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,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation
Roche Milano Ricerche, Milan, Italy
1
,25-Dihydroxyvitamin D3
(1,25(OH)2D3), the active form of vitamin
D3, is a potent immunomodulatory agent. Here we show that
dendritic cells (DCs) are major targets of
1,25(OH)2D3-induced immunosuppressive activity.
1,25(OH)2D3 prevents the differentiation in
immature DCs of human monocytes cultured with GM-CSF and IL-4. Addition
of 1,25(OH)2D3 during LPS-induced maturation
maintains the immature DC phenotype characterized by high mannose
receptor and low CD83 expression and markedly inhibits up-regulation of
the costimulatory molecules CD40, CD80, and CD86 and of class II MHC
molecules. This is associated with a reduced capacity of DCs to
activate alloreactive T cells, as determined by decreased proliferation
and IFN-
secretion in mixed leukocyte cultures.
1,25(OH)2D3 also affects maturing DCs, leading
to inhibition of IL-12p75 and enhanced IL-10 secretion upon activation
by CD40 ligation. In addition, 1,25(OH)2D3
promotes the spontaneous apoptosis of mature DCs. The modulation of
phenotype and function of DCs matured in the presence of
1,25(OH)2D3 induces cocultured alloreactive
CD4+ cells to secrete less IFN- upon restimulation,
up-regulate CD152, and down-regulate CD154 molecules. The inhibition of
DC differentiation and maturation as well as modulation of their
activation and survival leading to T cell hyporesponsiveness may
explain the immunosuppressive activity of
1,25(OH)2D3.
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 X. Dong, T. Craig, N. Xing, L. A. Bachman, C. V. Paya, F. Weih, D. J. McKean, R. Kumar, and M. D. Griffin Direct Transcriptional Regulation of RelB by 1{alpha},25-Dihydroxyvitamin D3 and Its Analogs: PHYSIOLOGIC AND THERAPEUTIC IMPLICATIONS FOR DENDRITIC CELL FUNCTION J. Biol. Chem., December 5, 2003; 278(49): 49378 - 49385. [Abstract] [Full Text] [PDF]
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K. Yokomura, T. Suda, S. Sasaki, N. Inui, K. Chida, and H. Nakamura Increased Expression of the 25-Hydroxyvitamin D3-1{alpha}-Hydroxylase Gene in Alveolar Macrophages of Patients with Lung Cancer J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5704 - 5709. [Abstract] [Full Text] [PDF]
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 S. G. Rhodes, L. A. Terry, J. Hope, R. G. Hewinson, and H. M. Vordermeier 1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle Clin. Vaccine Immunol., November 1, 2003; 10(6): 1129 - 1135. [Abstract] [Full Text] [PDF]
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J. Fritsche, K. Mondal, A. Ehrnsperger, R. Andreesen, and M. Kreutz Regulation of 25-hydroxyvitamin D3-1{alpha}-hydroxylase and production of 1{alpha},25-dihydroxyvitamin D3 by human dendritic cells Blood, November 1, 2003; 102(9): 3314 - 3316. [Abstract] [Full Text] [PDF]
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R. Morita, N. Ukyo, M. Furuya, T. Uchiyama, and T. Hori Atrial Natriuretic Peptide Polarizes Human Dendritic Cells Toward a Th2-Promoting Phenotype Through Its Receptor Guanylyl Cyclase-Coupled Receptor A J. Immunol., June 15, 2003; 170(12): 5869 - 5875. [Abstract] [Full Text] [PDF]
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M. Hewison, L. Freeman, S. V. Hughes, K. N. Evans, R. Bland, A. G. Eliopoulos, M. D. Kilby, P. A. H. Moss, and R. Chakraverty Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells J. Immunol., June 1, 2003; 170(11): 5382 - 5390. [Abstract] [Full Text] [PDF]
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K. Sato, N. Yamashita, M. Baba, and T. Matsuyama Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells Blood, May 1, 2003; 101(9): 3581 - 3589. [Abstract] [Full Text] [PDF]
