To avoid immune rejection, allograft recipients require drug-based immunosuppression, which has significant toxicity. An emerging approach is adoptive transfer of immunoregulatory cells. While mature dendritic cells (DCs) present donor antigen to the immune system, triggering rejection, regulatory DCs interact with regulatory T cells to promote immune tolerance. Intravenous injection of immature DCs of either donor or host origin at the time of transplantation have prolonged allograft survival in solid-organ transplant models. DCs can be treated with pharmacological agents before injection, which may attenuate their maturation in vivo. Recent data suggest that injected immunosuppressive DCs may inhibit allograft rejection, not by themselves, but through conventional DCs of the host. Genetically engineered DCs have also been tested. Two clinical trials in type-1 diabetes and rheumatoid arthritis have been carried out, and other trials, including one trial in kidney transplantation, are in progress or are imminent. 1. Introduction Allogeneic cell and solid-organ grafts trigger immune responses that cause destructive graft rejection in the absence of sustained drug-based immunosuppression [1]. Unfortunately, the latter is associated with major side effects including severe infections and cancer, especially after many years of treatment. Moreover, immunosuppressive drugs have failed to prevent chronic graft rejection, which is primarily manifested by allograft vasculopathy. The hope in the immunotherapy field is to develop a therapy that targets and neutralizes the alloimmune response selectively, while leaving protective immunity intact. Patients with a functioning allograft in the absence of maintenance immunosuppression have been described occasionally [2]. In some of them, immunosuppressive drugs were discontinued because of infection or cancer [3]. Others decided to stop taking the drugs [4]. Some liver transplant recipients were enrolled in studies of weaning immunosuppression [5]. Moreover, some kidney transplant recipients participated in studies of tolerance induction [6–9] which, in part, included hematopoietic cell transplantation [8, 9]. These reports demonstrate the sporadic occurrence of operational tolerance, as defined by lack of destructive graft rejection in the absence of maintenance immunosuppression [10]. Sixty years ago, Billingham et al. described “actively acquired tolerance” of foreign cells. They claimed that, “if the first presentation of foreign cells takes place in fetal life, resistance to a graft [from the same donor or from
References
[1]
K. J. Wood and R. Goto, “Mechanisms of rejection: current perspectives,” Transplantation, vol. 93, no. 1, pp. 1–10, 2012.
[2]
K. J. Wood, A. Bushell, and J. Hester, “Regulatory immune cells in transplantation,” Nature Reviews Immunology, vol. 12, pp. 417–430, 2012.
[3]
S. I. Alexander, N. Smith, D. Verran et al., “Chimerism and tolerance in a recipient of a deceased-donor liver transplant,” The New England Journal of Medicine, vol. 358, no. 4, pp. 369–374, 2008.
[4]
L. J. West, “ABO-incompatible hearts for infant transplantation,” Current Opinion in Organ Transplantation, vol. 16, no. 5, pp. 548–554, 2011.
[5]
M. Takatsuki, S. Uemoto, Y. Inomata et al., “Weaning of immunosuppression in living donor liver transplant recipients,” Transplantation, vol. 72, no. 3, pp. 449–454, 2001.
[6]
S. Strober, M. Dhillon, M. Schubert et al., “Acquired immune tolerance to cadaveric renal allografts. A study of three patients treated with total lymphoid irradiation,” The New England Journal of Medicine, vol. 321, no. 1, pp. 28–33, 1989.
[7]
T. Kawai, D. H. Sachs, M. Sykes, A. B. Cosimi, and Immune Tolerance Network, “HLA-mismatched renal transplantation without maintenance immunosuppression,” The New England Journal of Medicine, vol. 368, no. 19, pp. 1850–1852, 2013.
[8]
J. D. Scandling, S. Busque, S. Dejbakhsh-Jones et al., “Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants,” American Journal of Transplantation, vol. 12, no. 5, pp. 1133–1145, 2012.
[9]
J. Leventhal, M. Abecassis, J. Miller, et al., “Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome,” Transplantation, vol. 95, no. 1, pp. 169–176, 2013.
[10]
A. D. Salama, G. Remuzzi, W. E. Harmon, and M. H. Sayegh, “Challenges to achieving clinical transplantation tolerance,” Journal of Clinical Investigation, vol. 108, no. 7, pp. 943–948, 2001.
[11]
R. E. Billingham, L. Brent, and P. B. Medawar, “‘Actively acquired tolerance’ of foreign cells,” Nature, vol. 172, no. 4379, pp. 603–606, 1953.
[12]
B. M. Hall, M. E. Jelbart, and S. E. Dorsch, “Suppressor T cells in rats with prolonged cardiac allograft survival after treatment with cyclosporine,” Transplantation, vol. 37, no. 6, pp. 595–600, 1984.
[13]
K. J. Wood and S. Sakaguchi, “Regulatory T cells in transplantation tolerance,” Nature Reviews Immunology, vol. 3, no. 3, pp. 199–210, 2003.
[14]
Y. Li, T. Koshiba, A. Yoshizawa et al., “Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation,” American Journal of Transplantation, vol. 4, no. 12, pp. 2118–2125, 2004.
[15]
M. Martínez-Llordella, I. Puig-Pey, G. Orlando et al., “Multiparameter immune profiling of operational tolerance in liver transplantation,” American Journal of Transplantation, vol. 7, no. 2, pp. 309–319, 2007.
[16]
S. Brouard, E. Mansfield, C. Braud et al., “Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 39, pp. 15448–15453, 2007.
[17]
K. A. Newell, A. Asare, A. D. Kirk et al., “Identification of a B cell signature associated with renal transplant tolerance in humans,” Journal of Clinical Investigation, vol. 120, no. 6, pp. 1836–1847, 2010.
[18]
P. Sagoo, E. Perucha, B. Sawitzki et al., “Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans,” Journal of Clinical Investigation, vol. 120, no. 6, pp. 1848–1861, 2010.
[19]
C. Ohnmacht, A. Pullner, S. B. S. King et al., “Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity,” Journal of Experimental Medicine, vol. 206, no. 3, pp. 549–559, 2009.
[20]
M. Hill, P. Thebault, M. Segovia et al., “Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and Epstein-Barr virus-induced gene 3,” American Journal of Transplantation, vol. 11, no. 10, pp. 2036–2045, 2011.
[21]
H. Torres-Aguilar, S. R. Aguilar-Ruiz, G. González-Pérez et al., “Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells,” Journal of Immunology, vol. 184, no. 4, pp. 1765–1775, 2010.
[22]
K. Liu and M. C. Nussenzweig, “Origin and development of dendritic cells,” Immunological Reviews, vol. 234, no. 1, pp. 45–54, 2010.
[23]
R. M. Steinman and J. Idoyaga, “Features of the dendritic cell lineage,” Immunological Reviews, vol. 234, no. 1, pp. 5–17, 2010.
[24]
S. Laffont and F. Powrie, “Immunology: dendritic-cell genealogy,” Nature, vol. 462, no. 7274, pp. 732–733, 2009.
[25]
K. Crozat, R. Guiton, M. Guilliams et al., “Comparative genomics as a tool to reveal functional equivalences between human and mouse dendritic cell subsets,” Immunological Reviews, vol. 234, no. 1, pp. 177–198, 2010.
