, the attachments and adjacent brain parenchyma. Thus, bone marrow cells selectively enter the discrete brain regions adjacent to the attachments of choroid plexus and differentiate into ramified myeloid cells. Fractalkine in the attachments of choroid plexus and CXCL12 in the choroid plexus stroma may be involved in these brain-immune interactions.
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http://dx.doi.org/10.1016/j.bbi.2012.12.010DOI Listing
March 2013

Fetal thymus graft prevents age-related hearing loss and up regulation of the IL-1 receptor type II gene in CD4(+) T cells.

J Neuroimmunol 2012 Sep 29;250(1-2):1-8. Epub 2012 May 29.

Department of Otolaryngology, Kansai Medical University, Moriguchi City, Osaka, Japan.

We found that rejuvenation of the recipient immunity by inoculation of young CD4(+) T cells or a fetal thymus graft led to down regulation of the interleukin 1 receptor type II (IL-1R2) gene in CD4(+) T cells and reduced age-related hearing loss and degeneration of the spiral ganglion in SAMP1 mice, a murine model of human senescence. Our studies on the relationship between age-related systemic immune dysfunctions and neurodegeneration mechanisms open up new avenues of treatment of neurosenescence, including presbycusis, for which there is no effective therapy.
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http://dx.doi.org/10.1016/j.jneuroim.2012.05.007DOI Listing
September 2012

Amelioration of 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by immunoregulatory dendritic cells.

J Gastroenterol 2011 Dec 16;46(12):1368-81. Epub 2011 Sep 16.

Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Osaka, Japan.

Background: Dendritic cells (DCs) are widely distributed throughout the lymphoid and nonlymphoid tissues, and are important initiators of acquired immunity. They also serve as regulators by inducing self-tolerance. However, it has not been thoroughly clarified whether DCs are somehow involved in the regulation or treatment of inflammatory bowel diseases.

Methods: We established an ileitis model by transmurally injecting 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the lumen of the ileocolonic junction. The kinetic movement of DCs at the inflammatory sites was analyzed histologically and by flow cytometry, and DCs obtained from the small intestine were analyzed in order to determine the expression of paired immunoglobulin-like receptor-A/B (PIR-A/B) by flow cytometry and quantitative RT-PCR. Furthermore, the regulatory role of DCs was directly determined by a transfer experiment using TNBS-induced colitis model mice.

Results: We observed three DC subsets (PIR-A/B(high), PIR-A/B(med), and PIR-A/B(-) DCs) in the conventional DCs (cDCs) from day 3, and the number of PIR-A/B(med) cDCs increased from the time the inflammatory responses ceased (day 7). PIR-A/B(med) cDCs actually migrated to the inflamed colon, and ameliorated the colitis induced by TNBS when transferred to colitis-induced recipients. The colitis was greatly exacerbated when mice had been treated with the indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-mT) at the time PIR-A/B(med) cDCs were transferred, indicating that the therapeutic ability of PIR-A/B(med) cDCs is partially dependent on IDO.

Conclusion: The PIR-A/B(med) cDCs, which increase in number during the final stages of inflammation, can be used to treat colitis via an IDO-dependent mechanism.
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http://dx.doi.org/10.1007/s00535-011-0460-4DOI Listing
December 2011

Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow--bone marrow transplantation plus concurrent thymic transplantation.

J Autoimmun 2010 Dec;35(4):414-23

Department of Stem Cell Disorders, Kansai Medical University, Moriguchi City, Osaka 570-8506, Japan.