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C. Guillot, S. Menoret, C. Guillonneau, C. Braudeau, M. G. Castro, P. Lowenstein, and I. Anegon Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig Blood, April 15, 2003; 101(8): 3325 - 3333. [Abstract] [Full Text] [PDF]
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A. M. Woltman and C. van Kooten Functional modulation of dendritic cells to suppress adaptive immune responses J. Leukoc. Biol., April 1, 2003; 73(4): 428 - 441. [Abstract] [Full Text] [PDF]
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M. Vulcano, S. Struyf, P. Scapini, M. Cassatella, S. Bernasconi, R. Bonecchi, A. Calleri, G. Penna, L. Adorini, W. Luini, et al. Unique Regulation of CCL18 Production by Maturing Dendritic Cells J. Immunol., April 1, 2003; 170(7): 3843 - 3849. [Abstract] [Full Text] [PDF]
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J. Bayry, S. Lacroix-Desmazes, C. Carbonneil, N. Misra, V. Donkova, A. Pashov, A. Chevailler, L. Mouthon, B. Weill, P. Bruneval, et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin Blood, January 15, 2003; 101(2): 758 - 765. [Abstract] [Full Text] [PDF]
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 K. G. Brinker, H. Garner, and J. R. Wright Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L232 - L241. [Abstract] [Full Text] [PDF]
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G. Penna, M. Vulcano, A. Roncari, F. Facchetti, S. Sozzani, and L. Adorini Cutting Edge: Differential Chemokine Production by Myeloid and Plasmacytoid Dendritic Cells J. Immunol., December 15, 2002; 169(12): 6673 - 6676. [Abstract] [Full Text] [PDF]
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A. Gurlek, M. R. Pittelkow, and R. Kumar Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1{alpha},25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation Endocr. Rev., December 1, 2002; 23(6): 763 - 786. [Abstract] [Full Text] [PDF]
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A. G.S. van Halteren, E. van Etten, E. C. de Jong, R. Bouillon, B. O. Roep, and C. Mathieu Redirection of Human Autoreactive T-Cells Upon Interaction With Dendritic Cells Modulated by TX527, an Analog of 1,25 Dihydroxyvitamin D3 Diabetes, July 1, 2002; 51(7): 2119 - 2125. [Abstract] [Full Text] [PDF]
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E. A. Roig, E. Richer, F. Canonne-Hergaux, P. Gros, and M. F. M. Cellier Regulation of NRAMP1 gene expression by 1{alpha},25-dihydroxy-vitamin D3 in HL-60 phagocytes J. Leukoc. Biol., May 1, 2002; 71(5): 890 - 904. [Abstract] [Full Text] [PDF]
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S. Gregori, N. Giarratana, S. Smiroldo, M. Uskokovic, and L. Adorini A 1{alpha},25-Dihydroxyvitamin D3 Analog Enhances Regulatory T-Cells and Arrests Autoimmune Diabetes in NOD Mice Diabetes, May 1, 2002; 51(5): 1367 - 1374. [Abstract] [Full Text] [PDF]
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M. D. Saemann, O. Parolini, G. A. Bohmig, P. Kelemen, P.-M. Krieger, J. Neumuller, K. Knarr, W. Kammlander, W. H. Horl, C. Diakos, et al. Bacterial metabolite interference with maturation of human monocyte-derived dendritic cells J. Leukoc. Biol., February 1, 2002; 71(2): 238 - 246. [Abstract] [Full Text] [PDF]
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M. Cippitelli, C. Fionda, D. Di Bona, F. Di Rosa, A. Lupo, M. Piccoli, L. Frati, and A. Santoni Negative Regulation of CD95 Ligand Gene Expression by Vitamin D3 in T Lymphocytes J. Immunol., February 1, 2002; 168(3): 1154 - 1166. [Abstract] [Full Text] [PDF]