[26]
N. M. Rogers, J. S. Isenberg, and A. W. Thomson, “Plasmacytoid dendritic cells: no longer an enigma and now key to transplant tolerance?” American Journal of Transplantation, vol. 13, no. 5, pp. 1125–1133, 2013.
[27]
W. Cao and L. Bover, “Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells,” Immunological Reviews, vol. 234, no. 1, pp. 163–176, 2010.
[28]
A. W. Thomson, R. Fischer, H. R. Turnquist, and T. Taner, “Use of rapamycin in the induction of tolerogenic dendritic cells,” Handbook of Experimental Pharmacology, vol. 188, pp. 215–232, 2009.
[29]
R. T. Fischer, H. R. Turnquist, Z. Wang, D. Beer-Stolz, and A. W. Thomson, “Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8+ T cells in vitro and in vivo,” Transplant Immunology, vol. 25, no. 1, pp. 20–26, 2011.
[30]
C. Macedo, H. Turquist, D. Metes, and A. W. Thomson, “Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation,” Transplantation Research, vol. 1, no. 1, article 16, 2012.
[31]
L. Li, L. Huang, H. Ye, et al., “Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury,” Journal of Clinical Investigation, vol. 122, no. 11, pp. 3931–3942, 2012.
[32]
T. Nikolic and B. O. Roep, “Regulatory multitasking of tolerogenic dendritic cells—lessons taken from vitamin d3-treated tolerogenic dendritic cells,” Frontiers in Immunology, vol. 4, article 113, 2013.
[33]
S. J. Divito, Z. Wang, W. J. Shufesky et al., “Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation,” Blood, vol. 116, no. 15, pp. 2694–2705, 2010.
[34]
Z. Wang, S. J. Divito, W. J. Shufesky et al., “Dendritic cell therapies in transplantation revisited: deletion of recipient DCs deters the effect of therapeutic DCs,” American Journal of Transplantation, vol. 12, no. 6, pp. 1398–1408, 2012.
[35]
A. Montecalvo, A. T. Larregina, W. J. Shufesky et al., “Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes,” Blood, vol. 119, no. 3, pp. 756–766, 2012.
[36]
X. Li, J. J. Li, J. Y. Yang, et al., “Tolerance induction by exosomes from immature dendritic cells and rapamycin in a mouse cardiac allograft model,” PLoS ONE, vol. 7, no. 8, Article ID e44045, 2012.
[37]
N. Giannoukakis, B. Phillips, D. Finegold, J. Harnaha, and M. Trucco, “Phase I, (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients,” Diabetes Care, vol. 34, pp. 2026–2032, 2011.
[38]
C. M. Hilkens and J. D. Isaacs, “Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now?” Clinical and Experimental Immunology, vol. 172, no. 2, pp. 148–157, 2013.
[39]
A. Moreau, E. Varey, L. Bouchet-Delbos, and M. C. Cuturi, “Cell therapy using tolerogenic dendritic cells in transplantation,” Transplantation Research, vol. 1, article 13, 2012.
[40]
J. Banchereau, F. Briere, C. Caux et al., “Immunobiology of dendritic cells,” Annual Review of Immunology, vol. 18, pp. 767–811, 2000.
[41]
D. Hawiger, K. Inaba, Y. Dorsett et al., “Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo,” Journal of Experimental Medicine, vol. 194, no. 6, pp. 769–779, 2001.
[42]
G. Süss and K. Shortman, “A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis,” Journal of Experimental Medicine, vol. 183, no. 4, pp. 1789–1796, 1996.
[43]
R. A. Maldonado and U. H. von Andrian, “How tolerogenic dendritic cells induce regulatory T cells,” Advances in Immunology, vol. 108, pp. 111–165, 2010.
[44]
A. E. Morelli and A. W. Thomson, “Tolerogenic dendritic cells and the quest for transplant tolerance,” Nature Reviews Immunology, vol. 7, no. 8, pp. 610–621, 2007.
[45]
K. Pletinckx, A. D？hler, V. Pavlovic, and M. B. Lutz, “Role of dendritic cell maturity/costimulation for generation, homeostasis, and suppressive activity of regulatory T cells,” Frontiers in Immunology, vol. 2, article 39, 2011.
[46]
M. Ezzelarab and A. W. Thomson, “Tolerogenic dendritic cells and their role in transplantation,” Seminars in Immunology, vol. 23, no. 4, pp. 252–263, 2011.
[47]
T. G. Berger, H. Schulze-Koops, M. Sch？fer, E. Müller, and M. B. Lutz, “Immature and maturation-resistant human dendritic cells generated from bone marrow require two stimulations to induce T cell anergy in vitro,” PLoS ONE, vol. 4, no. 8, Article ID e6645, 2009.
[48]
H. Ueno, E. Klechevsky, R. Morita et al., “Dendritic cell subsets in health and disease,” Immunological Reviews, vol. 219, no. 1, pp. 118–142, 2007.
[49]
B. Pulendran, H. Tang, and T. L. Denning, “Division of labor, plasticity, and crosstalk between dendritic cell subsets,” Current Opinion in Immunology, vol. 20, no. 1, pp. 61–67, 2008.
[50]
K. R. R. Siddiqui and F. Powrie, “CD103+ GALT DCs promote Foxp3+ regulatory T cells,” Mucosal Immunology, vol. 1, no. 1, pp. S34–S38, 2008.
[51]
K. Shortman and W. R. Heath, “The CD8+ dendritic cell subset,” Immunological Reviews, vol. 234, no. 1, pp. 18–31, 2010.
[52]
C. Coquerelle and M. Moser, “DC subsets in positive and negative regulation of immunity,” Immunological Reviews, vol. 234, no. 1, pp. 317–334, 2010.
[53]
S. Milling, U. Yrlid, V. Cerovic, and G. MacPherson, “Subsets of migrating intestinal dendritic cells,” Immunological Reviews, vol. 234, no. 1, pp. 259–267, 2010.
[54]
M. Swiecki and M. Colonna, “Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance,” Immunological Reviews, vol. 234, no. 1, pp. 142–162, 2010.
[55]
D. Vremec, M. Zorbas, R. Scollay et al., “The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells,” Journal of Experimental Medicine, vol. 176, no. 1, pp. 47–58, 1992.
[56]
X. Ju, G. Clark, and D. N. J. Hart, “Review of human DC subtypes,” Methods in Molecular Biology, vol. 595, pp. 3–20, 2010.
[57]
A. G. Jegalian, F. Facchetti, and E. S. Jaffe, “Plasmacytoid dendritic cells physiologic roles and pathologic states,” Advances in Anatomic Pathology, vol. 16, no. 6, pp. 392–404, 2009.
[58]
C. Varol, L. Landsman, D. K. Fogg et al., “Monocytes give rise to mucosal, but not splenic, conventional dendritic cells,” Journal of Experimental Medicine, vol. 204, no. 1, pp. 171–180, 2007.
[59]
M. A. Schmid, D. Kingston, S. Boddupalli, and M. G. Manz, “Instructive cytokine signals in dendritic cell lineage commitment,” Immunological Reviews, vol. 234, no. 1, pp. 32–44, 2010.
