Immune suppression is a very stable property of multipotent stromal cells also known as mesenchymal stem cells (MSCs). All cell lines tested showed robust immune suppression not affected by a long culture history. Several mechanisms were described to account for this capability. Since several of the described mechanisms were not causing the immune suppression, the expression pattern of cord-blood-derived MSCs by microarray experiments was determined. Dendritic cells cocultured with cord blood MSCs were compared with cord blood MSCs. Putative immune suppressive candidates were tested to explain this inhibition. We find that cord blood MSCs themselves are hardly immunogenic as tested with allogeneic T-cells. Dendritic cells cocultured with second-party T-cells evoked abundant proliferation that was inhibited by third-party cord blood MSCs. Optimal inhibition was seen with one cord blood MSC for every dendritic cell. Blocking human leukocyte antigen G only saw partial recovery of proliferation. Several cytokines, gangliosides, enzymes like arginase, NO synthase, and indole amine 2,3-dioxygenase as well as the induction of Treg were not involved in the inhibition. The inhibiting moiety was identified as prostaglandin B2 by lipid metabolite analysis of the culture supernatant and confirmed with purified prostaglandin B2.
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References
1.
EricesA, CongetP and MinguellJJ. (2000). Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol, 109:235–242.
2.
LeeOK, KuoTK, ChenWM, LeeKD, HsiehSL and ChenTH. (2004). Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood, 103:1669–1675.
3.
BiebackK, KernS, KluterH and EichlerH. (2004). Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells, 22:625–634.
4.
KöglerG, SenskenS, AireyJA, TrappT, MuschenM, FeldhahnN, LiedtkeS, SorgRV, FischerJ, et al. (2004). A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med, 200:123–135.
5.
GhodsizadA, NiehausM, KöglerG, MartinU, WernetP, BaraC, KhaladjN, LoosA, MakouiM, et al. (2009). Transplanted human cord blood-derived unrestricted somatic stem cells improve left-ventricular function and prevent left-ventricular dilation and scar formation after acute myocardial infarction. Heart, 95:27–35.
WernetP, FischerJ, CaplanA, ZanjaniE, MüllerH, KnipperA and KöglerG. (2004). Isolation of non-hematopoietic stem cells from umbilical cord blood. Biol Blood Marrow Transplant, 10:738–739.
8.
KöglerG, RadkeTF, LefortA, SenskenS, FischerJ, SorgRV and WernetP. (2005). Cytokine production and hematopoiesis supporting activity of cord blood-derived unrestricted somatic stem cells. Exp Hematol, 33:573–583.
9.
JansenBJ, GilissenC, RoelofsH, Schaap-OziemlakA, VeltmanJA, RaymakersRA, JansenJH, KoglerG, FigdorCG, TorensmaR and AdemaGJ. (2010). Functional differences between mesenchymal stem cell populations are reflected by their transcriptome. Stem Cells Dev, 19:481–490.
10.
BartholomewA, SturgeonC, SiatskasM, FerrerK, McIntoshK, PatilS, HardyW, DevineS, UckerD, et al. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol, 30:42–48.
11.
Di NicolaM, Carlo-StellaC, MagniM, MilanesiM, LongoniPD, MatteucciP, GrisantiS and GianniAM. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99:3838–3843.
12.
KramperaM, GlennieS, DysonJ, ScottD, LaylorR, SimpsonE and DazziF. (2003). Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood, 101:3722–3729.
13.
TseWT, PendletonJD, BeyerWM, EgalkaMC and GuinanEC. (2003). Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation, 75:389–397.
14.
van den BerkLC, FigdorCG and TorensmaR. (2008). Mesenchymal stromal cells: tissue engineers and immune response modulators. Archivum immunologiae et therapiae experimentalis, 56:325–329.
15.
DjouadF, PlenceP, BonyC, TropelP, ApparaillyF, SanyJ, NoelD and JorgensenC. (2003). Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood, 102:3837–3844.
16.
van den BerkLC, JansenBJH, Siebers-VermeulenKGC, NeteaMG, LatuhininT, BergevoetS, RaymakersRA, KöglerG, FigdorCG, AdemaGJ and TorensmaR. (2009). Toll-like receptor triggering in cord blood mesenchymal stem cells. J Cell Mol Med, 13:3415–3426.
17.
van den BerkLC, JansenBJ, Siebers-VermeulenKG, RoelofsH, FigdorCG, AdemaGJ and TorensmaR. (2010). Mesenchymal stem cells respond to TNF but do not produce TNF. J Leukoc Biol, 87:283–289.
