SEARCH:   Advanced

Blood, 15 June 2004, Vol. 103, No. 12, pp. 4619-4621. Prepublished online as a Blood First Edition Paper on March 4, 2004; DOI 10.1182/blood-2003-11-3909. This Article Abstract Full Text (PDF) All Versions of this Article: 2003-11-3909v1 103/12/4619    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meisel, R. Articles by Dilloo, D. Search for Related Content PubMed PubMed Citation Articles by Meisel, R. Articles by Dilloo, D. Related Collections Immunobiology Transplantation Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Brief report Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase–mediated tryptophan degradation Roland Meisel, Andree Zibert, Maurice Laryea, Ulrich Göbel, Walter Däubener, and Dagmar Dilloo From the Clinic of Pediatric Oncology, Hematology and Immunology, University Hospital, Düsseldorf, Germany; Clinic of General Pediatrics, University Hospital, Düsseldorf, Germany; and Institute of Medical Microbiology, University Hospital, Düsseldorf, Germany.    Abstract Top Abstract Introduction Study design Results and discussion References   Marrow stromal cells (MSCs) inhibit allogeneic T-cell responses, yet the molecular mechanism mediating this immunosuppressive effect of MSCs remains controversial. Recently, expression of indoleamine 2,3-dioxygenase (IDO), which is induced by interferon- (IFN-) and catalyzes the conversion from tryptophan to kynurenine, has been identified as a T-cell inhibitory effector pathway in professional antigen-presenting cells. Here we show that human MSCs express IDO protein and exhibit functional IDO activity upon stimulation with IFN-. MSCs inhibit allogeneic T-cell responses in mixed lymphocyte reactions (MLRs). Concomitantly, IDO activity resulting in tryptophan depletion and kynurenine production is detected in MSC/MLR coculture supernatants. Addition of tryptophan significantly restores allogeneic T-cell proliferation, thus identifying IDO-mediated tryptophan catabolism as a novel T-cell inhibitory effector mechanism in human MSCs. As IDO-mediated T-cell inhibition depends on MSC activation, modulation of IDO activity might alter the immunosuppressive properties of MSCs in different therapeutic applications. (Blood. 2004;103:4619-4621)    Introduction Top Abstract Introduction Study design Results and discussion References   Human bone marrow stromal cells (MSCs), more recently referred to as mesenchymal stem cells, are capable of differentiating along multiple mesenchymal lineages in addition to supporting hematopoiesis.1,2 Due to their potential for differentiation into osteocytes, chondrocytes, myocytes, and adipocytes, MSCs have emerged as a promising tool for clinical applications such as tissue engineering and cell and gene therapy.3,4 MSCs are of inherently low immunogenicity and, more importantly, are capable of inhibiting allogeneic T-cell responses.5-8 These intriguing observations have prompted clinical studies to investigate cotransplantation of MSCs in allogeneic hematopoietic stem cell transplantation (HSCT) in order to promote hematopoietic engraftment by preventing host-versus-graft reactivity and to suppress graft-versus-host reactions.9,10 As of yet, the molecular mechanisms responsible for the immunosuppressive effects of MSCs have not been unequivocally identified. The reports describing a potential role of transforming growth factor-1 and hepatocyte growth factor as mediators of T-cell inhibition remain controversial, but most studies agree that soluble factors are involved.6-8,11 In professional antigen-presenting cells (APCs), expression of indoleamine 2,3-dioxygenase (IDO) induced by interferon- (IFN-) and other proinflammatory cytokines catalyzes conversion from tryptophan to kynurenine and has recently been identified as a major immunosuppressive effector pathway that inhibits T-cell responses to autoantigens and fetal alloantigens in vivo.12-16 Based on these findings, we investigated whether MSCs exhibit IFN--inducible IDO activity and whether this mechanism contributes to T-cell inhibition mediated by MSCs.    