Dendritic cells: Emerging pharmacological targets of immunosuppressive drugs

Nature Reviews Immunology

Volumn 4, Issue 1, 2004, Pages 24-34

  Hackstein, Holger ^a   Thomson, Angus W ^b  

^a JUSTUS LIEBIG UNIVERSITY   (Germany)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOSUPPRESSIVE AGENT;

AUTOIMMUNE DISEASE; CELL DIFFERENTIATION; CELL FUNCTION; CELL MATURATION; DENDRITIC CELL; HUMAN; IMMUNE RESPONSE; IMMUNITY; IMMUNOLOGICAL TOLERANCE; IMMUNOSUPPRESSIVE TREATMENT; LYMPHOCYTE; ORGAN TRANSPLANTATION; PRIORITY JOURNAL; REVIEW; TARGET CELL;

EID: 0345827684     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1256     Document Type: Review

References (116)

1. Schwartz, R. & Dameshek, W. Drug-induced immunological tolerance. Nature 183, 1682-1683 (1959).
2. Schwartz, R. & Dameshek, W. The effects of 6-mercaptopurine on homograft reactions. J. Clin. Invest. 39, 952-958 (1960). References 1 and 2 initiated the era of drug-based immunosuppression by showing that mercaptopurine inhibited lymphocyte proliferation and prolonged graft survival.
3. Starzl, T. E. & Zinkernagel, R. M. Transplantation tolerance from a historical perspective. Nature Rev. Immunol. 1, 233-239 (2001).
4. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767-811 (2000).
5. Piemonti, L. et al. Glucocorticoids affect human dendritic cell differentiation and maturation. J. Immunol. 162, 6473-6481 (1999).
6. Matasic, R., Dietz, A. B. & Vuk-Pavlovic, S. Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells. J. Leukoc. Biol. 66, 909-914 (1999).
7. Woltman, A. M. et al. The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur. J. Immunol. 30, 1807-1812 (2000).
8. +-derived dermal dendritic cells but do not inhibit Langerhans cell development. J. Immunol. 168, 6181-6188 (2002).
9. Moser, M. et al. Glucocorticoids downregulate dendritic cell function in vitro and in vivo. Eur. J. Immunol. 25, 2818-2824 (1995). An early report showing that corticosteroids strongly suppress the maturation and T-cell stimulatory capacity of dendritic cells (DCs) in vitro and in vivo.
10. + Langerhans cells to the nasal mucosa in seasonal allergic rhinitis and effects of topical corticosteroid therapy. Allergy 56, 126-131 (2001).
11. Moller, G. M. et al. Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: down-regulation by inhaled corticosteroids. Clin. Exp. Allergy 26, 517-524 (1996).
12. Shodell, M. & Siegal, F. P. Corticosteroids depress IFN-α-producing plasmacytoid dendritic cells in human blood. J. Allergy Clin. Immunol. 108, 446-448 (2001).
13. Sacedon, R., Vicente, A., Varas, A., Jimenez, E. & Zapata, A. G. Early differentiation of thymic dendritic cells in the absence of glucocorticoids. J. Neuroimmunol. 94, 103-108 (1999).
14. 3 inhibits dendritic cell differentiation and maturation in vitro. Exp. Hematol. 28, 575-583 (2000).
15. 3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405-2411 (2000).
16. 3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J. Immunol. 164, 4443-4451 (2000).
17. Griffin, M. D. et al. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem. Biophys. Res. Commun. 270, 701-708 (2000).
18. 3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc. Natl Acad. Sci. USA 98, 6800-6805 (2001).
19. Hewison, M. et al. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J. Immunol. 170, 5382-5390 (2003).
20. Millard, A. L. et al. Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin. Exp. Immunol. 130, 245-255 (2002).
21. Saemann, M. D. et al. Bacterial metabolite interference with maturation of human monocyte-derived dendritic cells. J. Leukoc. Biol. 71, 238-246 (2002).
22. Sehgal, S. N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin. Biochem. 31, 335-340 (1998).
23. Woltman, A. M. et al. Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages. Blood 98, 174-180 (2001).
24. Monti, P. et al. Rapamycin impairs antigen uptake of human dendritic cells. Transplantation 75, 137-145 (2003).
25. Hackstein, H. et al. Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 101, 4457-4463 (2003).
26. Woltman, A. M. et al. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. Blood 101, 1439-1445 (2003).
27. Lennon-Dumenil, A. M., Bakker, A. H., Wolf-Bryant, P., Ploegh, H. L. & Lagaudriere-Gesbert, C. A closer look at proteolysis and MHC-class-II-restricted antigen presentation. Curr. Opin. Immunol. 14, 15-21 (2002).
28. Gromme, M. & Neefjes, J. Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. Mol. Immunol. 39, 181-202 (2002).