[60]
J. Helft, F. Ginhoux, M. Bogunovic, and M. Merad, “Origin and functional heterogeneity of non-lymphoid tissue dendritic cells in mice,” Immunological Reviews, vol. 234, no. 1, pp. 55–75, 2010.
[61]
L. Bar-On and S. Jung, “Defining dendritic cells by conditional and constitutive cell ablation,” Immunological Reviews, vol. 234, no. 1, pp. 76–89, 2010.
[62]
N. Romani, B. E. Clausen, and P. Stoitzner, “Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin,” Immunological Reviews, vol. 234, no. 1, pp. 120–141, 2010.
[63]
R. Maarten Egeler, A. G. S. Van Halteren, P. C. W. Hogendoorn, J. D. Laman, and P. J. M. Leenen, “Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage,” Immunological Reviews, vol. 234, no. 1, pp. 213–232, 2010.
[64]
S.-Y. Chang and M.-N. Kweon, “Langerin-expressing dendritic cells in gut-associated lymphoid tissues,” Immunological Reviews, vol. 234, no. 1, pp. 233–246, 2010.
[65]
H. Tezuka and T. Ohteki, “Regulation of intestinal homeostasis by dendritic cells,” Immunological Reviews, vol. 234, no. 1, pp. 247–258, 2010.
[66]
M.-L. Del Rio, G. Bernhardt, J.-I. Rodriguez-Barbosa, and R. F？rster, “Development and functional specialization of CD103+ dendritic cells,” Immunological Reviews, vol. 234, no. 1, pp. 268–281, 2010.
[67]
A. M. Kerrigan and G. D. Brown, “Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs,” Immunological Reviews, vol. 234, no. 1, pp. 335–352, 2010.
[68]
B. León, M. López-Bravo, and C. Ardavín, “Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against leishmania,” Immunity, vol. 26, no. 4, pp. 519–531, 2007.
[69]
N. V. Serbina, T. P. Salazar-Mather, C. A. Biron, W. A. Kuziel, and E. G. Pamer, “TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection,” Immunity, vol. 19, no. 1, pp. 59–70, 2003.
[70]
F. Sallusto, P. Schaerli, P. Loetscher, et al., “Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation,” European Journal of Immunology, vol. 28, pp. 2760–2769, 1998.
[71]
F. Re and J. L. Strominger, “Heterogeneity of TLR-induced responses in dendritic cells: from innate to adaptive immunity,” Immunobiology, vol. 209, no. 1-2, pp. 191–198, 2004.
[72]
E. Meylan and J. Tschopp, “Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses,” Molecular Cell, vol. 22, no. 5, pp. 561–569, 2006.
[73]
R. M. Steinman, G. Kaplan, M. D. Witmer, and Z. A. Cohn, “Identification of a novel cell type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro,” Journal of Experimental Medicine, vol. 149, no. 1, pp. 1–16, 1979.
[74]
W. C. Van Voorhis, L. S. Hair, R. M. Steinman, and G. Kaplan, “Human dendritic cells. Enrichment and characterization from peripheral blood,” Journal of Experimental Medicine, vol. 155, no. 4, pp. 1172–1187, 1982.
[75]
？. Türeci, H. Bian, F. O. Nestle et al., “Cascades of transcriptional induction during dendritic cell maturation revealed by genome-wide expression analysis,” FASEB Journal, vol. 17, no. 8, pp. 836–847, 2003.
[76]
D. McIlroy, S. Tanguy-Royer, N. Le Meur et al., “Profiling dendritic cell maturation with dedicated microarrays,” Journal of Leukocyte Biology, vol. 78, no. 3, pp. 794–803, 2005.
[77]
M.-C. Dieu, B. Vanbervliet, A. Vicari et al., “Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites,” Journal of Experimental Medicine, vol. 188, no. 2, pp. 373–386, 1998.
[78]
A. Martín-Fontecha, S. Sebastiani, U. E. H？pken et al., “Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming,” Journal of Experimental Medicine, vol. 198, no. 4, pp. 615–621, 2003.
[79]
R. M. Steinman and Z. A. Cohn, “Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution,” Journal of Experimental Medicine, vol. 137, pp. 1142–1162, 1973.
[80]
R. L. Lindquist, G. Shakhar, D. Dudziak et al., “Visualizing dendritic cell networks in vivo,” Nature Immunology, vol. 5, no. 12, pp. 1243–1250, 2004.
[81]
K. Inaba, M. Inaba, M. Naito, and R. M. Steinman, “Dendritic cell progenitors phagocytose particulates, including Bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo,” Journal of Experimental Medicine, vol. 178, no. 2, pp. 479–488, 1993.
[82]
F.-P. Huang, N. Platt, M. Wykes et al., “A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes,” Journal of Experimental Medicine, vol. 191, no. 3, pp. 435–443, 2000.
[83]
W. R. Heath, G. T. Belz, G. M. N. Behrens et al., “Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens,” Immunological Reviews, vol. 199, pp. 9–26, 2004.
[84]
D. Schmid, M. Pypaert, and C. Münz, “Antigen-loading compartments for major histocompatibility complex class ii molecules continuously receive input from autophagosomes,” Immunity, vol. 26, no. 1, pp. 79–92, 2007.
[85]
K. Inaba, S. Turley, T. Iyoda et al., “The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli,” Journal of Experimental Medicine, vol. 191, no. 6, pp. 927–936, 2000.
[86]
S. J. Turley, K. Inaba, W. S. Garrett et al., “Transport of peptide-MHC class II complexes in developing dendritic cells,” Science, vol. 288, no. 5465, pp. 522–527, 2000.
[87]
A. Chow, D. Toomre, W. Garrett, and I. Mellman, “Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane,” Nature, vol. 418, no. 6901, pp. 988–994, 2002.
[88]
M. H. Sayegh and L. A. Turka, “Thr role of T-cell costimulatory activation pathways in transplant rejection,” The New England Journal of Medicine, vol. 338, no. 25, pp. 1813–1821, 1998.
[89]
S. J. F. Cronin and J. M. Penninger, “From T-cell activation signals to signaling control of anti-cancer immunity,” Immunological Reviews, vol. 220, no. 1, pp. 151–168, 2007.
[90]
H. Jonuleit, E. Schmitt, G. Schuler, J. Knop, and A. H. Enk, “Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells,” Journal of Experimental Medicine, vol. 192, no. 9, pp. 1213–1222, 2000.
[91]
F. Fu, Y. Li, S. Qian et al., “Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80(dim), CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients,” Transplantation, vol. 62, no. 5, pp. 659–665, 1996.
[92]
M. B. Lutz, R. M. Suri, M. Niimi, et al., “Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo,” European Journal of Immunology, vol. 30, pp. 1813–1822, 2000.
[93]
P. J. O'Connell, W. Li, Z. Wang, S. M. Specht, A. J. Logar, and A. W. Thomson, “Immature and mature CD8α+ dendritic cells prolong the survival of vascularized heart allografts,” Journal of Immunology, vol. 168, no. 1, pp. 143–154, 2002.
[94]
D. L. Roelen, D. H. Schuurhuis, D. E. M. Van Den Boogaardt et al., “Prolongation of skin graft survival by modulation of the alloimmune response with alternatively activated dendritic cells,” Transplantation, vol. 76, no. 11, pp. 1608–1615, 2003.