18.
van den BerkLC, RoelofsH, HuijsT, Siebers-VermeulenKG, RaymakersRA, KoglerG, FigdorCG and TorensmaR. (2009). Cord blood mesenchymal stem cells propel human dendritic cells to an intermediate maturation state and boost interleukin-12 production by mature dendritic cells. Immunology, 128:564–572.
19.
VianelloF and DazziF. (2008). Mesenchymal stem cells for graft-versus-host disease: a double edged sword?. Leukemia, 22:463–465.
20.
SalemHK and ThiemermannC. (2010). Mesenchymal stromal cells: current understanding and clinical status. Stem Cells, 28:585–596.
21.
PhinneyDG and ProckopDJ. (2007). Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells, 25:2896–2902.
22.
ChamberlainG, FoxJ, AshtonB and MiddletonJ. (2007). Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, 25:2739–2749.
23.
TolarJ, Le BlancK, KeatingA and BlazarBR. (2010). Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells, 28:1446–1455.
24.
RingdenO and KeatingA. (2011). Mesenchymal stromal cells as treatment for chronic GVHD. Bone Marrow Transplant, 46:163–164.
25.
KimN, ImKI, LimJY, JeonEJ, NamYS, KimEJ and ChoSG. (2013). Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice. Ann Hematol, 92:1295–1308.
KluthSM, BuchheiserA, HoubenAP, GeyhS, KrenzT, RadkeTF, WiekC, HanenbergH, ReineckeP, WernetP and KoglerG. (2010). DLK-1 as a marker to distinguish unrestricted somatic stem cells and mesenchymal stromal cells in cord blood. Stem Cells Dev, 19:1471–1483.
28.
PiaoYF, IchijoH, MiyagawaK, OhashiH, TakakuF and MiyazonoK. (1990). Latent form of transforming growth factor-beta 1 acts as a potent growth inhibitor on a human erythroleukemia cell line. Biochem Biophys Res Commun, 167:27–32.
29.
LundströmSL, SalujaR, AdnerM, HaeggströmJZ, NilssonG and WheelockCE. (2013). Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations. J Lipid Res, 54:116–126.
30.
Baecher-AllanC, BrownJA, FreemanGJ and HaflerDA. (2001). CD4+CD25high regulatory cells in human peripheral blood. J Immunol, 167:1245–1253.
31.
FontenotJD, RasmussenJP, WilliamsLM, DooleyJL, FarrAG and RudenskyAY. (2005). Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity, 22:329–341.
32.
RoncadorG, BrownPJ, MaestreL, HueS, Martinez-TorrecuadradaJL, LingKL, PratapS, TomsC, FoxBC, et al. (2005). Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol, 35:1681–1691.
33.
Le BlancK, RasmussonI, SundbergB, GotherstromC, HassanM, UzunelM and RingdenO. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet, 363:1439–1441.
34.
MaccarioR, PodestaM, MorettaA, CometaA, ComoliP, MontagnaD, DaudtL, IbaticiA, PiaggioG, et al. (2005). Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica, 90:516–525.
35.
PrevostoC, ZancolliM, CanevaliP, ZocchiMR and PoggiA. (2007). Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica, 92:881–888.
36.
Di IanniM, Del PapaB, De IoanniM, MorettiL, BonifacioE, CecchiniD, SportolettiP, FalzettiF and TabilioA. (2008). Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol, 36:309–318.
37.
BeythS, BorovskyZ, MevorachD, LiebergallM, GazitZ, AslanH, GalunE and RachmilewitzJ. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood, 105:2214–2219.
38.
AggarwalS and PittengerMF. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105:1815–1822.
39.
ShiraishiH, YoshidaH, SaekiK, MiuraY, WatanabeS, IshizakiT, HashimotoM, TakaesuG, KobayashiT and YoshimuraA. (2008). Prostaglandin E2 is a major soluble factor produced by stromal cells for preventing inflammatory cytokine production from dendritic cells. Int Immunol, 20:1219–1229.
40.
SatoK, OzakiK, OhI, MeguroA, HatanakaK, NagaiT, MuroiK and OzawaK. (2007). Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood, 109:228–234.
41.
NoëlD, DjouadF, BouffiC, MrugalaD and JorgensenC. (2007). Multipotent mesenchymal stromal cells and immune tolerance. Leuk Lymphoma, 48:1283–1289.
42.
MeiselR, ZibertA, LaryeaM, GobelU, DaubenerW and DillooD. (2004). Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood, 103:4619–4621.
43.
RizzoR, CampioniD, StignaniM, MelchiorriL, BagnaraGP, BonsiL, AlvianoF, LanzoniG, MorettiS, et al. (2008). A functional role for soluble HLA-G antigens in immune modulation mediated by mesenchymal stromal cells. Cytotherapy, 10:364–375.
44.
