On the interactions between mesenchymal stem cells and regulatory T cells for immunomodulation in transplantation

Frontiers in Immunology

Volumn 3, Issue MAY, 2012, Pages

  Engela, Anja U ^a   Baan, Carla C ^a   Dor, Frank J M F ^a   Weimar, Williem ^a   Hoogduijn, Martin J ^a  

^a ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

Mesenchymal stem cell; Regulatory T cell; Transplantation

Indexed keywords

EID: 84873366721     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00126     Document Type: Review

References (103)

1. Aggarwal,S. and Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cellresponses. Blood 105,1815-1822.
2. Akimova, T., Beier, U. H., Wang, L., Levine, M. H., and Hancock, W. W. (2011). Helios expression is a marker of T cell activation and proliferation. PLoS ONE 6, e24226. doi: 10.1371/journal.pone.0024226
3. Antonucci, I., Stuppia, L., Kaneko, Y., Yu, S., Tajiri, N., Bae, E. C., Chheda, S. H., Weinbren, N. L., and Borlongan, C. V. (2011). Amniotic fluid as a rich source of mesenchymal stromal cells for transplantation therapy. Cell Transplant. 20, 789-795.
4. Assis,A.C.,Carvalho,J.L.,Jacoby,B.A., Ferreira, R. L., Castanheira, P., Diniz, S. O., Cardoso, V. N., Goes, A. M., and Ferreira, A. J. (2010). Timedependent migration of systemically deliveredbonemarrowmesenchymal stem cells to the infarcted heart. Cell Transplant. 19, 219-230.
5. Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., and Roncarolo, M. G. (2006). Defective regulatory and effector T cellfunctionsinpatientswithFOXP3 mutations. J. Clin. Invest. 116, 1713-1722.
6. +T cells. J. Immunol. 175,1483-1490.
7. Barbash, I. M., Chouraqui, P., Baron, J., Feinberg, M. S., Etzion, S., Tessone, A., Miller, L., Guetta, E., Zipori, D., Kedes, L. H., Kloner, R. A., and Leor, J. (2003). Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation 108, 863-868.
8. Baron, U., Floess, S., Wieczorek, G., Baumann, K., Grutzkau, A., Dong, J., Thiel, A., Boeld, T. J., Hoffmann, P., Edinger, M., Turbachova, I., Hamann, A., Olek, S., and Huehn, J. (2007). DNA demethylation in the human FOXP3 locus discriminatesregulatoryTcellsfromactivated FOXP3(+) conventional T cells. Eur. J. Immunol. 37, 2378-2389.
9. Bartholomew,A.,Sturgeon,C.,Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans,R.,Moseley,A.,and Hoffman, R. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30,42-48.
10. Battaglia, M., Stabilini,A., and Tresoldi, E. (2012). Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol. Biol. 821, 279-293.
11. Batten, P., Sarathchandra, P., Antoniw, J. W., Tay, S. S., Lowdell, M. W., Taylor, P. M., and Yacoub, M. H. (2006). Human mesenchymal stem cells induce T cell anergy and downregulate T cell allo-responses via the TH2 pathway: relevance to tissue engineering human heart valves. Tissue Eng. 12,2263-2273.
12. Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., and Ochs, H. D. (2001). The immune dysregulation, polyendocrinopathy, enteropathy, Xlinked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20-21.
13. + regulatory T cell recruitment in human renal allograft infiltrates. J. Immunol. 179, 4901-4909.
14. Brunstein, C. G., Miller, J. S., Cao, Q., McKenna, D. H., Hippen, K. L., Curtsinger, J., Defor, T., Levine, B. L., June, C. H., Rubinstein, P., McGlave, P. B., Blazar, B. R., and Wagner, J. E. (2011). Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117, 1061-1070.