[95]
K. Sato, N. Yamashita, N. Yamashita, M. Baba, and T. Matsuyama, “Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse,” Immunity, vol. 18, no. 3, pp. 367–379, 2003.
[96]
H. Pêche, B. Trinité, B. Martinet, and M. C. Cuturi, “Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors,” American Journal of Transplantation, vol. 5, no. 2, pp. 255–267, 2005.
[97]
C. Caux, C. Dezutter-Dambuyant, D. Schmit, and J. Banchereau, “GM-CSF and TNF-α cooperate in the generation of dendritic Langerhans cells,” Nature, vol. 360, no. 6401, pp. 258–261, 1992.
[98]
M. Arpinati, C. L. Green, S. Heimfeld, J. E. Heuser, and C. Anasetti, “Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells,” Blood, vol. 95, no. 8, pp. 2484–2490, 2000.
[99]
K. Y. Vermaelen, I. Carro-Muino, B. N. Lambrecht, and R. A. Pauwels, “Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes,” Journal of Experimental Medicine, vol. 193, no. 1, pp. 51–60, 2001.
[100]
I. Apostolou and H. Von Boehmer, “In vivo instruction of suppressor commitment in naive T cells,” Journal of Experimental Medicine, vol. 199, no. 10, pp. 1401–1408, 2004.
[101]
M. Ostroukhova, C. Seguin-Devaux, T. B. Oriss et al., “Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3,” Journal of Clinical Investigation, vol. 114, no. 1, pp. 28–38, 2004.
[102]
H. J. De Heer, H. Hammad, T. Soullié et al., “Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen,” Journal of Experimental Medicine, vol. 200, no. 1, pp. 89–98, 2004.
[103]
K. Kretschmer, I. Apostolou, D. Hawiger, K. Khazaie, M. C. Nussenzweig, and H. von Boehmer, “Inducing and expanding regulatory T cell populations by foreign antigen,” Nature Immunology, vol. 6, no. 12, pp. 1219–1227, 2005.
[104]
S. Yamazaki, K. Inaba, K. V. Tarbell, and R. M. Steinman, “Dendritic cells expand antigen-specific Foxp3+CD25+ CD4+ regulatory T cells including suppressors of alloreactivity,” Immunological Reviews, vol. 212, pp. 314–329, 2006.
[105]
N. M. Tsuji and A. Kosaka, “Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells,” Trends in Immunology, vol. 29, no. 11, pp. 532–540, 2008.
[106]
B. N. Lambrecht and H. Hammad, “Biology of lung dendritic cells at the origin of asthma,” Immunity, vol. 31, no. 3, pp. 412–424, 2009.
[107]
T. Birnberg, L. Bar-On, A. Sapoznikov et al., “Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome,” Immunity, vol. 29, no. 6, pp. 986–997, 2008.
[108]
G. Darrasse-Jèze, S. Deroubaix, H. Mouquet et al., “Feedback control of regulatory T cell homeostasis by dendritic cells in vivo,” Journal of Experimental Medicine, vol. 206, no. 9, pp. 1853–1862, 2009.
[109]
S. Paust and H. Cantor, “Regulatory T cells and autoimmune disease,” Immunological Reviews, vol. 204, pp. 195–207, 2005.
[110]
Q. Tang and J. A. Bluestone, “The Foxp3+ regulatory T cell: a jack of all trades, master of regulation,” Nature Immunology, vol. 9, no. 3, pp. 239–244, 2008.
[111]
D. A. A. Vignali, L. W. Collison, and C. J. Workman, “How regulatory T cells work,” Nature Reviews Immunology, vol. 8, no. 7, pp. 523–532, 2008.
[112]
M. A. Travis, B. Reizis, A. C. Melton et al., “Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice,” Nature, vol. 449, no. 7160, pp. 361–365, 2007.
[113]
Y. Laouar, T. Town, D. Jeng et al., “TGF-β signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 31, pp. 10865–10870, 2008.
[114]
J. A. Bluestone and A. K. Abbas, “Natural versus adaptive regulatory T cells,” Nature Reviews Immunology, vol. 3, no. 3, pp. 253–257, 2003.
[115]
C.-W. J. Lio and C.-S. Hsieh, “A two-step process for thymic regulatory T cell development,” Immunity, vol. 28, no. 1, pp. 100–111, 2008.
[116]
J. E. Mold, J. Micha？lsson, T. D. Burt et al., “Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero,” Science, vol. 322, no. 5907, pp. 1562–1565, 2008.
[117]
J. M. Kim and A. Rudensky, “The role of the transcription factor Foxp3 in the development of regulatory T cells,” Immunological Reviews, vol. 212, pp. 86–98, 2006.
[118]
M. V. Dhodapkar, R. M. Steinman, J. Krasovsky, C. Munz, and N. Bhardwaj, “Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells,” Journal of Experimental Medicine, vol. 193, no. 2, pp. 233–238, 2001.
[119]
C. Reis E Sousa, “Dendritic cells in a mature age,” Nature Reviews Immunology, vol. 6, no. 6, pp. 476–483, 2006.
[120]
R. Tisch, “Immunogenic versus tolerogenic dendritic cells: a matter of maturation,” International Reviews of Immunology, vol. 29, no. 2, pp. 111–118, 2010.
[121]
L. Ohl, M. Mohaupt, N. Czeloth et al., “CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions,” Immunity, vol. 21, no. 2, pp. 279–288, 2004.
[122]
G. Hintzen, L. Ohl, M.-L. Del Rio et al., “Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node,” Journal of Immunology, vol. 177, no. 10, pp. 7346–7354, 2006.
[123]
M. H. Jang, N. Sougawa, T. Tanaka et al., “CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes,” Journal of Immunology, vol. 176, no. 2, pp. 803–810, 2006.
[124]
T. Worbs, U. Bode, S. Yan et al., “Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells,” Journal of Experimental Medicine, vol. 203, no. 3, pp. 519–527, 2006.
[125]
R. F？rster, A. C. Davalos-Misslitz, and A. Rot, “CCR7 and its ligands: balancing immunity and tolerance,” Nature Reviews Immunology, vol. 8, no. 5, pp. 362–371, 2008.
[126]
M. Cella, F. Facchetti, A. Lanzavecchia, and M. Colonna, “Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization,” Nature Immunology, vol. 1, no. 4, pp. 305–310, 2000.
[127]
H. Hadeiba, T. Sato, A. Habtezion, C. Oderup, J. Pan, and E. C. Butcher, “CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease,” Nature Immunology, vol. 9, no. 11, pp. 1253–1260, 2008.
[128]
D. Tokita, G. V. Mazariegos, A. F. Zahorchak et al., “High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance,” Transplantation, vol. 85, no. 3, pp. 369–377, 2008.
[129]
M. Kool, M. Van Nimwegen, M. A. M. Willart et al., “An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation,” Journal of Immunology, vol. 183, no. 2, pp. 1074–1082, 2009.
[130]
Q. Tang and J. A. Bluestone, “Plasmacytoid DCs and Treg cells: casual acquaintance or monogamous relationship?” Nature Immunology, vol. 7, no. 6, pp. 551–553, 2006.
