Abstract
Tolerance is maintained by central and peripheral regulatory mechanisms and is essential to prevent autoimmunity. In the setting of solid organ or haematopoietic transplantation, the indirect pathway of allorecognition is a significant driver of chronic rejection. Chronic rejection proceeds despite effective immunosuppressive therapy, therefore achieving immunological tolerance to control the indirect pathway is a desirable goal. Tolerance induction may be achieved by vaccination with modified antigen presenting cells (APCs). Mature dendritic cells (DCs) are potent APCs, but immature DCs have been shown to have a reduced allo-stimulatory capacity and can be tolerogenic. Drug treatment has been shown to decrease the allo-stimulatory capacity of DC compared to immature DC. Dexamethasone and vitamin D3 have been established as having potent effects on dendritic cell immunogenicity.
The effects of Aspirin, a non-steroidal anti-inflammatory, on DCs have not previously been so extensively studied and here we will review the work which has been carried out using Aspirin to induce tolerogenic DCs.
We have examined the mechanisms of tolerance induction using human DCs and T cells. It has been possible to demonstrate that in aspirin treated, human DCs there is inhibition of the nuclear factor K-B (NFKB) signalling pathway, modified cytokine production, reduced expression of co-stimulatory molecules (CD40, CD80, and CD86) and increased expression of immunoglobulin-like transcript-3 (ILT3). The decreased expression of co-stimulatory molecules is maintained following cytokine or lipopolysaccharide (LPS) challenge. Drug treatment of DCs increases the expression of immunoglobulin-like transcript 3 (ILT3) when compared with immature DCs (iDCs), and these high levels of expression are maintained when the cells are challenged with a maturational stimulus. Aspirin also reduces the allo-stimulatory capacity of human DCs, and induces hypo-responsiveness and regulatory activity in responder T cells. These regulatory T-cells were CD4+ CD25+ FOXP3+ and by studying CD25− or CD45RA populations, it was possible to determine that these regulatory T cells were generated de novo rather than requiring the expansion of naturally occurring Tregs.
Aspirin continues therefore to be of interest with regard its wider effects on immune regulation, other than that mediated by direct inhibition of cyclo-oxygenase, in particular its ability to induce tolerogenic DCs at therapeutic concentrations in humans.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Akarasereenont P, Mitchell JA, Thiemermann C, Vane JR (1994) Relative potency of nonsteroid anti-inflammatory drugs as inhibitors of cyclooxygenase-1 or cyclooxygenase-2. Br J Pharmacol 112(suppl):183
Akiyama Y, Shirasugi N, Aramaki O, Matsumoto K, Shimazu M, Kitajima M, Ikeda Y, Niimi M (2002) Intratracheal delivery of a single major histocompatibility complex class I peptide induced prolonged survival of fully allogeneic cardiac grafts and generated regulatory cells. Hum Immunol 63:888–892
Albert ML, Jegathesan M, Darnell RB (2001) Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells. Nat Immunol 2:1010–1017
Aldigier JC, Gualde N, Mexmain S, Chable-Rabinovitch H, Ratinaud MH, Rigaud M (1984) Immunosuppression induced in vivo by 15 hydroxyeicosatetraenoic acid (15 HETE). Prostaglandins Leukot Med 13:99–107
Austyn JM, Larsen CP (1990) Migration patterns of dendritic leukocytes. Implications for transplantation. Transplantation 49:1–7
Bailey JM, Bryant RW, Low CE, Pupillo MB, Vanderhoek JY (1982) Regulation of T-lymphocyte mitogenesis by the leukocyte product 15-hydroxy-eicosatetraenoic acid (15-HETE). Cell Immunol 67:112–120
Belladonna ML, Grohmann U, Guidetti P, Volpi C, Bianchi R, Fioretti MC, Schwarcz R, Fallarino F, Puccetti P (2006) Kynurenine pathway enzymes in dendritic cells initiate toleroge-nesis in the absence of functional IDO. J Immunol 177:130–137