There is increasing evidence that both autoimmune and autoinflammatory mechanisms are involved in the development of not only type 1 diabetes mellitus (T1 DM), but also type 2 diabetes mellitus (T2 DM). Our laboratory has focused on this concept, and in earlier efforts replaced the bone marrow cells (BMCs) of leptin receptor-deficient (db/db) mice, an animal model of T2DM, with those of normal C57BL/6 (B6) mice by IBM-BMT. However, the outcome was poor due to incomplete recovery of T cell function. Therefore, we hypothesized that intra-bone marrow-bone marrow transplantation plus thymus transplantation (IBM-BMT + TT) could be used to treat T2 DM by normalizing the T cell imbalance. Hence we addressed this issue by using such dual transplantation and demonstrate herein that seven weeks later, recipient db/db mice manifested improved body weight, reduced levels of blood glucose, and a reduction of plasma IL-6 and IL-1β. More importantly, this treatment regimen showed normal CD4/CD8 ratios, and increased plasma adiponectin levels, insulin sensitivity, and the number of insulin-producing cells. Furthermore, the expression of pancreatic pAKT, pLKB1, pAMPK and HO-1 was increased in the mice treated with IBM-BMT + TT. Our data show that IBM-BMT + TT treatment normalizes T cell subsets, cytokine imbalance and insulin sensitivity in the db/db mouse, suggesting that IBM-BMT + TT is a viable therapeutic option in the treatment of T2 DM.
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http://dx.doi.org/10.1016/j.jaut.2010.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553687PMC
December 2010

Interferon-α and interleukin-12 are induced, respectively, by double-stranded DNA and single-stranded RNA in human myeloid dendritic cells.

Immunology 2011 Feb 28;132(2):165-73. Epub 2010 Sep 28.

First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

Dendritic cells (DCs) are initiators of innate immunity and acquired immunity as cells linking these two bio-defence systems through the production of cytokines such as interferon-α (IFN-α) and interleukin-12 (IL-12). Nucleic acids such as DNA from damaged cells or pathogens are important activators not only for anti-microbial innate immune responses but also in the pathogenesis of IFN-related autoimmune diseases. Plasmacytoid DCs are regarded as the main effectors for the DNA-mediated innate immunity by possessing DNA-sensing toll-like receptor 9 (TLR9). We here found that double-stranded DNA (dsDNA) complexed with lipotransfectants triggered activation of human monocyte-derived DCs (moDCs), leading to the preferential production of IFN-α but not IL-12. This indicates that myeloid DCs also function as supportive effectors against the invasion of pathogenic microbes through the DNA-mediated activation in innate immunity. The dsDNA with lipotransfectants can be taken up by moDCs without co-localization of endosomal LAMP1 staining, and the dsDNA-mediated IFN-α production was not impaired by chloroquine. These findings indicate that moDC activation by dsDNA does not involve the endosomal TLR pathway. In contrast, single-stranded RNA (ssRNA) stimulated moDCs to secrete IL-12 but not IFN-α. This process was inhibited by chloroquine, suggesting an involvement of the TLR pathway in ssRNA-mediated moDC activation. As might be inferred from our findings, myeloid DCs may function as a traffic control between innate immunity via IFN-α production and acquired immunity via IL-12 production, depending on the type of nucleic acids. Our results provide a new insight into the biological action of myeloid DCs underlying the DNA-mediated activation of protective or pathogenic immunity.
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http://dx.doi.org/10.1111/j.1365-2567.2010.03350.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050440PMC
February 2011

IFN{gamma} markedly cooperates with intratumoral dendritic cell vaccine in dog tumor models.

Cancer Res 2010 Sep 7;70(18):7093-101. Epub 2010 Sep 7.

Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-ourai-kita, Izumisano City, Osaka 598-8531, Japan.

Dendritic cell (DC)-based immunotherapy can trigger effective immune responses against cancer in human patients. Although accompanied by little toxicity, further improvements are needed to optimize immune responses for fully satisfactory clinical outcomes. IFNγ, a potent inducer of T helper type 1 immune responses, is considered an important tool to realize improvements. In this study, we sought to clarify the effect of IFNγ on the maturation and activation of DCs and the clinical outcome of DC-based cancer therapy in dogs. In vitro experiments indicated that IFNγ significantly enhanced the expression of immune stimulatory molecules and interleukin-12 by DCs derived from canine monocytes. IFNγ also significantly strengthened DC-mediated growth suppression against tumor cell lines. DC inoculation with concomitant delivery of IFNγ into primary or recurrent tumors elicited significant clinical responses, including four complete responses and two partial responses against malignant tumors, also eliciting partial responses against benign but actively growing tumors. Together, our results indicate that combining IFNγ and DCs could induce strong immune responses against tumors, significantly improving clinical outcomes. The present study of dogs bearing common types of cancer in humans offers a unique line of support for the development of human cancer therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-0600DOI Listing
September 2010

Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse.