Study design Top Abstract Introduction Study design Results and discussion References   Culture of human bone marrow-derived MSCs Bone marrow aspirates were harvested from volunteer donors who had provided informed consent; the study was approved by the institutional review board of the University Clinic, Düsseldorf, Germany. Primary human MSCs were generated as previously described17 except that culture medium was supplemented with 3 ng/mL basic fibroblast growth factor (R&D Systems, Minneapolis, MN). Mixed lymphocyte reactions (MLRs) Standard 5-day MLR cultures were set up with 5 x 104 mitomycin C-treated human peripheral blood mononuclear cells (PBMCs) as stimulators and 2 x 105 human T cells purified using sheep red blood cell rosetting as responder cells.5,11 In MSC/MLR coculture experiments, MLRs were performed on a layer of either 5 x 103 or 2 x 104 MSCs seeded one day before. IFN- concentration was determined in MSC/MLR coculture supernatants using a commercially available enzyme-linked immunosorbent assay (ELISA; R&D Systems) according to manufacturer's instructions. Detection of IDO expression and activity MSCs were stimulated with IFN- (R&D Systems) and assayed for IDO expression and function. Standard Western blot analysis for IDO protein expression was performed.18 IDO enzyme activity following IFN- stimulation of MSCs was measured by tryptophan-to-kynurenine conversion with photometric determination of kynurenine concentration in the supernatant as the readout.19 In addition, IDO activity was quantified in MSC/MLR cocultures. In MLR experiments, tryptophan and kynurenine concentrations were determined in cell culture supernatant by high-performance liquid chromatography (HPLC; Alliance Separations Module 2690; Waters, Milford, MA). For separation, reversed-phase C18 columns (Supelcosil; Supelco, Bellefonte, PA) were used. Tryptophan was detected by fluorescence at 285-nm excitation and 365-nm emission wavelengths, kynurenine was detected by UV absorption at 360 nm.    Results and discussion Top Abstract Introduction Study design Results and discussion References   Primary human MSC lines were generated from adherent fraction of bone marrow-derived mononuclear cells. After 2 to 3 passages, MSC cultures consist of a single spindle-shaped cell type devoid of contaminating hematopoietic cells and exhibit an immunophenotype characteristic for human MSCs (CD14-/CD34-/CD45-; CD29+/CD44+/CD90+/CD105+/SH-2+).2 Under appropriate culture conditions, MSCs differentiated along osteogenic and adipogenic lineages as verified by alkaline phosphatase staining and accumulation of lipid-containing droplets, respectively.2 To initially assess whether these MSCs inhibit allogeneic T-cell responses, MLRs were performed on a layer of MSCs. As shown in Figure 1A, the presence of 5 x 103 MSCs had no impact on allogeneic T-cell responses, while 2 x 104 MSCs significantly impaired T-cell proliferation in 7 of 8 experiments to 33% ± 4% of the T-cell response in the absence of MSCs (P < .001). This confirms previous reports describing dose-dependent inhibition of allogeneic T-cell responses by MSCs.5,6,8 View larger version (20K): [in this window] [in a new window]   Figure 1.. Human MSCs inhibit allogeneic T-cell responses and express IDO. (A) Human MSCs inhibit allogeneic T-cell responses in a dose-dependent manner. Responding T cells (1 x 105) were incubated for 5 days with 5 x 104 allogeneic PBMCs as stimulator cells in the presence (+) or absence (-) of 5 x 103 or 2 x 104 human MSCs. Each experiment was performed in triplicate. T-cell proliferation is expressed as averaged means of triplicates ± SEM obtained from a series of 11 experiments with 5 x 103 MSCs from 7 different donors and 7 experiments with 2 x 104 MSCs from 6 different donors. *P value of difference as calculated by Student t test. (B) Human MSCs express IDO protein upon stimulation with IFN-. MSCs were cultured in the absence (-) or presence (+) of 500 U/mL