Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells

International Immunopharmacology

Volumn 11, Issue 3, 2011, Pages 384-389

  Iwami, Daiki ^a,b   Nonomura, Katsuya ^b   Shirasugi, Nozomu ^a,c   Niimi, Masanori ^a  

^a TEIKYO UNIVERSITY   (Japan)

^b HOKKAIDO UNIVERSITY   (Japan)

^c Aisei Hospital   (Japan)

Author keywords

Eicosapentaenoic acid (EPA); Omega 3 polyunsaturated fatty acids (PUFAs); Peroxisome proliferator activated receptor (PPAR ); Regulatory T cells (Tregs); Transplantation

Indexed keywords

AZATHIOPRINE; CYCLOSPORIN A; ICOSAPENTAENOIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; OMEGA 3 FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; RAPAMYCIN; TACROLIMUS;

ANTIGEN SPECIFICITY; ANTIINFLAMMATORY ACTIVITY; AUTOIMMUNE DISEASE; CYTOKINE PRODUCTION; DOSE RESPONSE; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; ENZYME MECHANISM; EXPERIMENTAL MODEL; GRAFT REJECTION; GRAFT SURVIVAL; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOMODULATION; IMMUNOREGULATION; LOW DRUG DOSE; NONHUMAN; ORGAN TRANSPLANTATION; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SINGLE DRUG DOSE; T LYMPHOCYTE ACTIVATION;

ANIMALS; EICOSAPENTAENOIC ACID; FATTY ACIDS, UNSATURATED; IMMUNOSUPPRESSIVE AGENTS; PPAR GAMMA; T-LYMPHOCYTES, REGULATORY;

EID: 79952104241     PISSN: 15675769     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.intimp.2010.11.035     Document Type: Review

References (95)