[131]
J. C. Ochando, C. Homma, Y. Yang et al., “Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts,” Nature Immunology, vol. 7, no. 6, pp. 652–662, 2006.
[132]
M. Abe, Z. Wang, A. De Creus, and A. W. Thomson, “Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival,” American Journal of Transplantation, vol. 5, no. 8, pp. 1808–1819, 2005.
[133]
M. Gilliet and Y.-J. Liu, “Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells,” Journal of Experimental Medicine, vol. 195, no. 6, pp. 695–704, 2002.
[134]
A. I. Proietto, S. Van Dommelen, P. Zhou et al., “Dendritic cells in the thymus contribute to T-regulatory cell induction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19869–19874, 2008.
[135]
N. Watanabe, Y.-H. Wang, H. K. Lee et al., “Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus,” Nature, vol. 436, no. 7054, pp. 1181–1185, 2005.
[136]
G. Beriou, A. Moreau, and M. C. Cuturi, “Tolerogenic dendritic cells: applications for solid organ transplantation,” Current Opinion in Organ Transplantation, vol. 17, no. 1, pp. 42–47, 2012.
[137]
A. W. Thomson, “Tolerogenic dendritic cells: all present and correct?” American Journal of Transplantation, vol. 10, no. 2, pp. 214–219, 2010.
[138]
P. T. H. Coates, B. L. Colvin, H. Hackstein, and A. W. Thomson, “Manipulation of dendritic cells as an approach to improved outcomes in transplantation,” Expert Reviews in Molecular Medicine, vol. 4, no. 3, pp. 1–21, 2002.
[139]
P. T. H. Coates, B. L. Colvin, K. Kaneko, T. Taner, and A. W. Thomson, “Pharmacologic, biologic, and genetic engineering approaches to potentiation of donor-derived dendritic cell tolerogenicity,” Transplantation, vol. 75, no. 9, pp. 32S–36S, 2003.
[140]
H. Hackstein and A. W. Thomson, “Dendritic cells: emerging pharmacological targets of immunosuppressive drugs,” Nature Reviews Immunology, vol. 4, no. 1, pp. 24–34, 2004.
[141]
A. H. Enk, “Dendritic cells in tolerance induction,” Immunology Letters, vol. 99, no. 1, pp. 8–11, 2005.
[142]
K. R. McCurry, B. L. Colvin, A. F. Zahorchak, and A. W. Thomson, “Regulatory dendritic cell therapy in organ transplantation,” Transplant International, vol. 19, no. 7, pp. 525–538, 2006.
[143]
R. Schwartz and W. Dameshek, “Drug-induced immunological tolerance,” Nature, vol. 183, no. 4676, pp. 1682–1683, 1959.
[144]
M. Moser, T. De Smedt, T. Sornasse et al., “Glucocorticoids down-regulate dendritic cell function in vitro and in vivo,” European Journal of Immunology, vol. 25, no. 10, pp. 2818–2824, 1995.
[145]
L. Piemonti, P. Monti, P. Allavena et al., “Glucocorticoids affect human dendritic cell differentiation and maturation,” Journal of Immunology, vol. 162, no. 11, pp. 6473–6481, 1999.
[146]
N. Vanderheyde, V. Verhasselt, M. Goldman, and F. Willems, “Inhibition of human dendritic cell functions by methylprednisolone,” Transplantation, vol. 67, no. 10, pp. 1342–1347, 1999.
[147]
M. K. Matyszak, S. Citterio, and M. Rescigno, “Differential effects of corticosteroids during different stages of dendritic cell maturation,” European Journal of Immunology, vol. 30, pp. 1233–1242, 2000.
[148]
A. M. Woltman, J. W. de Fijter, S. W. Kamerling, L. C. Paul, M. R. Daha, and C. van Kooten, “The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells,” European Journal of Immunology, vol. 30, no. 7, pp. 1807–1812, 2000.
[149]
A. E. Pedersen, E. G. W. Schmidt, M. Gad, S. S. Poulsen, and M. H. Claesson, “Dexamethasone/1α-25-dihydroxyvitamin D3-treated dendritic cells suppress colitis in the SCID T-cell transfer model,” Immunology, vol. 127, no. 3, pp. 354–364, 2009.
[150]
M. Abe and A. W. Thomson, “Dexamethasone preferentially suppresses plasmacytoid dendritic cell differentiation and enhances their apoptotic death,” Clinical Immunology, vol. 118, no. 2-3, pp. 300–306, 2006.
[151]
L. Piemonti, P. Monti, M. Sironi et al., “Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells,” Journal of Immunology, vol. 164, no. 9, pp. 4443–4451, 2000.
[152]
M. D. Griffin, W. H. Lutz, V. A. Phan, L. A. Bachman, D. J. McKean, and R. Kumar, “Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs,” Biochemical and Biophysical Research Communications, vol. 270, no. 3, pp. 701–708, 2000.
[153]
D. Ra？ch-Regué, L. Grau-Lopez, M. Naranjo-Gomez, et al., “Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients,” European Journal of Immunology, vol. 42, no. 3, pp. 771–782, 2012.
[154]
R. A. Harry, A. E. Anderson, J. D. Isaacs, and C. M. U. Hilkens, “Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 69, no. 11, pp. 2042–2050, 2010.
[155]
A. E. Anderson, B. L. Sayers, M. A. Haniffa et al., “Differential regulation of na？ve and memory CD4+ T cells by alternatively activated dendritic cells,” Journal of Leukocyte Biology, vol. 84, no. 1, pp. 124–133, 2008.
[156]
A. E. Anderson, D. J. Swan, B. L. Sayers et al., “LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells,” Journal of Leukocyte Biology, vol. 85, no. 2, pp. 243–250, 2009.
[157]
K. Steinbrink, M. W？lfl, H. Jonuleit, J. Knop, and A. H. Enk, “Induction of tolerance by IL-10-treated dendritic cells,” Journal of Immunology, vol. 159, no. 10, pp. 4772–4780, 1997.
[158]
C. Buelens, F. Willems, A. Delvaux et al., “Interleukin-10 differentially regulates B7-1 (CD80) and B7-2 (CD86) expression on human peripheral blood dendritic cells,” European Journal of Immunology, vol. 25, no. 9, pp. 2668–2672, 1995.
[159]
C. Buelens, V. Verhasselt, D. De Groote, K. Thielemans, M. Goldman, and F. Willems, “Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by interleukin-10,” European Journal of Immunology, vol. 27, no. 8, pp. 1848–1852, 1997.
[160]
K. Steinbrink, H. Jonuleit, G. Müller, G. Schuler, J. Knop, and A. H. Enk, “Interleukin-10-treated human dendritic cells induce a melanoma-antigen- specific anergy in CD8+ T cells resulting in a failure to lyse tumor cells,” Blood, vol. 93, no. 5, pp. 1634–1642, 1999.
[161]
K. Steinbrink, E. Graulich, S. Kubsch, J. Knop, and A. H. Enk, “CD4+ and CD8+ anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity,” Blood, vol. 99, no. 7, pp. 2468–2476, 2002.