Brain Behav Immun 2011 Jan 9;25(1):83-100. Epub 2010 Sep 9.

Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392, Japan.

Aging is a result of damage accumulation, and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) has been established as an inbred strain exhibiting accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescence-resistant control (SAMR1) strain. We hypothesized that tissue-protective responses of glial cells are impaired in SAMP10 mice. We injected kainic acid (KA) to induce hippocampal injury and studied how cytokines were upregulated on Day 3 using 3-month-old SAMP10 and SAMR1 mice. Following microarray-based screening for upregulated genes, we performed real-time RT-PCR and immunohistochemistry. Results indicated well-orchestrated cytokine-mediated glial interactions in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon (IFN)-γ stimulated astrocytes via IFN-γ receptor and thereby induced expression of CXCL10 and macrophage inflammatory protein (MIP)-1α, and activated microglia produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and osteopontin (OPN). OPN was the most strongly upregulated cytokine. CD44, an OPN receptor, was also strongly upregulated in the neuropil, especially on neurons and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice compared to SAMR1 mice. On Day 30 after KA injection, SAMP10 but not SAMR1 mice exhibited hippocampal layer atrophy. Since the OPN-CD44 system is essential for neuroprotection and remodeling, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration.
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http://dx.doi.org/10.1016/j.bbi.2010.08.006DOI Listing
January 2011

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production.

Arthritis Rheum 2010 Jul;62(7):2073-85

Kansai Medical University, Moriguchi, Osaka, Japan.

Objective: Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs.

Methods: We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNalpha production, and intracellular signaling.

Results: Statins inhibited IFNalpha production profoundly and tumor necrosis factor alpha production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNalpha production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNalpha production by PDCs from SLE patients and SLE serum-induced IFNalpha production.

Conclusion: Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.
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http://dx.doi.org/10.1002/art.27478DOI Listing
July 2010

Prolonged survival in mice with advanced tumors treated with syngeneic or allogeneic intra-bone marrow-bone marrow transplantation plus fetal thymus transplantation.

Cancer Immunol Immunother 2010 Jul 13;59(7):1121-30. Epub 2010 Mar 13.

First Department of Pathology, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan.

Thymic function decreases in line with tumor progression in patients with cancer, resulting in immunodeficiency and a poor prognosis. In the present study, we attempted to restore thymic function by BALB/c (H-2(d)) syngeneic (Syn), or B6 (H-2(b)) allogeneic (Allo) bone marrow transplantation (BMT) using intra-bone marrow-bone marrow transplantation (IBM-BMT) plus Syn-, Allo- or C3H (H-2(k)) 3rd-party fetal thymus transplantation (TT). Although the BALB/c mice with advanced tumors (Meth-A sarcoma; H-2(d), >4 cm(2)) treated with either Syn- or Allo-BMT alone showed a slight improvement in survival compared with non-treated controls, the mice treated with BMT + TT showed a longer survival. The mice treated with Allo-BMT + Allo-TT or 3rd-party TT showed the longest survival. Interestingly, although there was no difference in main tumor size among the BMT groups, lung metastasis was significantly inhibited by Allo-BMT + Allo-TT or 3rd-party TT. Numbers of CD4(+) and CD8(+) T cells, Con A response, and IFN-gamma production increased significantly, whereas number of Gr-1(+)/CD11b(+) myeloid suppressor cells and the percentage of FoxP3(+) cells in CD4(+) T cells significantly decreased in these mice. Furthermore, there was a positive correlation between survival days and the number of T cells or T cell function, while there was a negative correlation between survival days and lung metastasis, the number of Gr-1(+)/CD11b(+) cells, or the percentage of FoxP3(+) cells. These results suggest that BMT + TT, particularly Allo-BMT + Allo-TT or 3rd-party TT, is most effective in prolonging survival as a result of the restoration of T cell function in hosts with advanced tumors.
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http://dx.doi.org/10.1007/s00262-010-0840-2DOI Listing
July 2010

Transformation potential of bone marrow stromal cells into undifferentiated high-grade pleomorphic sarcoma.