1. Kromann N, Green A. Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med Scand 1980;208:401-6.
2. Calder PC. Sir David Cuthbertson Medal Lecture. Immunomodulatory and antiinflammatory effects of n-3 polyunsaturated fatty acids. Proc Nutr Soc 1996;55: 737-74. (Pubitemid 126768953)
3. Calder PC. Immunoregulatory and anti-inflammatory effects of n-3 polyunsaturated fatty acids. Braz J Med Biol Res 1998;31:467-90. (Pubitemid 28223707)
4. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8. (Pubitemid 46483662)
5. Wood KJ, Luo S, Akl A. Regulatory T cells: potential in organ transplantation. Transplantation 2004;77:S6-8.
6. Long E, Wood KJ. Regulatory T cells in transplantation: transferring mouse studies to the clinic. Transplantation 2009;88:1050-6.
7. Forman BM, Chen J, Evans RM. The peroxisome proliferator-activated receptors: ligands and activators. Ann NY Acad Sci 1996;804:266-75. (Pubitemid 27056615)
8. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxydelta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995;83:803-12. (Pubitemid 3006324)
9. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995;83:813-9. (Pubitemid 3006325)
10. Krey G, Braissant O, L'Horset F, Kalkhoven E, Perroud M, Parker MG, et al. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 1997;11:779-91. (Pubitemid 27225305)
11. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, et al. EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPARgamma-dependent mechanism. Kidney Int 2005;67:867-74. (Pubitemid 41623311)
12. Sanchez-Hidalgo M, Martin AR, Villegas I, Alarcon De La Lastra C. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats. Biochem Pharmacol 2005;69:1733-44. (Pubitemid 40780073)
13. Wohlfert EA, Nichols FC, Nevius E, Clark RB. Peroxisome proliferator-activated receptor gamma (PPARgamma) and immunoregulation: enhancement of regulatory T cells through PPARgamma-dependent and -independent mechanisms. J Immunol 2007;178:4129-35. (Pubitemid 46492362)
14. Hontecillas R, Bassaganya-Riera J. Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol 2007;178:2940-9. (Pubitemid 46333173)
15. Gurr MI. The role of lipids in the regulation of the immune system. Prog Lipid Res 1983;22:257-87.
16. Yaqoob P, Calder PC. The effects of fatty acids on lymphocyte functions. Int J Biochem 1993;25:1705-14.
17. Calder PC, Bond JA, Newsholme EA. Fatty acid inhibition of concanavalin A-stimulated lymphocyte proliferation. Biochem Soc Trans 1989;17:1042-3. (Pubitemid 20028053)
18. Calder PC, Bond JA, Newsholme EA. Fatty acid inhibition of lipopolysaccharide-stimulated B lymphocyte proliferation. Biochem Soc Trans 1990;18:904-5. (Pubitemid 20359365)
19. Fujikawa M, Yamashita N, Yamazaki K, Sugiyama E, Suzuki H, Hamazaki T. Eicosapentaenoic acid inhibits antigen-presenting cell function of murine splenocytes. Immunology 1992;75:330-5.
20. Renier G, Skamene E, DeSanctis J, Radzioch D. Dietary n-3 polyunsaturated fatty acids prevent the development of atherosclerotic lesions in mice. Modulation of macrophage secretory activities. Arterioscler Thromb 1993;13:1515-24. (Pubitemid 23303406)
21. Yaqoob P, Calder P. Effects of dietary lipid manipulation upon inflammatory mediator production by murine macrophages. Cell Immunol 1995;163:120-8.
22. Calder PC, Newsholme EA. Unsaturated fatty acids suppress interleukin-2 production and transferrin receptor expression by concanavalin A-stimulated rat Iymphocytes. Mediat Inflamm 1992;1:107-12.
23. Kinsella JE, Lokesh B, Broughton S, Whelan J. Dietary polyunsaturated fatty acids and eicosanoids: potential effects on the modulation of inflammatory and immune cells: an overview. Nutrition 1990;6:24-44 [discussion 59-62].
24. Grimminger F, Grimm H, Fuhrer D, Papavassilis C, Lindemann G, Blecher C, et al. Omega-3 lipid infusion in a heart allotransplant model. Shift in fatty acid and lipid mediator profiles and prolongation of transplant survival. Circulation 1996;93: 365-71.
25. Gibson SW, Valente JF, Alexander JW, Custer DA, Li BG, Frede S, et al. Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506. Transplantation 2000;69:2034-8. (Pubitemid 30395029)
26. Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB. Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for cyclosporine. Transplantation 1989;48:98-102. (Pubitemid 19194047)
27. Otto DA, Kahn DR, Hamm MW, Forrest DE, Wooten JT. Improved survival of heterotopic cardiac allografts in rats with dietary n-3 polyunsaturated fatty acids. Transplantation 1990;50:193-8. (Pubitemid 20259159)
28. van der Heide JJ, Bilo HJ, Donker JM, Wilmink JM, Tegzess AM. Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants. N Engl J Med 1993;329:769-73. (Pubitemid 23262532)
29. Bennett WM, Carpenter CB, Shapiro ME, Strom TB, Hefty D, Tillman M, et al. Delayed omega-3 fatty acid supplements in renal transplantation. A double-blind, placebo-controlled study. Transplantation 1995;59:352-6.
30. Hernandez D, Guerra R, Milena A, Torres A, Garcia S, Garcia C, et al. Dietary fish oil does not influence acute rejection rate and graft survival after renal transplantation: a randomized placebo-controlled study. Nephrol Dial Transplant 2002;17:897-904. (Pubitemid 34521145)
31. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003;3:199-210. (Pubitemid 37323205)
32. Long ET, Wood KJ. Regulatory T cells-a journey from rodents to the clinic. Front Biosci 2007;12:4042-9.
33. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531-62. (Pubitemid 38680433)
34. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-61. (Pubitemid 36222930)
35. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245-53. (Pubitemid 32703119)
36. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192:303-10.
37. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000;192:295-302. (Pubitemid 30470312)
38. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+) CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135-42. (Pubitemid 34141443)
39. Hawrylowicz CM. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med 2005;202:1459-63. (Pubitemid 41746591)
40. Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, et al. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 2006;116:2423-33. (Pubitemid 44330141)
41. Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, et al. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 2004;172:6003-10. (Pubitemid 38621201)
42. de Lafaille MA Curotto, Kutchukhidze N, Shen S, Ding Y, Yee H, Lafaille JJ. Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 2008;29:114-26.
43. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 2005;202:1375-86. (Pubitemid 41668740)
44. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875-86. (Pubitemid 38032120)
45. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004;172:5149-53. (Pubitemid 38542009)
46. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009;30:616-25.
47. Gabrysova L, Nicolson KS, Streeter HB, Verhagen J, Sabatos-Peyton CA, Morgan DJ, et al. Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells. J Exp Med 2009;206:1755-67.
48. Sundstedt A, O'Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol 2003;170:1240-8. (Pubitemid 36139489)
49. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med 2008;205:2887-98.
50. O'Garra A, Barrat FJ, Castro AG, Vicari A, Hawrylowicz C. Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev 2008;223:114-31. (Pubitemid 351986180)
51. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28:546-58.
52. Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 2005;201:1061-7. (Pubitemid 40524674)
53. Collison LW,Workman CJ, Kuo TT, Boyd K,Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450:566-9. (Pubitemid 350190247)
54. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007;8:1353-62. (Pubitemid 350131172)
55. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21:589-601. (Pubitemid 39370513)
56. Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005;174:1783-6. (Pubitemid 40223916)
57. Brusko TM, Wasserfall CH, Agarwal A, Kapturczak MH, Atkinson MA. An integral role for heme oxygenase-1 and carbon monoxide in maintaining peripheral tolerance by CD4+CD25+ regulatory T cells. J Immunol 2005;174:5181-6. (Pubitemid 40593154)
58. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008;8:523-32.
59. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206-12. (Pubitemid 37547898)
60. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004;4:762-74. (Pubitemid 39336293)
61. Szatmari I, Nagy L. Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function. EMBO J 2008;27:2353-62.
62. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992;358:771-4.
63. Harris SG, Phipps RP. The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol 2001;31: 1098-105.
64. Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 2006;116:571-80. (Pubitemid 43326861)
65. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001;70:341-67. (Pubitemid 32662214)
66. Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590-7. (Pubitemid 43326863)
67. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999;20:649-88. (Pubitemid 30650602)
68. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000;405:421-4. (Pubitemid 30367411)
69. Murphy GJ, Holder JC. PPAR-gamma agonists: therapeutic role in diabetes, inflammation and cancer. Trends Pharmacol Sci 2000;21:469-74.
70. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996;1302:93-109. (Pubitemid 26247079)
71. Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008;181:2277-84.
72. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol 2000;164:1364-71. (Pubitemid 30067250)
73. Gosset P, Charbonnier AS, Delerive P, Fontaine J, Staels B, Pestel J, et al. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur J Immunol 2001;31:2857-65. (Pubitemid 32994536)
74. Nencioni A, Grunebach F, Zobywlaski A, Denzlinger C, Brugger W, Brossart P. Dendritic cell immunogenicity is regulated by peroxisome proliferator- activated receptor gamma. J Immunol 2002;169:1228-35. (Pubitemid 34809163)
75. Klotz L, Dani I, Edenhofer F, Nolden L, Evert B, Paul B, et al. Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy. J Immunol 2007;178:2122-31. (Pubitemid 46233409)
76. Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P, et al. Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett 2000;486:261-6.
77. Szatmari I, Pap A, Ruhl R, Ma JX, Illarionov PA, Besra GS, et al. PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med 2006;203:2351-62. (Pubitemid 44498369)
78. Housley WJ, O'Conor CA, Nichols F, Puddington L, Lingenheld EG, Zhu L, et al. PPARgamma regulates retinoic acid-mediated DC induction of Tregs. J Leukoc Biol 2009;86:293-301.
79. Iwami D, Zhang Q, Aramaki O, Nonomura K, Shirasugi N, Niimi M. Purified eicosapentaenoic acid induces prolonged survival of cardiac allografts and generates regulatory T cells. Am J Transplant 2009;9:1294-307.
80. Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 2001;166:3789-96. (Pubitemid 32224903)
81. Aramaki O, Inoue F, Takayama T, Shimazu M, Kitajima M, Ikeda Y, et al. Interleukin-10 but not transforming growth factor-beta is essential for generation and suppressor function of regulatory cells induced by intratracheal delivery of alloantigen. Transplantation 2005;79:568-76. (Pubitemid 40365885)
82. Raikwar HP, Muthian G, Rajasingh J, Johnson CN, Bright JJ. PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12, 14-prostaglandin J2. J Neuroimmunol 2006;178:76-86. (Pubitemid 44307334)
83. Zhang X, Rodriguez-Galan MC, Subleski JJ, Ortaldo JR, Hodge DL, Wang JM, et al. Peroxisome proliferator-activated receptor-gamma and its ligands attenuate biologic functions of human natural killer cells. Blood 2004;104:3276-84. (Pubitemid 39507146)
84. Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet 1999;353:1083-91. (Pubitemid 29149926)
85. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 2002;73:775-82. (Pubitemid 34260577)
86. Massy ZA. Hyperlipidemia and cardiovascular disease after organ transplantation. Transplantation 2001;72:S13-5.
87. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996;7:158-65. (Pubitemid 26067103)
88. Marcen R. Cardiovascular risk factors in renal transplantation-current controversies. Nephrol Dial Transplant 2006;21(Suppl 3):iii3-8.
89. Lindholm A, Albrechtsen D, Frodin L, Tufveson G, Persson NH, Lundgren G. Ischemic heart disease-major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation 1995;60:451-7.
90. Baan CC, van der Mast BJ, Klepper M, Mol WM, Peeters AM, Korevaar SS, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation 2005;80:110-7. (Pubitemid 40980903)
91. Coenen JJ, Koenen HJ, van Rijssen E, Hilbrands LB, Joosten I. Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells. Blood 2006;107:1018-23. (Pubitemid 43156300)
92. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006;108:390-9. (Pubitemid 43990654)
93. Gao W, Lu Y, El Essawy B, Oukka M, Kuchroo VK, Strom TB. Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells. Am J Transplant 2007;7:1722-32. (Pubitemid 46905432)
94. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 2005;11:1238-43. (Pubitemid 43093672)
95. Shibutani S, Inoue F, Aramaki O, Akiyama Y, Matsumoto K, Shimazu M, et al. Effects of immunosuppressants on induction of regulatory cells after intratracheal delivery of alloantigen. Transplantation 2005;79:904-13. (Pubitemid 40586862)