IFN-. After 3 days, cells were harvested and subjected to Western blot analysis using an IDO-specific monoclonal antibody. As a control, expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was analyzed in parallel. (C) Human MSCs express functional IDO activity upon stimulation with IFN-. MSCs (2 x 104) were stimulated with increasing amounts of IFN-. After 3 days of culture, supernatant was harvested and IDO activity was measured by determining kynurenine concentration as absorbance (OD) at 492 nm. Background OD (approximately 0.15) was subtracted. Data obtained from 4 independent experiments each using MSCs from different individual donors are presented as mean OD ± SEM.   As induction of IDO activity has recently been described as a major T-cell inhibitory mechanism in APC/T-cell interactions,13,14,16 we next investigated whether IDO is also expressed in MSCs. Western blot analysis demonstrates that human MSCs do not constitutively express IDO, but a substantial amount of IDO protein is induced by IFN- (Figure 1B). Moreover, in MSCs, IFN- stimulates IDO enzyme activity in a dose-dependent manner (Figure 1C). Of note, IDO activity is observed at IFN- concentrations as low as 10 to 50 U/mL. This level is readily generated in allogeneic T-cell reactions even in the presence of MSCs, as verified in our experimental setting by measurement of IFN- concentration in supernatants of MSC/MLR cocultures with 23.3 ± 7.3 U/mL (mean ± SEM; n = 3). Next, MSC/MLR cocultures set up in parallel to those documenting MSC-mediated T-cell inhibition (Figure 1A) were assessed for IDO activity by measuring tryptophan-to-kynurenine conversion. Significant IDO activity was detected in MSC/MLR cocultures in comparison to background levels observed in MLRs and MSCs alone (Figure 2A). Taken together these data provide evidence that MSCs are the primary source of IDO activity in MSC/MLR cocultures. MSC activation, provided in our study by allogeneic responder T cells, is required for induction of functional IDO activity. View larger version (14K): [in this window] [in a new window]   Figure 2.. IDO-mediated tryptophan degradation can act as T-cell inhibitory effector pathway in human MSCs. (A) Cocultures of MSCs and MLRs exhibit IDO activity. Supernatants from 4-day cultures of MSCs alone, MLRs alone, or MLR/MSC coculture were harvested and set up for analysis of IDO activity in triplicates. Background OD was not subtracted to allow for comparison of IDO activity of MLRs and MSCs alone. ODs are shown as averaged means of triplicates ± SEM obtained from a total of 5 experiments using MSCs from 4 different donors. *P value of difference as calculated by Student t test. (B) Addition of tryptophan restores T-cell proliferation in MLR/MSC cocultures. MLR cultures were set up in presence (+MSC) or absence of 2 x 104 MSCs. Proliferation is depicted relative to the proliferation of MLR cultures in the absence of MSCs (100%). In parallel experiments, 100 µg/mL tryptophan was added (+Tryp) at the time of initiation and at day 3 of MLR culture or was left out. Relative proliferation is depicted as averaged means of triplicates ± SEM from a series of 5 experiments using MSCs from 4 individual donors. *P value of difference as calculated by Student t test.   In previous reports, IDO-mediated tryptophan depletion from culture medium to levels less than 1 µM has been shown to inhibit allogeneic T-cell responses. Consequently, T-cell proliferation can partially be restored by addition of tryptophan.13,14 Therefore, to unequivocally demonstrate IDO-mediated tryptophan degradation in our experimental setup, we performed HPLC analysis in supernatants directly obtained from MSC/MLR cocultures exhibiting MSC-mediated T-cell inhibition. Tryptophan was depleted to less than 0.3 µM from culture medium initially containing 20.2 ± 0.3 µM (mean ± SEM; n = 3). Concomitantly, a significant increase of the tryptophan metabolite kynurenine from 0.4 ± 0.1 to 17.7 ± 4.9 µM was observed in these supernatants. To finally confirm