J Cancer Res Clin Oncol 2010 Jun 21;136(6):829-38. Epub 2009 Nov 21.

First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan.

Purpose: Bone marrow adherent cells contain conventional bone marrow stromal cells and mesenchymal stem cells and these cells constitute the hematopoietic microenvironment. Mesenchymal stem cells have the capacity to give rise to multiple mesenchymal lineage cells and even ectodermal lineage cells. In the present study, we investigated what types of tumor cells are inducible from BM adherent cells by chemical carcinogens.

Methods: Bone marrow cells from neonatal C3H/HeN mice were collected within 24 h after birth and then cultured. Four days later, bone marrow adherent cells were obtained and the cells were treated with 3-methylcholanthrene.

Results: By this treatment, some transformed clones consisting of large spindle cells were obtained. The transformed cells were highly positive for CD44 and were positive for Sca-1, CD49d and CD106, whereas the cells were negative for hematolymphoid markers. The cell clones had the ability to support hematopoiesis in vitro. These results indicate that the transformed cell lines have the characteristics of BM stromal cells/mesenchymal stem cells. Moreover, during culture of the transformed cells, spontaneous bone nodule formation was observed. When the transformed cells were inoculated into immunodeficient mice subcutaneously, the neoplasms grew in the subcutaneous tissue of the mice. Microscopically and ultrastructurally, the neoplasms showed the typical morphology of undifferentiated high-grade pleomorphic sarcoma (UHGPS). Bone-related genes have been found to be expressed in both transformed cells and UHGPSs.

Conclusion: The present study suggests that UHGPSs are derived from BM stromal cells, probably mesenchymal stem cells.
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http://dx.doi.org/10.1007/s00432-009-0723-0DOI Listing
June 2010

The role of dendritic cell subsets in 2,4,6-trinitrobenzene sulfonic acid-induced ileitis.

J Autoimmun 2010 Jun 30;34(4):380-9. Epub 2009 Oct 30.

First Department of Pathology, Kansai Medical University, Osaka, Japan.

Dendritic cells (DCs) are widely distributed throughout the lymphoid and nonlymphoid tissues, and are important initiators of acquired immunity and also serve as regulators by inducing self-tolerance. However, it has not been thoroughly clarified whether DCs are involved in the termination of immune responses. In this paper, we have examined the kinetical movement of dendritic cells (DCs) in the lamina propria using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ileitis model (an animal model for Crohn's disease). Increased numbers of DCs were recruited to the inflammatory sites from day 1 to day 3 at which time the inflammatory responses was clearly observed, then gradually decreased to a steady-state level on day 7 along with the cessation of responses. Three subsets of DCs, PIR-A/B(high), PIR-A/B(med), and PIR-A/B(-) DCs in the CD11c(+)/B220(-) conventional DCs (cDCs) were noted on day 3; the number of PIR-A/B(med) cDCs increased when the inflammatory responses ceased on day 7. The expression of costimulatory molecules such as CD86 and CD54 was lower in the PIR-A/B(med) DCs compared with the other two cDC subsets or splenic DCs. Furthermore, the stimulatory activity of PIR-A/B(med) cDCs was lower than those of PIR-A/B(high) or PIR-A/B(-) cDCs, and far lower than that of splenic DCs. In addition, an increase in the message level of IL-10 was clearly observed in the PIR-A/B(med) cDCs on day 7 while that of proinflammatory cytokines such as IL-6 and IL-12 was low. These data demonstrate that PIR-A/B(med) cDCs which increase at the final stage of inflammation may be involved in the termination of the TNBS-induced ileitis by the delivery of anergic signals to effector T cells due to the lower expressions of costimulatory molecules and the production of immunoregulatory cytokine.
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http://dx.doi.org/10.1016/j.jaut.2009.10.002DOI Listing
June 2010

Amelioration of cognitive ability in senescence-accelerated mouse prone 8 (SAMP8) by intra-bone marrow-bone marrow transplantation.