Bjercke S, Gaudernack G (1985) Dendritic cells and monocytes as accessory cells in T-Cell responses in man .2. Function as antigen-presenting cells. Scand J Immunol 21:501–508
Buckland M, Jago C, Fazekesova H, George A, Lechler R, Lombardi G (2006a) Aspirin modified dendritic cells are potent inducers of allo-specific regulatory T-cells. Int Immunopharmacol 6:1895–1901
Buckland M, Jago CB, Fazekasova H, Scott K, Tan PH, George AJ, Lechler R, Lombardi G (2006b) Aspirin-treated human DCs up-regulate ILT-3 and induce hyporesponsiveness and regulatory activity in responder T cells. Am J Transplant 6:2046–2059
Cella M, Dohring C, Samaridis J, Dessing M, Brockhaus M, Lanzavecchia A, Colonna M (1997) A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. J Exp Med 185:1743–1751
Cohn SM, Schloemann S, Tessner T, Seibert K, Stenson WF (1997) Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. J Clin Invest 99:1367–1379
De Smedt T, Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M (1997) Effect of interleukin-10 on dendritic cell maturation and function. Eur J Immunol 27:1229–1235
Fazekas de St Groth B (1998) The evolution of self-tolerance: a new cell arises to meet the challenge of self-reactivity. Immunol Today 19:448–454
Griffin MD (2000) Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun 270:701–708
Hachicha M, Pouliot M, Petasis NA, Serhan CN (1999) Lipoxin (LX)A(4) and aspirin-triggered 15-epi-LXA(4) inhibit tumor necrosis factor 1 alpha-initiated neutrophil responses and trafficking: Regulators of a cytokine-chemokine axis. J Exp Med 189:1923–1929
Hackstein H, Morelli AE, Larregina AT, Ganster RW, Papworth GD, Logar AJ, Watkins SC, Falo LD, Thomson AW (2001) Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. J Immunol 166:7053–7062
Harizi H, Juzan M, Grosset C, Rashedi M, Gualde N (2001) Dendritic cells issued in vitro from bone marrow produce PGE(2) that contributes to the immunomodulation induced by antigen-presenting cells. Cell Immunol 209:19–28
Herschman HR (1999) Function and regulation of prostaglandin synthase 2. Adv Exp Med Biol 469:3–8
Ho LJ, Chang DM, Shiau HY, Chen CH, Hsieh TY, Hsu YL, Wong CS, Lai JH (2001) Aspirin differentially regulates endotoxin-induced IL-12 and TNF-alpha production in human dendritic cells. Scand J Rheumatol 30:346–352
Hou WS, Van Parijs LA (2004) Bcl-2-dependent molecular timer regulates the lifespan and im-munogenicity of dendritic cells. Nat Immunol 5:583–589
Inaba K, Turley S, Yamaide F, Iyoda T, Mahnke K (1998) Efficient presentation of phagocytosed cellular fragments on the MHC class II products of dendritic cells. J Exp Med 188:2163
Ito T, Nayer A, Yagita H, Auchincloss JH, Sayegh MH, Najafian N (2003) The role of inhibitory costimulatory pathway PD-1 in regulating alloimmune responses in vivo. Am J Transplant 3:169
Iwakoshi NN, Mordes JP, Markees TG, Phillips NE, Rossini AA, Greiner DL (2000) Treatment of allograft recipients with donor-specific transfusion and anti-CD154 antibody leads to deletion of alloreactive CD8+ T cells and prolonged graft survival in a CTLA4-dependent manner. J Immunol 164:512–521
Jing H, Vassiliou E, Ganea D (2003) Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells. J Leukoc Biol 74:868–879
Jonuleit H, Kuhn U, Muller G, Steinbrink K, Paragnik L, Schmitt E, Knop J, Enk AH (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27:3135–3142
Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH (2000) Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allo-geneic immature human dendritic cells. J Exp Med 192:1213–1222
Kargman S, Charleson S, Cartwright M, Frank J, Riendeau D, Mancini J, Evans J, O'Neill G (1996) Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology 111:445–454
Larsen CP, Steinman RM, Witmer-Pack M, Hankins DF, Morris PJ, Austyn JM (1990) Migration and maturation of langerhans cells in skin transplants and explants. J Exp Med 172:1483–1493
Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG (2005) Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105:1162–1169
Low CE, Pupillo MB, Bryant RW, Bailey JM (1984) Inhibition of phytohemagglutinin-induced lymphocyte mitogenesis by lipoxygenase metabolites of arachidonic acid: structure-activity relationships. J Lipid Res 25:1090–1095
Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DH, Thomson AW (1997) Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol 158:5676–5684
Lu L, Lee WC, Takayama T, Qian S, Gambotto A, Robbins PD, Thomson AW (1999) Genetic engineering of dendritic cells to express immunosuppressive molecules (viral IL-10, TGF-beta, and CTLA4Ig). J Leukoc Biol 66:293–296
Machado FS, Johndrow JE, Esper L, Dias A, Bafica A, Serhan CN, Aliberti J (2006) Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat Med 12:330–334
Marnett LJ, Kalgutkar AS (1999) Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol Sci 20:465–469
Matasic R, Dietz AB, Vuk-Pavlovic S (2000) Cyclooxygenase-independent inhibition of dendritic cell maturation by aspirin. Immunology 101:53–60
Meade EA, Smith WL, DeWitt DL (1993) Differential inhibition of prostaglandin endoperox-ide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 268:6610–6614
Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774
Menges M, Rossner S, Voigtlander C, Schindler H, Kukutsch NA (2002) Repetitive injections of dendritic cells matured with tumor necrosis factor induce antigen-specific protection of mice from autoimmunity. J Exp Med 195:15–21
Mexmain S, Cook J, Aldigier JC, Gualde N, Rigaud M (1985) Thymocyte cyclic AMP and cyclic GMP response to treatment with metabolites issued from the lipoxygenase pathway. J Immunol 135:1361–1365
Mitchell JA, Akarasereenont P, Bishop-Bailey D, Wood EG, Thiemermann C, Vane JR (1993) Aspirin is a more potent inhibitor of prostacyclin biosynthesis by endothelial cells than by LPS-treated J774 macrophages. Br J Pharmacol 109(suppl):2
Newberry RD, Stenson WF, Lorenz RG (1999) Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 5:900–906
Nishimura H, Minato N, Nakano T, Honjo T (1998) Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 10:1563–1572
Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151
Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322
Nossal GJV (1994) Negative selection of lymphocytes. Cell 76:229–239
Parkinson JF (2006) Lipoxin and synthetic lipoxin analogs: an overview of anti-inflammatory functions and new concepts in immunomodulation. Inflamm Allergy Drug Targets 5:91–106
Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+T cell-mediated suppression by dendritic cells. Science 299:1033–1036
Penna G, Adorini L (2000) 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164:2405–2411
Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:3490–3497
Picot D, Loll PJ, Garavito RM (1994) The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367:243–249
Pierce JW, Read MA, Ding H, Luscinskas FW, Collins T (1996) Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration. J Immunol 156:3961–3969
Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6:280–286
Rainsford E, Reen DJ (2002) Interleukin 10, produced in abundance by human newborn T cells, may be the regulator of increased tolerance associated with cord blood stem cell transplantation. Br J Haematol 116:702–709
Rea D, van Kooten C, van Meijgaarden KE, Ottenhoff TH, Melief CJ, Offringa R (2000) Gluco-corticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10. Blood 95:3162–3167
Reis e Sousa C (2006) Dendritic cells in a mature age. Nat Rev Immunol 6:476–483
Rieser C, Bock G, Klocker H, Bartsch G, Thurnher M (1997) Prostaglandin E2 and tumor necrosis factor alpha cooperate to activate human dendritic cells:synergistic activation of interleukin 12 production. J Exp Med 186:1603–1608
Rohn TA, Boes M, Wolters D, Spindeldreher S, Muller B, Langen H, Ploegh H, Vogt AB, Kropshofer H (2004) Upregulation of the CLIP self peptide on mature dendritic cells antagonizes T helper type 1 polarization. Nat Immunol 5:909–918