[162]
A. F. Zahorchak, L. S. Kean, D. Tokita et al., “Infusion of stably immature monocyte-derived dendritic cells plus CTLA4Ig modulates alloimmune reactivity in rhesus macaques,” Transplantation, vol. 84, no. 2, pp. 196–206, 2007.
[163]
S. Gregori, D. Tomasoni, V. Pacciani et al., “Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway,” Blood, vol. 116, no. 6, pp. 935–944, 2010.
[164]
M. K. Levings, S. Gregori, E. Tresoldi, S. Cazzaniga, C. Bonini, and M. G. Roncarolo, “Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells,” Blood, vol. 105, no. 3, pp. 1162–1169, 2005.
[165]
T. Takayama, A. E. Morelli, N. Onai et al., “Mammalian and viral IL-10 enhance C-C chemokine receptor 5 but down-regulate C-C chemokine receptor 7 expression by myeloid dendritic cells: impact on chemotactic responses and in vivo homing ability,” Journal of Immunology, vol. 166, no. 12, pp. 7136–7143, 2001.
[166]
V. Sordi, G. Bianchi, C. Buracchi et al., “Differential effects of immunosuppressive drugs on chemokine receptor CCR7 in human monocyte-derived dendritic cells: selective upregulation by rapamycin,” Transplantation, vol. 82, no. 6, pp. 826–834, 2006.
[167]
Y.-R. Lee, I.-H. Yang, Y.-H. Lee et al., “Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells,” Blood, vol. 105, no. 10, pp. 3951–3955, 2005.
[168]
H. Matsue, C. Yang, K. Matsue, D. Edelbaum, M. Mummert, and A. Takashima, “Contrasting impacts of immunosuppressive agents (rapamycin, FK506, cyclosporin A, and dexamethasone) on bidirectional dendritic cell-T cell interaction during antigen presentation,” Journal of Immunology, vol. 169, no. 7, pp. 3555–3564, 2002.
[169]
T. Chen, J. Guo, M. Yang et al., “Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression,” Blood, vol. 103, no. 2, pp. 413–421, 2004.
[170]
A. Mehling, S. Grabbe, M. Voskort, T. Schwarz, T. A. Luger, and S. Beissert, “Mycophenolate mofetil impairs the maturation and function of murine dendritic cells,” Journal of Immunology, vol. 165, no. 5, pp. 2374–2381, 2000.
[171]
R. Matasic, A. B. Dietz, and S. Vuk-Pavlovic, “Cyclooxygenase-independent inhibition of dendritic cell maturation by aspirin,” Immunology, vol. 101, no. 1, pp. 53–60, 2000.
[172]
H. Hackstein, A. E. Morelli, A. T. Larregina et al., “Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells,” Journal of Immunology, vol. 166, no. 12, pp. 7053–7062, 2001.
[173]
M. Buckland, C. B. Jago, H. Fazekasova et al., “Aspirin-treated human DCs up-regulate ILT-3 and induce hyporesponsiveness and regulatory activity in responder T cells,” American Journal of Transplantation, vol. 6, no. 9, pp. 2046–2059, 2006.
[174]
M. Buckland and G. Lombardi, “Aspirin and the induction of tolerance by dendritic cells,” Handbook of Experimental Pharmacology, vol. 188, pp. 197–213, 2009.
[175]
M. A. Tepper, S. G. Nadler, J. M. Esselstyn, and K. G. Sterbenz, “Deoxyspergualin inhibits κ light chain expression in 70Z/3 pre-B cells by blocking lipopolysaccharide-induced NF-κb activation,” Journal of Immunology, vol. 155, no. 5, pp. 2427–2436, 1995.
[176]
M.-M. Tiao, L. Lu, R. Tao, L. Wang, J. J. Fung, and S. Qian, “Prolongation of cardiac allograft survival by systemic administration of immature recipient dendritic cells deficient in NF-κB activity,” Annals of Surgery, vol. 241, no. 3, pp. 497–505, 2005.
[177]
A. Hernandez, M. Burger, B. B. Blomberg et al., “Inhibition of NF-κB during human dendritic cell differentiation generates anergy and regulatory T-cell activity for one but not two human leukocyte antigen DR mismatches,” Human Immunology, vol. 68, no. 9, pp. 715–729, 2007.
[178]
W. Grotz, S. Siebig, M. Olschewski, C. W. Strey, and K. Peter, “Low-dose aspirin therapy is associated with improved allograft function and prolonged allograft survival after kidney transplantation,” Transplantation, vol. 77, no. 12, pp. 1848–1853, 2004.
[179]
Z.-X. Zhang, L. Yang, K. J. Young, B. DuTemple, and L. Zhang, “Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression,” Nature Medicine, vol. 6, no. 7, pp. 782–789, 2000.
[180]
B. Sawitzki, C. I. Kingsley, V. Oliveira, M. Karim, M. Herber, and K. J. Wood, “IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo,” Journal of Experimental Medicine, vol. 201, no. 12, pp. 1925–1935, 2005.
[181]
L. Zhang and A. W. Thomson, “New partners for tolerogenic dendritic cells,” American Journal of Transplantation, vol. 11, no. 10, pp. 2003–2004, 2011.
[182]
A. W. Thomson, H. R. Turnquist, and G. Raimondi, “Immunoregulatory functions of mTOR inhibition,” Nature Reviews Immunology, vol. 9, no. 5, pp. 324–337, 2009.
[183]
T. Weichhart, G. Costantino, M. Poglitsch et al., “The TSC-mTOR signaling pathway regulates the innate inflammatory response,” Immunity, vol. 29, no. 4, pp. 565–577, 2008.
[184]
H. R. Turnquist, G. Raimondi, A. F. Zahorchak, R. T. Fischer, Z. Wang, and A. W. Thomson, “Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance,” Journal of Immunology, vol. 178, no. 11, pp. 7018–7031, 2007.
[185]
H. R. Turnquist, T. L. Sumpter, A. Tsung et al., “IL-1β-driven ST2L expression promotes maturation resistance in rapamycin-conditioned dendritic cells,” Journal of Immunology, vol. 181, no. 1, pp. 62–72, 2008.
[186]
H. R. Turnquist, J. Cardinal, C. Macedo et al., “mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPS,” Blood, vol. 115, no. 23, pp. 4758–4769, 2010.
[187]
M. Naranjo-Gomez, D. Ra？ch-Regué, C. O？ate, et al., “Comparative study of clinical grade human tolerogenic dendritic cells,” Journal of Translational Medicine, vol. 9, article 89, 2011.
[188]
T. Matsumoto, H. Hasegawa, S. Onishi, J. Ishizaki, K. Suemori, and M. Yasukawa, “Protein kinase C inhibitor generates stable human tolerogenic dendritic cells,” Journal of Immunology, vol. 191, no. 5, pp. 2247–2257, 2013.
[189]
A. Moreau, M. Hill, P. Thébault et al., “Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman primates,” FASEB Journal, vol. 23, no. 9, pp. 3070–3077, 2009.
[190]
S. Chitta, L. Santambrogio, and L. J. Stern, “GMCSF in the absence of other cytokines sustains human dendritic cell precursors with T cell regulatory activity and capacity to differentiate into functional dendritic cells,” Immunology Letters, vol. 116, no. 1, pp. 41–54, 2008.