that IDO-mediated tryptophan depletion functions as a T-cell inhibitory effector mechanism in MSC/MLR cocultures, tryptophan repletion experiments were performed. Addition of tryptophan to MSC/MLR cocultures significantly restored T-cell proliferation without any stimulatory capacity of tryptophan on T-cell proliferation in the absence of MSCs (Figure 2B). Restoration of T-cell function was consistently demonstrated in a series of 5 individual experiments using MSCs generated from a total of 4 different donors, even though the degree of restoration was variable. These results demonstrate that IDO-mediated tryptophan depletion can act as a T-cell inhibitory effector mechanism in human MSCs. Recent data suggest that IDO-facilitated conversion of tryptophan to kynurenine not only depletes tryptophan from the cellular environment but also results in production of kynurenine downstream metabolites that mediate inhibition of T-cell proliferation in their own right.20,21 As a consequence, inhibition of T-cell proliferation mediated by such kynurenine breakdown products is not reversible by tryptophan replacement. Thus, variable reversibility of T-cell proliferation by tryptophan replacement might reflect variable amounts of T-cell inhibitory kynurenine metabolites produced in individual MSC/MLR cocultures. As more than one T-cell inhibitory mechanism seems to play a role in IDO-mediated tryptophan breakdown,20,21 the recently reported failure to achieve significant restoration of T-cell proliferation via tryptophan addition in one MSC line might be attributed to the production of T-cell inhibitory kynurenine metabolites in this experiment.8 IDO expression by tumor cells has recently been shown to prevent T-cell-mediated tumor rejection in vivo.22 In addition, coadministration of MSCs and tumor cells at a distant site resulted in accelerated tumor outgrowth in a murine melanoma model.11 Our finding that MSCs can limit T-cell responses via IDO-mediated tryptophan degradation links these observations. Thus, careful evaluation of potential beneficial and undesirable effects of MSC-mediated inhibition of allogeneic T-cell responses with regard to modulation of graft-versus-host and graft-versus-tumor reactions is warranted. Yet, the identification of IDO as a T-cell inhibitory effector pathway that is not constitutively expressed in MSCs but depends on their activation might allow for modulation of this effector mechanism, when MSCs are used in different therapeutic applications.    Acknowledgements   The authors want to thank D. Klostermann for technical assistance. Bone marrow samples were partially provided by J. Fischer (Institute for Transplantation Diagnostics and Cell Therapy, Düsseldorf University Hospital, Germany), and IDO-specific mouse monoclonal antibody was provided by O. Takikawa (Department of Chemistry and Australian Cataract Research Foundation, University of Wollongton, Australia).    Footnotes   Submitted November 18, 2003; accepted February 24, 2004. Prepublished online as Blood First Edition Paper, March 4, 2004; DOI 10.1182/blood-2003-11-3909. Supported by German Federal Ministry of Education and Research grant no. 01GN0130 (D.D.), German Research Council grant no. 221/3-1 (W.D.), and "Elterninitiative Kinderkrebsklinik Düsseldorf e.V." R.M. and A.Z. contributed equally to this work. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Dagmar Dilloo, Clinic of Pediatric Oncology, Hematology and Immunology, University Hospital, Moorenstrasse 5, D-40225 Düsseldorf, Germany; e-mail: dilloo{at}uni-duesseldorf.de.    References Top Abstract Introduction Study design Results and discussion References   Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276: 71-74.[Abstract/Free Full Text] Pittenger MF, Mackay AM, Beck SC, et al. Multi-lineage potential of adult human mesenchymal stem cells. Science. 1999;284: 143-147.[Abstract/Free Full Text] Asahara T, Kalka C, Isner JM. Stem cell therapy and gene transfer for regeneration. Gene Ther. 2000;7: 451-457.