Roth GJ, Siok CJ (1978) Acetylation of the NH2-terminal serine of prostaglandin synthetase by aspirin. J Biol Chem 253:3782–3784
Sato K, Yamashita N, Yamashita N, Baba M, Matsuyama T (2003) Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18: 367–379
Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ (2005) IFN-[Gamma] production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 201:1925–1935
Scheinecker C, McHugh R, Shevach EM, Germain RN (2002) Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 196:1079–1090
Smith JB, Willis AL (1971) Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol 231:235–237
Smith WL, Meade EA, DeWitt DL (1994) Pharmacology of prostaglandin endoperoxide synthase isozymes-1 and -2. Ann N Y Acad Sci 714:136–142
Sporri R, Reis e Sousa C (2005) Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol 6:163–170
Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH (1997) Induction of tolerance. by IL-10-treated dendritic cells. J Immunol 159:4772–4780
Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99:351
Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711
Suss G, Shortman K (1996) A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis. J Exp Med 183:1789–1796
Tan PH, Beutelspacher SC, Wang YH, McClure MO, Ritter MA, Lombardi G, George AJ (2005a) Immunolipoplexes: an efficient, nonviral alternative for transfection of human dendritic cells with potential for clinical vaccination. Mol Ther 11:790–800
Tan PH, Sagoo P, Chan C, Yates JB, Campbell J, Beutelspacher SC, Foxwell BM, Lombardi G, George AJ (2005b) Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. J Immunol 174:7633–7644
Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA (1994) Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci USA 91:2046–2050
Vella JP, Spadafora-Ferreira M, Murphy B, Alexander SI, Harmon W, Carpenter CB, Sayegh MH (1997) Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation 64:795–800
Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P (2000) Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol 164:4507–4512
Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68
Weissmann G, Montesinos MC, Pillinger M, Cronstein BN (2002) Non-prostaglandin effects of aspirin III and salicylate: inhibition of integrin-dependent human neutrophil aggregation and inflammation in COX 2- and NF kappa B (P105)-knockout mice. Adv Exp Med Biol 507: 571–577
Whittaker DS, Bahjat KS, Moldawer LL, Clare-Salzler MJ (2000) Autoregulation of human monocyte-derived dendritic cell maturation and IL-12 production by cyclooxygenase-2-mediated prostanoid production. J Immunol 165:4298–4304
Wilson NS, Villadangos JA (2004) Lymphoid organ dendritic cells: beyond the Langerhans cells paradigm. Immunol. Cell Biol 82:91–98
Xia CQ, Kao KJ (2003) Suppression of interleukin-12 production through endogenously secreted interleukin-10 in activated dendritic cells: involvement of activation of extracellular signal-regulated protein kinase. Scand J Immunol 58:23–32
Yoshimura S, Bondeson J, Foxwell BM, Brennan FM, Feldmann M (2001) Effective antigen presentation by dendritic cells is NF-kappaB dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines. Int Immunol 13:675–683
Zinkernagel RM (2000) Localization dose and time of antigens determine immune reactivity. Semin Immunol 12:163–171
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Buckland, M., Lombardi, G. (2009). Aspirin and the Induction of Tolerance by Dendritic Cells. In: Lombardi, G., Riffo-Vasquez, Y. (eds) Dendritic Cells. Handbook of Experimental Pharmacology, vol 188. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-71029-5_9
Download citation
DOI: https://doi.org/10.1007/978-3-540-71029-5_9
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-71028-8
Online ISBN: 978-3-540-71029-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)