15. Buckner, J. H. (2010). Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat. Rev. Immunol. 10, 849-859.
16. Buron, F., Perrin, H., Malcus, C., Hequet, O., Thaunat, O., KholoppSarda, M. N., Moulin, F. T., and Morelon, E. (2009). Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneicresponses:aninvitrostudy using human cells. Transplant. Proc. 41, 3347-3352.
17. Carlson, M. J., West, M. L., Coghill, J. M., Panoskaltsis-Mortari, A., Blazar, B. R., and Serody, J. S. (2009). In vitro-differentiated TH17 cells mediate lethal acute graft-versushost disease with severe cutaneous and pulmonary pathologic manifestations. Blood 113,1365-1374.
18. Casiraghi, F., Azzollini, N., Cassis, P., Imberti, B., Morigi, M., Cugini, D., Cavinato, R. A., Todeschini, M., Solini, S., Sonzogni, A., Perico, N., Remuzzi, G., and Noris, M. (2008). Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J. Immunol. 181, 3933-3946.
19. + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198,1875-1886.
20. Corcione, A., Benvenuto, F., Ferretti, E., Giunti, D., Cappiello, V., Cazzanti, F., Risso, M., Gualandi, F., Mancardi,G.L.,Pistoia,V.,and Uccelli,A. (2006). Human mesenchymal stem cellsmodulateB-cellfunctions.Blood 107,367-372.
21. Crop, M. J., Baan, C. C., Korevaar, S. S., Ijzermans, J. N., Pescatori, M., Stubbs, A. P., van Ijcken, W. F., Dahlke, M. H., Eggenhofer, E., Weimar, W., and Hoogduijn, M. J. (2010). Inflammatory conditions affect gene expression and functionof humanadiposetissue-derived mesenchymal stem cells. Clin. Exp. Immunol. 162,474-486.
22. de la Garza-Rodea, A. S., van der Velde-van Dijke, L., Boersma, H., Goncalves, M. A., van Bekkum, D. W., de Vries, A. A., and KnaanShanzer, S. (2012). Myogenic properties of human mesenchymal stem cells derived from three different sources. CellTransplant. 21,153-173.
23. Deuse, T., Stubbendorff, M., TangQuan, K., Phillips, N., Kay, M. A., Eiermann, T., Phan, T. T., Volk, H. D., Reichenspurner, H., Robbins, R. C., and Schrepfer, S. (2011). Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant. 20, 655-667.
24. Di Ianni, M., Del Papa, B., De Ioanni, M., Moretti, L., Bonifacio, E., Cecchini, D., Sportoletti, P., Falzetti, F., and Tabilio, A. (2008). Mesenchymal cellsrecruitandregulateTregulatory cells. Exp. Hematol. 36,309-318.
25. Di Ianni, M., Falzetti, F., Carotti, A., Terenzi, A., Castellino, F., Bonifacio, E., Del Papa, B., Zei, T., Ostini, R. I., Cecchini, D., Aloisi, T., Perruccio, K., Ruggeri, L., Balucani, C., Pierini, A., Sportoletti, P., Aristei, C., Falini, B., Reisner, Y., Velardi, A., Aversa, F., and Martelli, M. F. (2011). Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 117, 3921-3928.
26. Di Nicola, M., Carlo-Stella, C., Magni, M.,Milanesi,M.,Longoni,P.D.,Matteucci, P., Grisanti, S., and Gianni, A. M. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99,3838-3843.
27. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D., and Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8,315-317.
28. Eggenhofer, E., Renner, P., Soeder, Y., Popp, F. C., Hoogduijn, M. J., Geissler, E. K., Schlitt, H. J., and Dahlke, M. H. (2011). Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. Transpl. Immunol. 25, 141-147.
29. Engela, A. U., Baan, C. C., Peeters, A. M., Weimar, W., and Hoogduijn, M. J. (2012). Interaction between adipose-tissue derived mesenchymal stem cells and regulatory T cells. Cell Transplant.doi:10.3727/096368912X 636984 [Epub ahead of print].