[191]
L. Lu, W. Li, C. Zhong et al., “Increased apoptosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor dendritic cells plus anti-CD40L mAb,” Transplantation, vol. 68, no. 6, pp. 747–757, 1999.
[192]
Q. Wang, M. Zhang, G. Ding et al., “Anti-ICAM-1 antibody and CTLA-4Ig synergistically enhance immature dendritic cells to induce donor-specific immune tolerance in vivo,” Immunology Letters, vol. 90, no. 1, pp. 33–42, 2003.
[193]
Z. Wang, A. E. Morelli, H. Hackstein, K. Kaneko, and A. W. Thomson, “Marked inhibition of transplant vascular sclerosis by in vivo-mobilized donor dendritic cells and anti-CD154 mAb,” Transplantation, vol. 76, no. 3, pp. 562–571, 2003.
[194]
O. Azhipa, K. Kimizuka, A. Nakao et al., “Comparative analysis of the fate of donor dendritic cells and B cells and their influence on alloreactive T cell responses under tacrolimus immunosuppression,” Clinical Immunology, vol. 114, no. 2, pp. 199–209, 2005.
[195]
A. Imai, H. Sahara, Y. Tamura et al., “Inhibition of endogenous MHC class II-restricted antigen presentation by tacrolimus (FK506) via FKBP51,” European Journal of Immunology, vol. 37, no. 7, pp. 1730–1738, 2007.
[196]
C. Voigtl？nder, S. R？？ner, E. Cierpka et al., “Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity,” Journal of Immunotherapy, vol. 29, no. 4, pp. 407–415, 2006.
[197]
D.-S. Lim, M.-S. Kang, J.-A. Jeong, and Y.-S. Bae, “Semi-mature DC are immunogenic and not tolerogenic when inoculated at a high dose in collagen-induced arthritis mice,” European Journal of Immunology, vol. 39, no. 5, pp. 1334–1343, 2009.
[198]
A. E. Morelli, A. T. Larregina, R. W. Ganster et al., “Recombinant adenovirus induces maturation of dendritic cells via an NF-κB-dependent pathway,” Journal of Virology, vol. 74, no. 20, pp. 9617–9628, 2000.
[199]
J.-M. Humbert and F. Halary, “Viral and non-viral methods to genetically modify Dendritic cells,” Current Gene Therapy, vol. 12, no. 2, pp. 127–136, 2012.
[200]
D. Rea, D. Laface, B. Hutchins et al., “Recombinant adenovirus-transduced human dendritic cells engineered to secrete interleukin-10 (IL-10) suppress Th1-type responses while selectively activating IL-10-producing CD4+ T cells,” Human Immunology, vol. 65, no. 11, pp. 1344–1355, 2004.
[201]
P. T. H. Coates, R. Krishnan, S. Kireta, J. Johnston, and G. R. Russ, “Human myeloid dendritic cells transduced with an adenoviral interleukin-10 gene construct inhibit human skin graft rejection in humanized NOD-scid chimeric mice,” Gene Therapy, vol. 8, no. 16, pp. 1224–1233, 2001.
[202]
T. Takayama, H. Tahara, and A. W. Thomson, “Differential effects of myeloid dendritic cells retrovirally transduced to express mammalian or viral interleukin-10 on cytotoxic T lymphocyte and natural killer cell functions and resistance to tumor growth,” Transplantation, vol. 71, no. 9, pp. 1334–1340, 2001.
[203]
W.-C. Lee, C. Zhong, S. Qian et al., “Phenotype, function, and in vivo migration and survival of allogeneic dendritic cell progenitors genetically engineered to express TGF-β,” Transplantation, vol. 66, no. 12, pp. 1810–1817, 1998.
[204]
T. Takayama, K. Kaneko, A. E. Morelli, W. Li, H. Tahara, and A. W. Thomson, “Retroviral delivery of transforming growth factor-β1 to myeloid dendritic cells: inhibition of T-cell priming ability and influence on allograft survival,” Transplantation, vol. 74, no. 1, pp. 112–119, 2002.
[205]
C. Asiedu, S. S. Dong, A. Pereboev et al., “Rhesus monocyte-derived dendritic cells modified to over-express TGF-β1 exhibit potent veto activity,” Transplantation, vol. 74, no. 5, pp. 629–637, 2002.
[206]
S. Buonocore, S. Van Meirvenne, F.-X. Demoor et al., “Dendritic cells transduced with viral interleukin 10 or Fas ligand: no evidence for induction of allotolerance in vivo,” Transplantation, vol. 73, no. 1, pp. S27–S30, 2002.
[207]
W.-C. Lee, S. Qiani, Y. Wan et al., “Contrasting effects of myeloid dendritic cells transduced with an adenoviral vector encoding interleukin-10 on organ allograft and tumour rejection,” Immunology, vol. 101, no. 2, pp. 233–241, 2000.
[208]
K. Kaneko, Z. Wang, S. H. Kim, A. E. Morelli, P. D. Robbins, and A. W. Thomson, “Dendritic cells genetically engineered to express IL-4 exhibit enhanced IL-12p70 production in response to CD40 ligation and accelerate organ allograft rejection,” Gene Therapy, vol. 10, no. 2, pp. 143–152, 2003.
[209]
J. Li, A. Meinhardt, M.-E. Roehrich et al., “Indoleamine 2,3-dioxygenase gene transfer prolongs cardiac allograft survival,” American Journal of Physiology, vol. 293, no. 6, pp. H3415–H3423, 2007.
[210]
C. A. Bonham, L. Peng, X. Liang et al., “Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-κB oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig,” Journal of Immunology, vol. 169, no. 6, pp. 3382–3391, 2002.
[211]
L. Lu, A. Gambotto, W.-C. Lee et al., “Adenoviral delivery of CTLA4lg into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients,” Gene Therapy, vol. 6, no. 4, pp. 554–563, 1999.
[212]
T. Takayama, A. E. Morelli, P. D. Robbins, H. Tahara, and A. W. Thomson, “Feasibility of CTLA4lg gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro,” Gene Therapy, vol. 7, no. 15, pp. 1265–1273, 2000.
[213]
R. W. O'Rourke, S.-M. Kang, J. A. Lower et al., “A dendritic cell line genetically modified to express CTLA4-Ig as a means to prolong islet allograft survival,” Transplantation, vol. 69, no. 7, pp. 1440–1446, 2000.
[214]
W. Sun, Q. Wang, L. Zhang et al., “Blockade of CD40 pathway enhances the induction of immune tolerance by immature dendritic cells genetically modified to express cytotoxic T lymphocyte antigen 4 immunoglobulin,” Transplantation, vol. 76, no. 9, pp. 1351–1359, 2003.
[215]
H. Matsue, K. Matsue, M. Walters, K. Okumura, H. Yagita, and A. Takashima, “Induction of antigen-specific immunosuppression by CD95L cDNA- transfected 'killer' dendritic cells,” Nature Medicine, vol. 5, no. 8, pp. 930–937, 1999.
[216]
W.-P. Min, R. Gorczynski, X.-Y. Huang et al., “Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival,” Journal of Immunology, vol. 164, no. 1, pp. 161–167, 2000.