[CrossRef][Medline] [Order article via Infotrieve] Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 2001;19: 180-192.[CrossRef][Medline] [Order article via Infotrieve] Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30: 42-48.[CrossRef][Medline] [Order article via Infotrieve] Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99: 3838-3843.[Abstract/Free Full Text] Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101: 3722-3729.[Abstract/Free Full Text] Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75: 389-397.[CrossRef][Medline] [Order article via Infotrieve] Koc ON, Lazarus HM. Mesenchymal stem cells: heading into the clinic. Bone Marrow Transplant. 2001;27: 235-239.[CrossRef][Medline] [Order article via Infotrieve] Jorgensen C, Djouad F, Apparailly F, Noel D. Engineering mesenchymal stem cells for immunotherapy. Gene Ther. 2003;10: 928-931.[CrossRef][Medline] [Order article via Infotrieve] Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102: 3837-3844.[Abstract/Free Full Text] Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281: 1191-1193.[Abstract/Free Full Text] Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189: 1363-1372.[Abstract/Free Full Text] Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol. 2000;164: 3596-3599.[Abstract/Free Full Text] Alexander AM, Crawford M, Bertera S, et al. Indoleamine 2,3-dioxygenase expression in transplanted NOD islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes. 2002;51: 356-365.[Abstract/Free Full Text] Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297: 1867-1870.[Abstract/Free Full Text] Horwitz EM, Gordon PL, Koo WK, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci U S A. 2002;99: 8932-8937.[Abstract/Free Full Text] Daubener W, Spors B, Hucke C, et al. Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect Immun. 2001;69: 6527-6531.[Abstract/Free Full Text] Daubener W, Wanagat N, Pilz K, Seghrouchni S, Fischer HG, Hadding U. A new, simple, bioassay for human IFN-gamma. J Immunol Methods. 1994;168: 39-47.[CrossRef][Medline] [Order article via Infotrieve] Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196: 459-468.[Abstract/Free Full Text] Terness P, Bauer TM, Rose L, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196: 447-457.[Abstract/Free Full Text] Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9: 1269-1274.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. Holan, K. Pokorna, J. Prochazkova, M. Krulova, and A. Zajicova Immunoregulatory Properties of Mouse Limbal Stem Cells J. Immunol., February 15, 2010; 184(4): 2124 - 2129. [Abstract] [Full Text] [PDF] M. E.J. Reinders, W. E. Fibbe, and T. J. Rabelink Multipotent mesenchymal stromal cell therapy in renal disease and kidney transplantation Nephrol. Dial. Transplant., January 1, 2010; 25(1): 17 - 24. [Abstract] [Full Text] [PDF] J. Godin-Ethier, S. Pelletier, L.-A. Hanafi, P. O. Gannon, M.-A. Forget, J.-P. Routy, M.-R. Boulassel, U. Krzemien, S. Tanguay, J.-B. Lattouf, et al. Human Activated T Lymphocytes Modulate IDO Expression in Tumors through Th1/Th2 Balance J. Immunol., December 15, 2009; 183(12): 7752 - 7760. [Abstract] [Full Text] [PDF] M. A. Avanzini, M. E. Bernardo, A. M. Cometa, C. Perotti, N. Zaffaroni, F. Novara, L. Visai, A. Moretta, C. Del Fante, R. Villa, et al. Generation of mesenchymal stromal cells in the presence of platelet lysate: a phenotypic and functional comparison of umbilical cord blood- and bone marrow-derived progenitors Haematologica, December 1, 2009; 94(12): 1649 - 1660. [Abstract] [Full Text] [PDF] T. M. Brusko Mesenchymal Stem Cells: A Potential Border Patrol for Transplanted Islets? Diabetes, August 1, 2009; 58(8): 1728 - 1729. [Full Text] [PDF] Y. Ding, D. Xu, G. Feng, A. Bushell, R. J. Muschel, and K. J. Wood Mesenchymal Stem Cells Prevent the Rejection of Fully Allogenic Islet Grafts by the Immunosuppressive Activity of Matrix Metalloproteinase-2 and -9 Diabetes, August 1, 2009; 58(8): 1797 - 1806. [Abstract] [Full Text] [PDF] C Bocelli-Tyndall, L Bracci, S Schaeren, C