30. English, K., Barry, F. P., FieldCorbett, C. P., and Mahon, B. P. (2007). IFN-gamma and TNF-alpha differentially regulate immunomodulationbymurinemesenchymalstem cells. Immunol. Lett. 110,91-100.
31. + regulatory T cells. Clin. Exp. Immunol. 156,149-160.
32. Fischer, U. M., Harting, M. T., Jimenez, F., Monzon-Posadas, W. O., Xue, H., Savitz, S. I., Laine, G. A., and Cox, C. S. Jr. (2009). Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 18, 683-692.
33. + regulatory T cells. Nat. Immunol. 4,330-336.
34. Ford McIntyre, M. S.,Young, K. J., Gao, J., Joe, B., and Zhang, L. (2008). Cutting edge: in vivo trogocytosis as a mechanism of double negative regulatory T cell-mediated antigenspecificsuppression.J.Immunol.181, 2271-2275.
35. Friedenstein, A. J., Chailakhjan, R. K., and Lalykina, K. S. (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3,393-403.
36. - precursors. Am. J. Transplant. 4,1614-1627.
37. Ge, W., Jiang, J., Arp, J., Liu, W., Garcia,B.,and Wang,H. (2010).Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 90,1312-1320.
38. Ge, W., Jiang, J., Baroja, M. L., Arp, J., Zassoko, R., Liu, W., Bartholomew, A., Garcia, B., and Wang, H. (2009). Infusion of mesenchymal stem cells andrapamycinsynergizetoattenuate alloimmune responses and promote cardiac allograft tolerance. Am. J. Transplant. 9,1760-1772.
39. Ghannam, S., Pene, J., Torcy-Moquet, G., Jorgensen, C., and Yssel, H. (2010). Mesenchymal stem cells inhibit human Th17 cell differentiationandfunctionandinduceaTregulatory cell phenotype. J. Immunol. 185,302-312.
40. + regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 17831786.
41. Gonzalez,M.A.,Gonzalez-Rey,E.,Rico, L., Buscher, D., and Delgado, M. (2009). Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 136, 978-989.
42. + regulatory T cells. J. Immunol. 188, 976-980.
43. Groh, M. E., Maitra, B., Szekely, E., and Koc,O.N. (2005).Humanmesenchymal stem cells require monocytemediated activation to suppress alloreactive T cells. Exp. Hematol. 33, 928-934.
44. Grossman, W. J., Verbsky, J. W., Tollefsen, B. L., Kemper, C., Atkinson, J. P., and Ley, T. J. (2004). Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets andT regulatory cells. Blood 104, 2840-2848.
45. Hayday, A., and Tigelaar, R. (2003). Immunoregulation in the tissues by gammadelta T cells. Nat. Rev. Immunol. 3,233-242.
46. Hendrikx, T. K., van Gurp, E. A., Sewgobind,V.D.,Mol,W.M.,Schoordijk, W., Klepper, M., Velthuis, J. H., Geel, A., Ijzermans, J. N., Weimar, W., and Baan, C. C. (2009a). Generation of donor-specificregulatoryT-cellfunction in kidney transplant patients. Transplantation 87,376-383.
47. Hendrikx, T. K., Velthuis, J. H., Klepper, M., van Gurp, E., Geel, A., Schoordijk, W., Baan, C. C., and Weimar, W. (2009b). Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients. Transpl. Int. 22,884-891.
48. Hoogduijn, M. J., Crop, M. J., Korevaar, S. S., Peeters, A. M., Eijken, M., Maat, L. P., Balk, A. H., Weimar, W., and Baan, C. C. (2008). Susceptibilityof humanmesenchymalstemcells to tacrolimus, mycophenolic acid, and rapamycin. Transplantation 86, 1283-1291.
49. Hoogduijn,M.J.,Crop,M.J.,Peeters,A. M., Van Osch, G. J., Balk, A. H., Ijzermans, J. N., Weimar, W., and Baan, C. C. (2007). Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. Stem Cells Dev. 16, 597-604.