29. Delamarre, L., Holcombe, H. & Mellman, I. Presentation of exogenous antigens on major histocompatibility complex (MHC) class I and MHC class II molecules is differentially regulated during dendritic cell maturation. J. Exp. Med. 198, 111-122 (2003).
30. Hackstein, H. et al. Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. J. Immunol. 166, 7053-7062 (2001).
31. Hackstein, H., Taner, T., Logar, A. J. & Thomson, A. W. Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells. Blood 100, 1084-1087 (2002). This study was the first to show inhibition by an immunosuppressive drug of antigen uptake by DCs.
32. Tajima, K. et al. Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets. Immunology 108, 321-328 (2003).
33. Groettrup, M. & Schmidtke, G. Selective proteasome inhibitors: modulators of antigen presentation? Drug Discov. Today 4, 63-71 (1999).
34. Fenteany, G. et al. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268, 726-731 (1995).
35. Cerundolo, V. et al. The proteasome-specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human and murine cells. Eur. J. Immunol. 27, 336-341 (1997).
36. Andre, P. et al. An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. Proc. Natl Acad. Sci. USA 95, 13120-13124 (1998).
37. Wang, X. et al. Rapamycin inhibits proteasome activator expression and proteasome activity. Eur. J. Immunol. 27, 2781-2786 (1997).
38. Groettrup, M. et al. A role for the proteasome regulator PA28α in antigen presentation. Nature 381, 166-168 (1996).
39. Streicher, H. Z., Berkower, I. J., Busch, M., Gurd, F. R. & Berzofsky, J. A. Antigen conformation determines processing requirements for T-cell activation. Proc. Natl Acad. Sci. USA 81, 6831-6835 (1984).
40. Schultz, K. R., Bader, S., Paquet, J. & Li, W. Chloroquine treatment affects T-cell priming to minor histocompatibility antigens and graft-versus-host disease. Blood 86, 4344-4352 (1995).
41. Lee, J. et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc. Natl Acad. Sci. USA 100, 6646-6651 (2003).
42. Hacker, H. et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by nonspecific endocytosis and endosomal maturation. EMBO J. 17, 6230-6240 (1998).
43. Meinao, I. M., Sato, E. I., Andrade, L. E., Ferraz, M. B. & Atra, E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus 5, 237-241 (1996).
44. Dieu, M. C. et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373-386 (1998).
45. Martin-Fontecha, A. et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615-621 (2003).
46. Lutz, M. B. & Schuler, G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 23, 445-449 (2002).
47. Cumberbatch, M., Dearman, R. J. & Kimber, I. Inhibition by dexamethasone of Langerhans cell migration: influence of epidermal cytokine signals. Immunopharmacology 41, 235-243 (1999).
48. 3 and glucocorticoid pathways. Biochem. Biophys. Res. Commun. 297, 645-652 (2002).
49. Vulcano, M. et al. Dendritic cells as a major source of macrophage-derived chemokine/CCL22 in vitro and in vivo. Eur. J. Immunol. 31, 812-822 (2001).
50. Vulcano, M. et al. Unique regulation of CCL18 production by maturing dendritic cells. J. Immunol. 170, 3843-3849 (2003).
51. Randolph, G. J. Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators. Semin. Immunol. 13, 267-274 (2001).
52. Randolph, G. J. et al. A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels. Proc. Natl Acad. Sci. USA 95, 6924-6929 (1998). A report indicating that the lipid transporter multidrug resistance protein 1 (MDR1) regulates DC migration to lymphatics.
53. Schinkel, A. H., Wagenaar, E., van Deemter, L., Mol, C. A. & Borst, P. Absence of the mdr1a p-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96, 1698-1705 (1995).
54. H2 cells after antigenic stimulation in vivo. J. Clin. Invest. 101, 703-710 (1998).
55. De Waal, E. J., Rademakers, L. H., Schuurman, H. J., Vos, J. G. & Van Loveren, H. Alterations of dendritic cells in the rat thymus without epithelial cell loss during cyclosporine treatment and recovery. Toxicology 110, 133-151 (1996).
56. Chen, T. et al. Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression. Blood 22 September 2003 (doi: 10.1182/blood-2003-07-2412). An important publication showing that cyclosporine A (CsA) inhibits DC migration by suppression of CC-chemokine receptor 7 (CCR7) expression.
57. 2 regulates the migratory capacity of specific DC subsets. Blood 100, 1362-1372 (2002).