Feder-Mengus, A Barbero, A Tyndall, and G C Spagnoli Human bone marrow mesenchymal stem cells and chondrocytes promote and/or suppress the in vitro proliferation of lymphocytes stimulated by interleukins 2, 7 and 15 Ann Rheum Dis, August 1, 2009; 68(8): 1352 - 1359. [Abstract] [Full Text] [PDF] S. L. Highfill, R. M. Kelly, M. J. O'Shaughnessy, Q. Zhou, L. Xia, A. Panoskaltsis-Mortari, P. A. Taylor, J. Tolar, and B. R. Blazar Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming Blood, July 16, 2009; 114(3): 693 - 701. [Abstract] [Full Text] [PDF] G. M. Spaggiari, H. Abdelrazik, F. Becchetti, and L. Moretta MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2 Blood, June 25, 2009; 113(26): 6576 - 6583. [Abstract] [Full Text] [PDF] J. Correale, M. C. Ysrraelit, and M. I. Gaitan Immunomodulatory effects of Vitamin D in multiple sclerosis Brain, May 1, 2009; 132(5): 1146 - 1160. [Abstract] [Full Text] [PDF] A Tyndall Cellular therapy of systemic lupus erythematosus Lupus, April 1, 2009; 18(5): 387 - 393. [Abstract] [PDF] H. Maby-El Hajjami, P. Ame-Thomas, C. Pangault, O. Tribut, J. DeVos, R. Jean, N. Bescher, C. Monvoisin, J. Dulong, T. Lamy, et al. Functional Alteration of the Lymphoma Stromal Cell Niche by the Cytokine Context: Role of Indoleamine-2,3 Dioxygenase Cancer Res., April 1, 2009; 69(7): 3228 - 3237. [Abstract] [Full Text] [PDF] A. Curti, S. Trabanelli, V. Salvestrini, M. Baccarani, and R. M. Lemoli The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology Blood, March 12, 2009; 113(11): 2394 - 2401. [Abstract] [Full Text] [PDF] Y.-I. Jeong, S. W. Kim, I. D. Jung, J. S. Lee, J. H. Chang, C.-M. Lee, S. H. Chun, M.-S. Yoon, G. T. Kim, S. W. Ryu, et al. Curcumin Suppresses the Induction of Indoleamine 2,3-Dioxygenase by Blocking the Janus-activated Kinase-Protein Kinase C{delta}-STAT1 Signaling Pathway in Interferon-{gamma}-stimulated Murine Dendritic Cells J. Biol. Chem., February 6, 2009; 284(6): 3700 - 3708. [Abstract] [Full Text] [PDF] M. A. Haniffa, M. P. Collin, C. D. Buckley, and F. Dazzi Mesenchymal stem cells: the fibroblasts' new clothes? Haematologica, February 1, 2009; 94(2): 258 - 263. [Abstract] [Full Text] [PDF] M. Rafei, J. Hsieh, S. Fortier, M. Li, S. Yuan, E. Birman, K. Forner, M.-N. Boivin, K. Doody, M. Tremblay, et al. Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction Blood, December 15, 2008; 112(13): 4991 - 4998. [Abstract] [Full Text] [PDF] F. Casiraghi, N. Azzollini, P. Cassis, B. Imberti, M. Morigi, D. Cugini, R. A. Cavinato, M. Todeschini, S. Solini, A. Sonzogni, et al. Pretransplant Infusion of Mesenchymal Stem Cells Prolongs the Survival of a Semiallogeneic Heart Transplant through the Generation of Regulatory T Cells J. Immunol., September 15, 2008; 181(6): 3933 - 3946. [Abstract] [Full Text] [PDF] H. Karlsson, S. Samarasinghe, L. M. Ball, B. Sundberg, A. C. Lankester, F. Dazzi, M. Uzunel, K. Rao, P. Veys, K. Le Blanc, et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses Blood, August 1, 2008; 112(3): 532 - 541. [Abstract] [Full Text] [PDF] D. J. Weiss, J. K. Kolls, L. A. Ortiz, A. Panoskaltsis-Mortari, and D. J. Prockop Stem Cells and Cell Therapies in Lung Biology and Lung Diseases Proceedings of the ATS, July 15, 2008; 5(5): 637 - 667. [Full Text] [PDF] R. Abdi, P. Fiorina, C. N. Adra, M. Atkinson, and M. H. Sayegh Immunomodulation by Mesenchymal Stem Cells: A Potential Therapeutic Strategy for Type 1 Diabetes Diabetes, July 1, 2008; 57(7): 1759 - 1767. [Abstract] [Full Text] [PDF] P. Comoli, F. Ginevri, R. Maccario, M. A. Avanzini, M. Marconi, A. Groff, A. Cometa, M. Cioni, L. Porretti, W. Barberi, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1196 - 1202. [Abstract] [Full Text] [PDF] J Larghero, D Farge, A Braccini, S Lecourt, A Scherberich, E Fois, F Verrecchia, T Daikeler, E Gluckman, A Tyndall, et al. Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis Ann Rheum Dis, April 1, 2008; 67(4): 443 - 449. [Abstract] [Full Text] [PDF] R. Atoui, J.-F. Asenjo, M. Duong, G. Chen, R. C.