50. Hoogduijn, M. J., Eggenhofer, E., Popp, F. C., Renner, P., Weimar, W., Baan, C. C., and Dahlke, M. H. (2011). Living mesenchymal stem cells disappear rapidly after intravenous infusion. Cytotherapy 13(Annual Meeting Abstract Supplement),abstract number 57.
51. Hoogduijn, M. J., Popp, F., Verbeek, R., Masoodi, M., Nicolaou, A., Baan, C., and Dahlke, M. H. (2010a). The immunomodulatory propertiesof mesenchymalstemcells andtheiruseforimmunotherapy.Int. Immunopharmacol. 10, 1496-1500.
52. Hoogduijn, M. J., Popp, F. C., Grohnert, A., Crop, M. J., van Rhijn, M., Rowshani,A. T., Eggenhofer, E., Renner, P., Reinders, M. E., Rabelink, T. J., van der Laan, L. J., Dor, F. J., Ijzermans, J. N., Genever, P. G., Lange, C., Durrbach, A., Houtgraaf, J. H., Christ, B., Seifert, M., Shagidulin, M., Donckier, V., Deans, R., Ringden, O., Perico, N., Remuzzi, G., Bartholomew, A., Schlitt, H. J., Weimar, W., Baan, C. C., Dahlke, M. H., and MISOT Study Group. (2010b). Advancement of mesenchymal stem cell therapy in solid organ transplantation(MISOT).Transplantation 90,124-126.
53. Issa, F., Hester, J., Goto, R., Nadig, S. N., Goodacre, T. E., and Wood, K. (2010). Ex vivo-expanded human regulatory T cells prevent the rejectionof skinallograftsinahumanized mouse model. Transplantation 90, 1321-1327.
54. Jiang,X. X.,Zhang,Y.,Liu,B.,Zhang,S. X., Wu, Y., Yu, X. D., and Mao, N. (2005). Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105, 4120-4126.
55. Jurgens, B., Hainz, U., Fuchs, D., Felzmann, T., and Heitger, A. (2009). Interferon-gamma-triggered indoleamine 2,3-dioxygenase competence in human monocyte-derived dendritic cells induces regulatory activity in allogeneic T cells. Blood 114,3235-3243.
56. Kappel, L. W., Goldberg, G. L., King, C. G., Suh, D. Y., Smith, O. M., Ligh, C., Holland, A. M., Grubin, J., Mark, N. M., Liu, C., Iwakura, Y., Heller, G., and van den Brink, M. R. (2009). IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 113, 945-952.
57. Kavanagh,H.,and Mahon,B. P. (2011). Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy 66,523-531.
58. Kobayashi, I., Shiari, R., Yamada, M., Kawamura, N., Okano, M., Yara, A., Iguchi, A., Ishikawa, N., Ariga, T., Sakiyama, Y., Ochs, H. D., and Kobayashi, K. (2001). Novel mutations of FOXP3 in two Japanese patients with immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX). J. Med. Genet. 38,874-876.
59. Kraitchman, D. L., Tatsumi, M., Gilson, W. D., Ishimori, T., Kedziorek, D., Walczak, P., Segars, W. P., Chen, H. H., Fritzges, D., Izbudak, I., Young, R. G., Marcelino, M., Pittenger, M. F., Solaiyappan, M., Boston, R. C., Tsui, B. M., Wahl, R. L., and Bulte, J. W. (2005). Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 112,1451-1461.
60. Le Blanc, K., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., Lanino, E., Sundberg, B., Bernardo, M. E., Remberger, M., Dini, G., Egeler, R. M., Bacigalupo, A., Fibbe, W., Ringden, O., (2008) Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371, 1579-1586.
61. Le Blanc, K., Rasmusson, I., Sundberg, B., Gotherstrom, C., Hassan, M., Uzunel, M., and Ringden, O. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 14391441.
62. + Treg cells. J. Exp. Med. 203, 1701-1711.