58. 2. Blood 100, 1354-1361 (2003).
59. Hackstein, H., Morelli, A. E. & Thomson, A. W. Designer dendritic cells for tolerance induction: guided not misguided missiles. Trends Immunol. 22, 437-442 (2001).
60. Rea, D. et al. Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10 Blood 95, 3162-3167 (2000).
61. Matyszak, M. K., Citterio, S., Rescigno, M. & Ricciardi-Castagnoli, P. Differential effects of corticosteroids during different stages of dendritic cell maturation. Eur. J. Immunol. 30, 1233-1242 (2000). This report shows that multiple restimulation of T cells with corticosteroid-treated DCs allows the in vitro generation of regulatory T cells.
62. + Langerhans cells in topical steroid-treated human skin express normal amounts of HLA-DR and CD1a/T6 antigens and exhibit normal alloantigen-presenting capacity. J. Invest. Dermatol. 92, 258-262 (1989).
63. Kiani, A., Rao, A. & Aramburu, J. Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity 12, 359-372 (2000).
64. Lee, J. I. et al. Cyclosporine A inhibits the expression of co-stimulatory molecules on in vitro-generated dendritic cells: association with reduced nuclear translocation of nuclear factor-κB. Transplantation 68, 1255-1263 (1999).
65. Morelli, A. E. et al. Microchimerism, donor dendritic cells, and alloimmune reactivity in recipients of Flt3 ligand-mobilized hemopoietic cells: modulation by tacrolimus. J. Immunol. 165, 226-237 (2000).
66. Szabo, G., Gavala, C. & Mandrekar, P. Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells. J. Investig. Med. 49, 442-449 (2001).
67. H2 responses. J. Leukoc. Biol. 68, 633-640 (2000).
68. Duperrier, K. et al. Cyclosporin A inhibits dendritic cell maturation promoted by TNF-α or LPS but not by double-stranded RNA or CD40L. J. Leukoc. Biol. 72, 953-961 (2002).
69. Matsue, H. et al. Contrasting impacts of immunosuppressive agents (rapamycin, FK506, cyclosporin A, and dexamethasone) on bidirectional dendritic cell-T cell interaction during antigen presentation. J. Immunol. 169, 3555-3564 (2002).
70. Zenke, G. et al. Sanglifehrin A, a novel cyclophilin-binding compound showing immunosuppressive activity with a new mechanism of action. J. Immunol. 166, 7165-7171 (2001).
71. Steinschulte, C., Taner, T., Thomson, A. W., Bein, G. & Hackstein, H. Cutting edge: sanglifehrin A, a novel cyclophilin-binding immunosuppressant blocks bioactive IL-12 production by human dendritic cells. J. Immunol. 171, 542-546 (2003). This study shows that the new cyclophilin-binding immunosuppressant sanglifehrin A rapidly blocks bioactive interleukin-12 (IL-12) production by human DCs. The effect was found to be unique in contrast to the related drugs CsA and rapamycin.
72. Mehling, A. et al. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J. Immunol. 165, 2374-2381 (2000). The first report showing that mycophenolate mofetil mediates its immunosuppressive effects not only by suppressing T-cell proliferation, but also by inhibiting DC maturation.
73. Matasic, R., Dietz, A. B. & Vuk-Pavlovic, S. Cyclooxygenase-independent inhibition of dendritic cell maturation by aspirin. Immunology 101, 53-60 (2000).
74. Verhasselt, V. et al. N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-κB inhibition. J. Immunol. 162, 2569-2574 (1999).
75. Ho, L. J. et al. Aspirin differentially regulates endotoxin-induced IL-12 and TNF-α production in human dendritic cells. Scand. J. Rheumatol. 30, 346-352 (2001).
76. Garg, S. et al. Genetic tagging shows increased frequency and longevity of antigen-presenting, skin-derived dendritic cells in vivo. Nature Immunol. 4, 907-912 (2003).
77. McLellan, A. et al. MHC clase II and CD40 play opposing roles in dendritic cell survival. Eur. J. Immunol. 30, 2612-2619 (2000).
78. Miga, A. J. et al. Dendritic cell longevity and T cell persistence is controlled by CD154-CD40 interactions. Eur. J. Immunol. 31, 959-965 (2001).
79. Kim, K. D., Choe, Y. K., Choe, I. S. & Lim, J. S. Inhibition of glucocorticoid-mediated, caspase-independent dendritic cell death by CD40 activation. J. Leukoc. Biol. 69, 426-434 (2001).
80. Castedo, M., Ferri, K. F. & Kroemer, G. Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ. 9, 99-100 (2002).
81. Morelli, A. E., Hackstein, H. & Thomson, A. W. Potential of tolerogenic dendritic cells for transplantation. Semin. Immunol. 13, 323-335 (2001).
82. Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685-711 (2003).
