記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

Previously, we have shown that IL-21R(-/-) splenocytes ameliorate GVHD as compared with wild-type splenocytes. Here, we investigated whether or not IL-21R(-/-) splenocytes diminish the graft-versus-leukemia (GVL) effect. Surprisingly, IL-21R(-/-) splenocytes efficiently eliminate leukemic cells as well as wild-type splenocytes, suggesting the retention of GVL effects in the absence of IL-21 signaling. To compare the GVL effect between IL-21R (/) and wildtype cells, we titrated the number of splenocytes required for the elimination of leukemic cells and found that the threshold of GVL effect was obtained between 5 x 10(5) and 5 x 10(6) with both types of splenocytes. Cotransplantation with CD8-depleted splenocytes but not with purified CD8 T-cells resulted in a significant reduction in anti-leukemic effect of IL-21R(-/-) cells compared with wild-type cells, suggesting that the lack of IL-21 signaling primarily impairs CD4 T-cell rather than CD8 T-cell function and the comparable GVL effect with IL-21R(-/-) bulk splenocytes results from cooperative compensation by CD8 T-cells. Bone Marrow Transplantation (2011) 46, 1557-1565; doi:10.1038/bmt.2010.342; published online 24 January 2011

DOI： 10.1038/bmt.2010.342

Web of Science

researchmap

記述言語：英語   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

We previously showed that transplantation with IL-21R gene-deficient splenocytes resulted in less severe graft-versus-host disease (GVHD) than was observed with wild type splenocytes. In this study, we sought to find mechanism(s) explaining this observation. Recipients of donor CD4(+) T cells lacking IL-21R exhibited diminished GVHD symptoms, with reduced inflammatory cell infiltration into the liver and intestine, leading to prolonged survival. After transplantation, CD4(+) T cell numbers in the spleen were reduced, and MLR and cytokine production by CD4(+) T cells were impaired. These results suggest that IL-21 might promote GVHD through enhanced production of effector CD4(+) T cells. Moreover, we found that CD25 depletion altered neither the impaired MLR in vitro nor the ameliorated GVHD symptoms in vivo. Thus, the attenuated GVHD might be caused by an impairment of effector T cell differentiation itself, rather than by an increase in regulatory T cells and suppression of effector T cells. The Journal of Immunology, 2010, 185: 1920-1926.

DOI： 10.4049/jimmunol.0902217

Web of Science

researchmap

記述言語：英語   出版者・発行元：ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

Mesenchymal stem cells (MSCs) are considered to be a promising platform for cell and gene therapy for a variety of diseases. First, in the field of hematopoietic stem cell transplantation, there are two applications of MSCs: 1) the improvement of stem cell engrafting and the acceleration of hematopoietic reconstitution based on the hematopoiesis-supporting ability; and 2) the treatment of severe graft-versus-host disease (GVHD) based on the immunomodulatory ability. Regarding the immunosuppressive ability, we found that nitric oxide (NO) is involved in the MSC-mediated suppression of T cell proliferation. Second, tumor-bearing nude mice were injected with luciferase-expressing MSCs. An in vivo imaging analysis showed the significant accumulation of the MSCs at the site of tumors. The findings suggest that MSCs can be utilized to target metastatic tumors and to deliver anti-cancer molecules locally. As the third application, MSCs may be utilized as a cellular vehicle for protein-supplement gene therapy. When long-term transgene expression is needed, a therapeutic gene should be introduced with a minimal risk of insertional mutagenesis. To this end, site-specific integration into the AAVS 1 locus on the chromosome 19 (19q13.4) by using the integration machinery of adeno-associated virus (AAV) would be particularly valuable. There will be wide-ranging applications of MSCs to frontier medical treatments in the near future. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jaut.2007.12.008

Web of Science

researchmap

記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell-receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor-beta-neutralizing antibody had no effect. Finally, MSCs from inducible NOS-/- mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs. (c) 2007 by The American Society of Hematology

DOI： 10.1182/blood-2006-02-002246

Web of Science

researchmap

記述言語：英語   出版者・発行元：TAYLOR & FRANCIS AS  

Background The molecular mechanisms underlying the biologic effects or differentiation of merenchymal stromal cells (MSC) have nor been clarified. Screening for genes differentially expressed at different stages is an important step in determining these molecular mechanisins.
Methods In this study, we analyzed the gene expression profiles of C3HOT1/2 (10T1/2) cells and two sublines, A54 (pre-adipocyte) and M1601 (myoblast), as a model of MSC and downstream committed progenitors.
Results We found up-regulated expression of delta-like-1 (Dlk), Wnt-5a and IL-1 receptor-like-1 (ST2) in IOT1/2 cells; stem cell factor (SCF) and stromal derived factor-1 (SDF-1) in A54 cells; and cardiac muscle-specific gene in M1601 cells. Overexpression of Dlk in A54 cells did not induce any effects on their differentiation into adipocyies. After differentiation into adipocyies, A54 cells reduced the expression of SCF SDF-1 and Ang-1 as well as the ability to support the formation Of a cobblestone appearance.
Discussion The results suggest that these three lines have different gene profiles and are a useful system for analyzing the differentiation and function of MSC and progenitor cells.

DOI： 10.1080/14653240601016374

Web of Science

researchmap