-J. Chiu, and D. Shum-Tim Marrow Stromal Cells as Universal Donor Cells for Myocardial Regenerative Therapy: Their Unique Immune Tolerance Ann. Thorac. Surg., February 1, 2008; 85(2): 571 - 579. [Abstract] [Full Text] [PDF] Y.-P. Li, S. Paczesny, E. Lauret, S. Poirault, P. Bordigoni, F. Mekhloufi, O. Hequet, Y. Bertrand, J.-P. Ou-Yang, J.-F. Stoltz, et al. Human Mesenchymal Stem Cells License Adult CD34+ Hemopoietic Progenitor Cells to Differentiate into Regulatory Dendritic Cells through Activation of the Notch Pathway J. Immunol., February 1, 2008; 180(3): 1598 - 1608. [Abstract] [Full Text] [PDF] G. M. Spaggiari, A. Capobianco, H. Abdelrazik, F. Becchetti, M. C. Mingari, and L. Moretta Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2 Blood, February 1, 2008; 111(3): 1327 - 1333. [Abstract] [Full Text] [PDF] J. Li, A. Meinhardt, M.-E. Roehrich, D. Golshayan, J. Dudler, M. Pagnotta, M. Trucco, and G. Vassalli Indoleamine 2,3-dioxygenase gene transfer prolongs cardiac allograft survival Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3415 - H3423. [Abstract] [Full Text] [PDF] A. J. Nauta and W. E. Fibbe Immunomodulatory properties of mesenchymal stromal cells Blood, November 15, 2007; 110(10): 3499 - 3506. [Abstract] [Full Text] [PDF] D. Chabannes, M. Hill, E. Merieau, J. Rossignol, R. Brion, J. P. Soulillou, I. Anegon, and M. C. Cuturi A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells Blood, November 15, 2007; 110(10): 3691 - 3694. [Abstract] [Full Text] [PDF] F. Gieseke, B. Schutt, S. Viebahn, E. Koscielniak, W. Friedrich, R. Handgretinger, and I. Muller Human multipotent mesenchymal stromal cells inhibit proliferation of PBMCs independently of IFN{gamma}R1 signaling and IDO expression Blood, September 15, 2007; 110(6): 2197 - 2200. [Abstract] [Full Text] [PDF] S. Jones, N. Horwood, A. Cope, and F. Dazzi The Antiproliferative Effect of Mesenchymal Stem Cells Is a Fundamental Property Shared by All Stromal Cells J. Immunol., September 1, 2007; 179(5): 2824 - 2831. [Abstract] [Full Text] [PDF] P. Batten, N. A Rosenthal, and M. H Yacoub Immune response to stem cells and strategies to induce tolerance Phil Trans R Soc B, August 29, 2007; 362(1484): 1343 - 1356. [Abstract] [Full Text] [PDF] M. A. Haniffa, X.-N. Wang, U. Holtick, M. Rae, J. D. Isaacs, A. M. Dickinson, C. M. U. Hilkens, and M. P. Collin Adult Human Fibroblasts Are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells J. Immunol., August 1, 2007; 179(3): 1595 - 1604. [Abstract] [Full Text] [PDF] C. Prevosto, M. Zancolli, P. Canevali, M. R. Zocchi, and A. Poggi Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction Haematologica, July 1, 2007; 92(7): 881 - 888. [Abstract] [Full Text] [PDF] A. Curti, S. Pandolfi, B. Valzasina, M. Aluigi, A. Isidori, E. Ferri, V. Salvestrini, G. Bonanno, S. Rutella, I. Durelli, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells Blood, April 1, 2007; 109(7): 2871 - 2877. [Abstract] [Full Text] [PDF] K. Sato, K. Ozaki, I. Oh, A. Meguro, K. Hatanaka, T. Nagai, K. Muroi, and K. Ozawa Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells Blood, January 1, 2007; 109(1): 228 - 234. [Abstract] [Full Text] [PDF] L. Zhu, F. Ji, Y. Wang, Y. Zhang, Q. Liu, J. Z. Zhang, K. Matsushima, Q. Cao, and Y. Zhang Synovial Autoreactive T Cells in Rheumatoid Arthritis Resist IDO-Mediated Inhibition J. Immunol., December 1, 2006; 177(11): 8226 - 8233. [Abstract] [Full Text] [PDF] L. Romani, F. Bistoni, K. Perruccio, C. Montagnoli, R. Gaziano, S. Bozza, P. Bonifazi, G. Bistoni, G. Rasi, A. Velardi, et al. Thymosin {alpha}1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance Blood, October 1, 2006; 108(7): 2265 - 2274. [Abstract] [Full Text] [PDF] J. M. van Laar and A. Tyndall Adult stem cells in the treatment of autoimmune diseases Rheumatology, October 1, 2006; 45(10): 1187 - 1193. [Abstract] [Full Text] [PDF] A. J. Nauta, G. Westerhuis, A. B. Kruisselbrink, E. G. A. Lurvink, R. Willemze, and W. E. Fibbe Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting Blood, September 15, 2006; 