[217]
S. Buonocore, F. Paulart, A. Le Moine et al., “Dendritic cells overexpressing CD95 (Fas) ligand elicit vigorous allospecific T-cell responses in vivo,” Blood, vol. 101, no. 4, pp. 1469–1476, 2003.
[218]
S. Buonocore, V. Flamand, N. Claessen, P. Heeringa, M. Goldman, and S. Florquin, “Dendritic cells overexpressing Fas-ligand induce pulmonary vasculitis in mice,” Clinical and Experimental Immunology, vol. 137, no. 1, pp. 74–80, 2004.
[219]
J. Machen, J. Harnaha, R. Lakomy, A. Styche, M. Trucco, and N. Giannoukakis, “Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells,” Journal of Immunology, vol. 173, no. 7, pp. 4331–4341, 2004.
[220]
X. Liang, L. Lu, Z. Chen et al., “Administration of dendritic cells transduced with antisense oligodeoxyribonucleotides targeting CD80 or CD86 prolongs allograft survival,” Transplantation, vol. 76, no. 4, pp. 721–729, 2003.
[221]
Q. Wang, Y. Liu, J. Wang et al., “Induction of allospecific tolerance by immature dendritic cells genetically modified to express soluble TNF receptor,” Journal of Immunology, vol. 177, no. 4, pp. 2175–2185, 2006.
[222]
K. R. Garrod, C. K. Chang, F.-C. Liu, T. V. Brennan, R. D. Foster, and S.-M. Kang, “Targeted lymphoid homing of dendritic cells is required for prolongation of allograft survival,” Journal of Immunology, vol. 177, no. 2, pp. 863–868, 2006.
[223]
M. J. Perone, S. Bertera, Z. S. Tawadrous et al., “Dendritic cells expressing transgenic galectin-1 delay onset of autoimmune diabetes in mice,” Journal of Immunology, vol. 177, no. 8, pp. 5278–5289, 2006.
[224]
D. Cooper, J. M. Ilarregui, S. A. Pesoa, D. O. Croci, M. Perretti, and G. A. Rabinovich, “Multiple functional targets of the immunoregulatory activity of Galectin-1. Control of immune cell trafficking, dendritic cell physiology, and T-cell fate,” Methods in Enzymology, vol. 480, pp. 199–244, 2010.
[225]
A. E. Morelli and A. W. Thomson, “Galectin-1, immune regulation and liver allograft survival,” American Journal of Transplantation, vol. 13, no. 3, pp. 535–536, 2013.
[226]
J. M. Ilarregui, D. O. Croci, G. A. Bianco et al., “Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10,” Nature Immunology, vol. 10, no. 9, pp. 981–991, 2009.
[227]
P.-L. Kuo, J.-Y. Hung, S.-K. Huang et al., “Lung cancer-derived galectin-1 mediates dendritic cell anergy through inhibitor of DNA binding 3/IL-10 signaling pathway,” Journal of Immunology, vol. 186, no. 3, pp. 1521–1530, 2011.
[228]
A. Mobergslien and M. Sioud, “Galectin-1 and -3 gene silencing in immature and mature dendritic cells enhances T cell activation and interferon-γ production,” Journal of Leukocyte Biology, vol. 91, no. 3, pp. 461–467, 2012.
[229]
Y. Ye, S. Yan, G. Jiang, et al., “Galectin-1 prolongs survival of mouse liver allografts from Flt3L-pretreated donors,” American Journal of Transplantation, vol. 13, no. 3, pp. 569–579, 2013.
[230]
A. Moreau, A. Noble, K. Ratnasothy, et al., “Absence of Galectin-1 accelerates CD8+ T cell-mediated graft rejection,” European Journal of Immunology, vol. 42, no. 11, pp. 2881–2888, 2012.
[231]
A. E. Morelli, “The immune regulatory effect of apoptotic cells and exosomes on dendritic cells: its impact on transplantation,” American Journal of Transplantation, vol. 6, no. 2, pp. 254–261, 2006.
[232]
A. E. Morelli and A. T. Larregina, “Apoptotic cell-based therapies against transplant rejection: role of recipient's dendritic cells,” Apoptosis, vol. 15, no. 9, pp. 1083–1097, 2010.
[233]
T. H. Lee, E. D'Asti, N. Magnus, K. Al-Nedawi, B. Meehan, and J. Rak, “Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular 'debris',” Seminars in Immunopathology, vol. 33, no. 5, pp. 455–467, 2011.
[234]
Z. Wang, W. J. Shufesky, A. Montecalvo, S. J. Divito, A. T. Larregina, and A. E. Morelli, “In situ-targeting of dendritic cells with donor-derived apoptopic cells restrains indirect allorecognition and ameliorates allograft vasculopathy,” PLoS ONE, vol. 4, no. 3, Article ID e4940, 2009.
[235]
M. Garrovillo, A. Ali, H. A. Depaz et al., “Induction of transplant tolerance with immunodominant allopeptide-pulsed host lymphoid and myeloid dendritic cells,” American Journal of Transplantation, vol. 1, no. 2, pp. 129–137, 2001.
[236]
T. Taner, H. Hackstein, Z. Wang, A. E. Morelli, and A. W. Thomson, “Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival,” American Journal of Transplantation, vol. 5, no. 2, pp. 228–236, 2005.
[237]
P. Correale, G. Campoccia, K. Y. Tsang et al., “Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hr-GM-CSF (Molgramostim) and hr-IL-2: results from a phase Ib clinical trial,” European Journal of Cancer, vol. 37, no. 7, pp. 892–902, 2001.
[238]
B. G. Redman, A. E. C. Alfred E. Chang, J. W. Joel Whitfield et al., “Phase Ib trial assessing autologous, tumor-pulsed dendritic cells as a vaccine administered with or without IL-2 in patients with metastatic melanoma,” Journal of Immunotherapy, vol. 31, no. 6, pp. 591–598, 2008.
[239]
M. V. Dhodapkar and R. M. Steinman, “Antigen-bearing immature dendritic cells induce peptide-specific CD8+ regulatory T cells in vivo in humans,” Blood, vol. 100, no. 1, pp. 174–177, 2002.
[240]
R. Thomas, S. Street, N. Ramnoruth, et al., “Safety and preliminary evidence of efficacy in a phase I clinical trial of autologous tolerising dendritic cells exposed to citrullinated peptides (Rheumavax) in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 70, supplement 3, article 169, 2011.
[241]
A. Moreau, E. Varey, G. Bériou, et al., “Tolerogenic dendritic cells and negative vaccination in transplantation: from rodents to clinical trials,” Frontiers in Immunology, vol. 3, article 218, 2012.
[242]
P. M. Emmer, J. Van Der Vlag, G. J. Adema, and L. B. Hilbrands, “Dendritic cells activated by lipopolysaccharide after dexamethasone treatment induce donor-specific allograft hyporesponsiveness,” Transplantation, vol. 81, no. 10, pp. 1451–1459, 2006.
[243]
G. Yu, X. Xu, D. V. Minh, E. D. Kilpatrick, and C. L. Xian, “NK cells promote transplant tolerance by killing donor antigen-presenting cells,” Journal of Experimental Medicine, vol. 203, no. 8, pp. 1851–1858, 2006.