63. + regulatory cells combined with lowdose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys. Int. Immunopharmacol. 11, 618-629.
64. + T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90, 516-525.
65. McHugh, R. S., Whitters, M. J., Piccirillo, C. A., Young, D. A., Shevach, E. M., Collins, M., and Byrne, M. C. (2002). CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoidinduced TNF receptor. Immunity 16, 311-323.
66. McMurchy, A. N., Bushell, A., Levings, M. K., and Wood, K. J. (2011). Moving to tolerance: clinical application of T regulatory cells. Semin. Immunol. 23, 304-313.
67. Meisel, R., Zibert, A., Laryea, M., Gobel, U., Daubener, W., and Dilloo, D. (2004). Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3dioxygenase-mediated tryptophan degradation. Blood 103, 4619-4621.
68. + invariant NKT cells induced by TGF-beta. J. Immunol. 185,2157-2163.
69. Nadig, S. N., Wieckiewicz, J., Wu, D. C., Warnecke, G., Zhang, W., Luo, S., Schiopu, A., Taggart, D. P., and Wood, K. J. (2010). In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat. Med. 16,809-813.
70. Nasef, A., Mathieu, N., Chapel, A., Frick, J., Francois, S., Mazurier, C., Boutarfa, A., Bouchet, S., Gorin, N. C., Thierry, D., and Fouillard, L. (2007). Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84, 231-237.
71. + -derived and monocytederived dendritic cells. J. Immunol. 177,2080-2087.
72. Nemeth,K.,Leelahavanichkul,A.,Yuen, P. S., Mayer, B., Parmelee, A., Doi, K., Robey, P. G., Leelahavanichkul, K., Koller, B. H., Brown, J. M., Hu, X., Jelinek, I., Star, R. A., and Mezey, E. (2009). Bone marrow stromal cells attenuate sepsis via prostaglandinE(2)-dependentreprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15,42-49.
73. Perico, N., Casiraghi, F., Introna, M., Gotti,E.,Todeschini,M.,Cavinato,R. A., Capelli, C., Rambaldi, A., Cassis, P., Rizzo, P., Cortinovis, M., Marasa, M.,Golay,J.,Noris,M.,andRemuzzi, G. (2011). Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin. J. Am. Soc. Nephrol. 6,412-422.
74. Pittenger, M. F., Mackay,A. M., Beck, S. C.,Jaiswal,R. K.,Douglas,R.,Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., and Marshak, D. R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147.
75. Popp, F. C., Eggenhofer, E., Renner, P., Slowik, P., Lang, S. A., Kaspar, H., Geissler, E. K., Piso, P., Schlitt, H. J., and Dahlke, M. H. (2008). Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transpl. Immunol. 20, 55-60.
76. + regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica 92,881-888.
77. Raffaghello, L., Bianchi, G., Bertolotto, M., Montecucco, F., Busca, A., Dallegri, F., Ottonello, L., and Pistoia, V. (2008). Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in thebonemarrowniche.StemCells26, 151-162.
78. Read, S., Malmstrom,V., and Powrie, F. (2000). Cytotoxic T lymphocyteassociated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 192,295-302.
79. Reibke, R., Garbi, N., Ganss, R., Hammerling, G. J.,Ar+nold,B., and Oelert, T. (2006). CD8 regulatory T cells generated by neonatal recognition of peripheral self-antigen. Proc. Natl. Acad. Sci. U.S.A. 103,15142-15147.
80. Roncarolo, M. G., Gregori, S., Battaglia, M., Bacchetta, R., Fleischhauer, K., and Levings, M. K. (2006). Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212,28-50.
81. Ryan, J. M., Barry, F., Murphy, J. M., and Mahon, B. P. (2007). Interferongammadoesnotbreak,butpromotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin. Exp. Immunol. 149, 353363.
82. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). Immunologic self-tolerance maintained by activated T cells expressingIL-2receptoralpha-chains (CD25).Breakdownofasinglemechanismofself-tolerancecausesvarious autoimmune diseases. J. Immunol. 155,1151-1164.
83. + immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431-440.
84. Sato, K., Ozaki, K., Oh, I., Meguro, A., Hatanaka, K., Nagai, T., Muroi, K., and Ozawa, K. (2007). Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109,228-234.
85. Schliesser, U., Streitz, M., and Sawitzki, B. (2012). Tregs: application forsolid-organtransplantation.Curr. Opin. Organ Transplant. 17,34-41.
86. Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M., Selby, W., Alexander, S. I., Nanan, R., Kelleher, A., and Fazekas de St Groth, B. (2006). Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693-1700.
87. + regulatory T cells. Stem Cells 26, 212-222.
88. Shi, X. L., Gu, J. Y., Han, B., Xu, H. Y., Fang,L.,andDing,Y.T. (2010). Magnetically labeled mesenchymal stem cells after autologous transplantation into acutely injured liver. World J. Gastroenterol. 16,3674-3679.
89. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., and Sakaguchi, S. (2002). Stimulation of CD25(+) CD4(+) regulatory T cells through GITR breaks immunological selftolerance. Nat. Immunol. 3,135-142.
90. + regulatory T cells. Blood 118, 2342-2350.
91. Sotiropoulou, P. A., Perez, S. A., Gritzapis, A. D., Baxevanis, C. N., and Papamichail, M. (2006). Interactions between human mesenchymal stem cellsandnaturalkillercells.StemCells 24, 74-85.
92. Spaggiari, G. M., Abdelrazik, H., Becchetti, F., and Moretta, L. (2009). 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 113, 6576-6583.
93. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak,T.W.,and Sakaguchi,S. (2000). Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303-310.
94. + regulatory T cell: a jack of all trades, master of regulation. Nat. Immunol. 9,239-244.
95. Tatara, R., Ozaki, K., Kikuchi, Y., Hatanaka, K., Oh, I., Meguro, A., Matsu, H., Sato, K., and Ozawa, K. (2011). Mesenchymal stromal cells inhibit Th17 but not regulatory Tcell differentiation. Cytotherapy 13, 686-694.
96. + T regulatory cells. J. Immunol. 184, 3433-3441.
97. - T regulatory cells. Clin. Immunol. 133,22-26.
98. + regulatory T cells can mediate donor nonreactivity in long-term immunosuppressed kidney allograft patients. Am. J. Transplant. 6,2955-2964.
99. Weiner, H. L. (2001). The mucosal milieu creates tolerogenic dendritic cellsandT(R)1andT(H)3regulatory cells. Nat. Immunol. 2, 671-672.
100. Wieczorek, G., Asemissen, A., Model, F., Turbachova, I., Floess, S., Liebenberg,V.,Baron,U.,Stauch,D.,Kotsch, K., Pratschke, J., Hamann, A., Loddenkemper, C., Stein, H.,Volk, H. D., Hoffmuller,U.,Grutzkau,A.,Mustea, A.,Huehn,J.,Scheibenbogen,C.,and Olek, S. (2009). Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res. 69,599-608.
101. Ziegler, S. F. (2006). FOXP3: of mice and men. Annu. Rev. Immunol. 24, 209-226.
102. Zonta, S., De Martino, M., Bedino, G., Piotti, G., Rampino, T., Gregorini, M., Frassoni, F., Dal Canton, A., Dionigi, P., and Alessiani, M. (2010). Which is the most suitable and effective route of administration for mesenchymal stem cellbased immunomodulation therapy in experimental kidney transplantation: endovenous or arterial? Transplant. Proc. 42,1336-1340.
103. Zuk, P. A., Zhu, M., Ashjian, P., De Ugarte, D. A., Huang, J. I., Mizuno, H., Alfonso, Z. C., Fraser, J. K., Benhaim, P., and Hedrick, M. H. (2002). Human adipose tissue is a source of multipotentstemcells. Mol. Biol. Cell 13, 4279-4295.