83. Menges, M. et al. Repetitive injections of dendritic cells matured with tumor necrosis factor α induce antigen-specific protection of mice from autoimmunity. J. Exp. Med. 195, 15-21 (2002).
84. Gilliet, M. & Liu, Y. J. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J. Exp. Med. 195, 695-704 (2002).
85. Huang, F. P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435-444 (2000).
86. Scheinecker, C., McHugh, R., Shevach, E. M. & Germain, R. N. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J. Exp. Med. 196, 1079-1090 (2002).
87. + regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235-247 (2003).
88. + dendritic cells prolong the survival of vascularized heart allografts. J. Immunol. 168, 143-154 (2002).
89. Akbari O., DeKruyff, R. H. & Umetsu, D. T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nature Immunol. 2, 725-731 (2001).
90. Akbari, O. et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nature Med. 8, 1024-1032 (2002).
91. 3 and mycophenolate mofetil treatment mediate transplantation tolerance J. Immunol. 167, 1945-1953 (2001).
92. Muller, G. et al. Interleukin-10-treated dendritic cells modulate immune responses of naive and sensitized T cells in vivo. J. Invest. Dermatol. 119, 836-841 (2002).
93. + anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 99, 2468-2476 (2002).
94. Thomas, J. M. et al. Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotoxin and deoxyspergualin. Transplantation 68, 1660-1673 (1999).
95. Yang, J. et al. LF15-0195 generates tolerogenic dendritic cells by suppression of NF-κB signaling through inhibition of IKK activity. J. Leukoc. Biol. 74, 438-447 (2003).
96. Min, W. P. et al. Synergistic tolerance induced by LF15-0195 and anti-CD45RB monoclonal antibody through suppressive dendritic cells. Transplantation 75, 1160-1165 (2003).
97. Giannoukakis, N. et al. Prolongation of cardiac allograft survival using dendritic cells treated with NF-κB decoy oligodeoxyribonucleotides. Mol. Ther. 1, 430-437 (2000).
98. Martin, E., O'Sullivan, B., Low, P. & Thomas, R. Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 18, 155-167 (2003).
99. Sato, K., Yamashita, N., Baba, M. & Matsuyama, T. Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18, 367-379 (2003).
100. Sato, K., Yamashita, N., Baba, M. & Matsuyama, T. Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells. Blood 101, 3581-3589 (2003).
101. Grohmann, U., Fallarino, F. & Puccetti, P. Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol. 24, 242-248 (2003).
102. Munn, D. H. et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867-1870 (2002).
103. Wirleitner, B. et al. Monocyte-derived dendritic cells release neopterin. J. Leukoc. Biol. 72, 1148-1153 (2002).
104. Mellor, A. L. et al. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol. 171, 1652-1655 (2003).
105. Hench, P. S., Kendall, E. C., Slocumb, C. H. & Polley, H. F. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Preliminary report. Annu. Rheum. Dis. 8, 97-104 (1949).
106. Calne, R. Y. The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine. Lancet 1, 417-418 (1960).
107. Murray, J. E., Merrill, J. P., Harrison, J. H., Wilson, R. E. & Dammin, G. J. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N. Engl. J. Med. 268, 1315-1323 (1963).
108. Starzl, T. E., Marchioro, T. L. & Waddell, W. R. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg. Gynecol. Obstet. 117, 385-395 (1963).
109. Waksman, B. H., Arbouys, S. & Arnason, B. G. The use of specific 'lymphocyte' antisera to inhibit hypersensitive reactions of the 'delayed' type. J. Exp. Med. 114, 997-1022 (1961).
110. Starzl, T. E., Marchioro, T. L., Porter, K. A., Iwasaki, Y. & Cerilli, G. J. The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg. Gyneco. Obstet. 124, 301-308 (1967).
111. Borel, J. F., Feurer, C., Gubler H. U. & Stahelin, H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6, 468-475 (1976).
112. Calne, R. Y. et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2, 1323-1327 (1978).
113. Kino, T. et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J. Antibiot. (Tokyo) 40, 1256-1265 (1987).
114. Starzl, T. E. et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 2, 1000-1004 (1989).
115. Sehgal, S. N., Baker, H. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. (Tokyo) 28, 727-732 (1975).
116. Martel, R. R., Klicius, J. & Galet, S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can. J. Physiol. Pharmacol. 55, 48-51 (1977).