108(6): 2114 - 2120. [Abstract] [Full Text] [PDF] A. J. Nauta, A. B. Kruisselbrink, E. Lurvink, R. Willemze, and W. E. Fibbe Mesenchymal Stem Cells Inhibit Generation and Function of Both CD34+-Derived and Monocyte-Derived Dendritic Cells J. Immunol., August 15, 2006; 177(4): 2080 - 2087. [Abstract] [Full Text] [PDF] J. Stagg, S. Pommey, N. Eliopoulos, and J. Galipeau Interferon-{gamma}-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell Blood, March 15, 2006; 107(6): 2570 - 2577. [Abstract] [Full Text] [PDF] G. M. Spaggiari, A. Capobianco, S. Becchetti, M. C. Mingari, and L. Moretta Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation Blood, February 15, 2006; 107(4): 1484 - 1490. [Abstract] [Full Text] [PDF] J. J. Minguell and A. Erices Mesenchymal Stem Cells and the Treatment of Cardiac Disease Exp Biol Med, January 1, 2006; 231(1): 39 - 49. [Abstract] [Full Text] [PDF] H. Fujigaki, K. Saito, F. Lin, S. Fujigaki, K. Takahashi, B. M. Martin, C. Y. Chen, J. Masuda, J. Kowalak, O. Takikawa, et al. Nitration and Inactivation of IDO by Peroxynitrite J. Immunol., January 1, 2006; 176(1): 372 - 379. [Abstract] [Full Text] [PDF] A. Corcione, F. Benvenuto, E. Ferretti, D. Giunti, V. Cappiello, F. Cazzanti, M. Risso, F. Gualandi, G. L. Mancardi, V. Pistoia, et al. Human mesenchymal stem cells modulate B-cell functions Blood, January 1, 2006; 107(1): 367 - 372. [Abstract] [Full Text] [PDF] N. Eliopoulos, J. Stagg, L. Lejeune, S. Pommey, and J. Galipeau Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice Blood, December 15, 2005; 106(13): 4057 - 4065. [Abstract] [Full Text] [PDF] A. Poggi, C. Prevosto, A.-M. Massaro, S. Negrini, S. Urbani, I. Pierri, R. Saccardi, M. Gobbi, and M. R. Zocchi Interaction between Human NK Cells and Bone Marrow Stromal Cells Induces NK Cell Triggering: Role of NKp30 and NKG2D Receptors J. Immunol., November 15, 2005; 175(10): 6352 - 6360. [Abstract] [Full Text] [PDF] R. Potula, L. Poluektova, B. Knipe, J. Chrastil, D. Heilman, H. Dou, O. Takikawa, D. H. Munn, H. E. Gendelman, and Y. Persidsky Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis Blood, October 1, 2005; 106(7): 2382 - 2390. [Abstract] [Full Text] [PDF] B. R Blazar and W. J Murphy Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD) Phil Trans R Soc B, September 29, 2005; 360(1461): 1747 - 1767. [Abstract] [Full Text] [PDF] E. Zappia, S. Casazza, E. Pedemonte, F. Benvenuto, I. Bonanni, E. Gerdoni, D. Giunti, A. Ceravolo, F. Cazzanti, F. Frassoni, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy Blood, September 1, 2005; 106(5): 1755 - 1761. [Abstract] [Full Text] [PDF] U. Hainz, P. Obexer, C. Winkler, P. Sedlmayr, O. Takikawa, H. Greinix, A. Lawitschka, U. Putschger, D. Fuchs, S. Ladisch, et al. Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation Blood, May 15, 2005; 105(10): 4127 - 4134. [Abstract] [Full Text] [PDF] S. Glennie, I. Soeiro, P. J. Dyson, E. W.-F. Lam, and F. Dazzi Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells Blood, April 1, 2005; 105(7): 2821 - 2827. [Abstract] [Full Text] [PDF] P. Terness, J.-J. Chuang, T. Bauer, L. Jiga, and G. Opelz Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)-producing dendritic cells: too much ado about IDO? Blood, March 15, 2005; 105(6): 2480 - 2486. [Abstract] [Full Text] [PDF] S. Aggarwal and M. F. Pittenger Human mesenchymal stem cells modulate allogeneic immune cell responses Blood, February 15, 2005; 105(4): 1815 - 1822. [Abstract] [Full Text] [PDF] H. McDevitt Specific antigen vaccination to treat autoimmune disease PNAS, October 5, 2004; 101(suppl_2): 14627 - 14630. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2003-11-3909v1 103/12/4619    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meisel, R. Articles by Dilloo, D. Search for Related Content PubMed PubMed Citation Articles by Meisel, R. Articles by Dilloo, D. Related Collections Immunobiology Transplantation Brief Reports Social Bookmarking                   What's this?

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020