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T. P. Staeva-Vieira and L. P. Freedman 1,25-Dihydroxyvitamin D3 Inhibits IFN-{gamma} and IL-4 Levels During In Vitro Polarization of Primary Murine CD4+ T Cells J. Immunol., February 1, 2002; 168(3): 1181 - 1189. [Abstract] [Full Text] [PDF]
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A. Boonstra, F. J. Barrat, C. Crain, V. L. Heath, H. F. J. Savelkoul, and A. O'Garra 1{alpha},25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells J. Immunol., November 1, 2001; 167(9): 4974 - 4980. [Abstract] [Full Text] [PDF]
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S. Latour, H. Tanaka, C. Demeure, V. Mateo, M. Rubio, E. J. Brown, C. Maliszewski, F. P. Lindberg, A. Oldenborg, A. Ullrich, et al. Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-{alpha}: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation J. Immunol., September 1, 2001; 167(5): 2547 - 2554. [Abstract] [Full Text] [PDF]
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G. Penna, S. Sozzani, and L. Adorini Cutting Edge: Selective Usage of Chemokine Receptors by Plasmacytoid Dendritic Cells J. Immunol., August 15, 2001; 167(4): 1862 - 1866. [Abstract] [Full Text] [PDF]
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S. Gregori, M. Casorati, S. Amuchastegui, S. Smiroldo, A. M. Davalli, and L. Adorini Regulatory T Cells Induced by 1{alpha},25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance J. Immunol., August 15, 2001; 167(4): 1945 - 1953. [Abstract] [Full Text] [PDF]
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R. Furlan, E. Brambilla, F. Ruffini, P. L. Poliani, A. Bergami, P. C. Marconi, D. M. Franciotta, G. Penna, G. Comi, L. Adorini, et al. Intrathecal Delivery of IFN-{gamma} Protects C57BL/6 Mice from Chronic-Progressive Experimental Autoimmune Encephalomyelitis by Increasing Apoptosis of Central Nervous System-Infiltrating Lymphocytes J. Immunol., August 1, 2001; 167(3): 1821 - 1829. [Abstract] [Full Text] [PDF]
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H. Hackstein, A. E. Morelli, A. T. Larregina, R. W. Ganster, G. D. Papworth, A. J. Logar, S. C. Watkins, L. D. Falo, and A. W. Thomson Aspirin Inhibits In Vitro Maturation and In Vivo Immunostimulatory Function of Murine Myeloid Dendritic Cells J. Immunol., June 15, 2001; 166(12): 7053 - 7062. [Abstract] [Full Text] [PDF]
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S. Corinti, C. Albanesi, A. la Sala, S. Pastore, and G. Girolomoni Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions J. Immunol., April 1, 2001; 166(7): 4312 - 4318. [Abstract] [Full Text] [PDF]
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A. la Sala, D. Ferrari, S. Corinti, A. Cavani, F. Di Virgilio, and G. Girolomoni Extracellular ATP Induces a Distorted Maturation of Dendritic Cells and Inhibits Their Capacity to Initiate Th1 Responses J. Immunol., February 1, 2001; 166(3): 1611 - 1617. [Abstract] [Full Text] [PDF]
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M. Feldmann, J. Miotla, E. Paleolog, R. Williams, A.-M. Malfait, P. Taylor, F. M Brennan, and R. N Maini Future prospects for anti-cytokine treatment Ann Rheum Dis, November 1, 2000; 59(90001): i119 - 122. [Abstract] [Full Text] [PDF]
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M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
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 M. D. Griffin, W. Lutz, V. A. Phan, L. A. Bachman, D. J. McKean, and R. Kumar Dendritic cell modulation by 1alpha ,25 dihydroxyvitamin D3 and its analogs: A vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo PNAS, June 5, 2001; 98(12): 6800 - 6805. [Abstract] [Full Text] [PDF]
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