Neurosci Lett 2009 Nov 5;465(1):36-40. Epub 2009 Sep 5.

First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan.

Bone marrow cells (BMCs) can increase the number of activated microglias, which play a central role in the inflammatory response in Alzheimer's disease (AD). Senescence-accelerated mouse (SAM) prone 8 (SAMP8) are widely used in various experiments because of cognitive deficits observed with age. In the present study, 4-month-old SAMP8 were reconstituted with BMCs of C57BL/6 mice by intra-bone marrow-bone marrow transplantation (IBM-BMT), which can reconstitute both donor-derived hemopoietic stem cells and mesenchymal stem cells. Three months after IBM-BMT, the impairment of spatial memory in SAMP8 was found to be ameliorated after analyzing the results of the water maze test. Although IL-1beta, IL-6 and iNOS increased and TGF-beta decreased in 7M SAMP8, IL-1beta, IL-6 and iNOS decreased while TGF-beta increased after IBM-BMT by RT-PCR. Moreover, oxidative stress-related heme oxygenase-1 (HO-1) increased in 7M SAMP8, but significantly decreased after IBM-BMT. In conclusion, this is the first report suggesting that the impaired cognitive ability of SAMP8 is ameliorated by IBM-BMT. It seems likely that decreases in IL-1beta, IL-6, iNOS and HO-1 are a result of the development of donor-derived BMCs.
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http://dx.doi.org/10.1016/j.neulet.2009.09.001DOI Listing
November 2009

Induction of parotitis by fine-needle aspiration in parotid Warthin's tumor.

Otolaryngol Head Neck Surg 2009 Aug;141(2):282-4

Department of Otolaryngology, Takii Hospital, Kansai Medical University, Osaka 570-8507, Japan.

Objectives: To estimate parotitis caused by fine-needle aspiration (FNA) in parotid Warthin tumor.

Study Design: Case series with chart review.

Setting: Hospital records were reviewed for 104 parotid tumors (103 patients) including 35 Warthin tumors, which underwent FNA within our department.

Results: Three patients with four Warthin tumors among them noticed parotid pain, swelling, and abscess formation as a consequence of acute parotitis after FNA. Examinations of the materials obtained from tumor puncture or drainage before the start of antibiotic therapy showed no bacterial association in any patient. Two of the patients with Warthin tumor underwent parotidectomy, and the surgical specimens indicated histopathological changes with necrosis, abscess, granuloma, and the infiltration of inflammatory cells including Langhans-type multinucleated giant cells.

Conclusions: It is conceivable that Warthin tumor bears the characteristics of inflammation induced by the FNA procedure without any relation to infection. Therefore, it may be better to avoid routine FNA and give priority to diagnostic imagings over FNA in the diagnosis of tumors strongly suspected as Warthin tumor.
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http://dx.doi.org/10.1016/j.otohns.2009.05.023DOI Listing
August 2009

Parotid mucosa-associated lymphoid tissue lymphoma regression after Helicobacter pylori eradication.

Laryngoscope 2009 Aug;119(8):1491-4

Department of Otolaryngology, Takii Hospital, Kansai Medical University, Osaka, Japan.

A 60-year-old woman with Sjögren's syndrome showed recurrence of parotid mucosa-associated lymphoid tissue (MALT) lymphoma with a simultaneous increase of serum sIL-2R antigen levels 10 years after surgical treatment. Helicobacter pylori infection had been detected in the stomach since the beginning of the lymphoma. Although H. pylori was not detected in the recurrent parotid lymphoma, antibiotic therapy contributed not only to successful eradication of gastric H. pylori but also to disappearance of the recurrent lymphoma. Further studies on the mechanisms of occurrence of extragastric MALT lymphomas are needed to establish the treatment of extragastric MALT lymphomas.
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http://dx.doi.org/10.1002/lary.20258DOI Listing
August 2009
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