NasefA, MathieuN, ChapelA, FrickJ, FrancoisS, MazurierC, BoutarfaA, BouchetS, GorinNC, ThierryD and FouillardL. (2007). Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation, 84:231–237.
45.
Rouas-FreissN, GoncalvesRM, MenierC, DaussetJ and CarosellaED. (1997). Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci U S A, 94:11520–11525.
46.
IshitaniA and GeraghtyDE. (1992). Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci U S A, 89:3947–3951.
47.
FujiiT, IshitaniA and GeraghtyDE. (1994). A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol, 153:5516–5524.
48.
LilaN, Rouas-FreissN, DaussetJ, CarpentierA and CarosellaED. (2001). Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci U S A, 98:12150–12155.
49.
Le FriecG, LaupezeB, FardelO, SebtiY, PangaultC, GuillouxV, BeaupletA, FauchetR and AmiotL. (2003). Soluble HLA-G inhibits human dendritic cell-triggered allogeneic T-cell proliferation without altering dendritic differentiation and maturation processes. Hum Immunol, 64:752–761.
50.
BennaceurK, PopaI, PortoukalianJ, Berthier-VergnesO and Peguet-NavarroJ. (2006). Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis. Int Immunol, 18:879–886.
51.
BergelsonLD, DyatlovitskayaEV, KlyucharevaTE, KryukovaEV, LemenovskayaAF, MatveevaVA and SinitsynaEV. (1989). The role of glycosphingolipids in natural immunity. Gangliosides modulate the cytotoxicity of natural killer cells. Eur J Immunol, 19:1979–1983.
52.
Peguet-NavarroJ, SportouchM, PopaI, BerthierO, SchmittD and PortoukalianJ. (2003). Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J Immunol, 170:3488–3494.
53.
PalaciosR and SugawaraI. (1982). Hydrocortisone abrogates proliferation of T cells in autologous mixed lymphocyte reaction by rendering the interleukin-2 Producer T cells unresponsive to interleukin-1 and unable to synthesize the T-cell growth factor. Scand J Immunol, 15:25–31.
OtaniT, YamaguchiK, ScherlE, DuB, TaiHH, GreiferM, PetrovicL, DaikokuT, DeySK, SubbaramaiahK and DannenbergAJ. (2006). Levels of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease: evidence for involvement of TNF-alpha. Am J Physiol Gastrointest Liver Physiol, 290:G361–G368.
56.
YangJ, PetersenCE, HaC-E and BhagavanNV. (2002). Structural insights into human serum albumin-mediated prostaglandin catalysis. Protein Sci, 11:538–545.
57.
PotianJA, AvivH, PonzioNM, HarrisonJS and RameshwarP. (2003). Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol, 171:3426–3434.
58.
GhannamS, BouffiC, DjouadF, JorgensenC and NoelD. (2010). Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther, 1:2.
59.
RobbRJ and SmithKA. (1981). Heterogeneity of human T-cell growth factor(s) due to variable glycosylation. Mol Immunol, 18:1087–1094.
60.
NishihiraJ. (2000). Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth. J Interferon Cytokine Res, 20:751–762.
61.
CampioniD, RizzoR, StignaniM, MelchiorriL, FerrariL, MorettiS, RussoA, BagnaraGP, BonsiL, et al. (2008). A decreased positivity for CD90 on human mesenchymal stromal cells (MSCs) is associated with a loss of immunosuppressive activity by MSCs. Cytometry B Clin Cytom, 76:225–230.
62.
Le BlancK, RasmussonI, GotherstromC, SeidelC, SundbergB, SundinM, RosendahlK, TammikC and RingdenO. (2004). Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol, 60:307–315.
63.
RamkissoonA, ShapiroAM, LoniewskaMM and Wells.PG (2013). Neurodegeneration from drugs and aging-derived free radicals. In: Molecular basis of oxidative stress: chemistry, mechanisms and disease pathogene. VillamenaFA, ed. John Wiley & Sons, Inc., Hoboken, New Jersey, pp 242–244.
64.
CattanN, MaryD, PelerauxA, MariB, AusselC and RossiB. (2000). Prostaglandin B(2) delivers a co-stimulatory signal leading to T cell activation. Eur Cytokine Netw, 11:293–299.
65.
LiuF, OrrJA and WuJY. (1994). Prostaglandin B2-induced pulmonary hypertension is mediated by TxA2/PGH2 receptor stimulation. Am J Physiol, 267:L602–L608.
66.
KabashimaK, MurataT, TanakaH, MatsuokaT, SakataD, YoshidaN, KatagiriK, KinashiT, TanakaT, et al. (2003). Thromboxane A2 modulates interaction of dendritic cells and T cells and regulates acquired immunity. Nat Immunol, 4:694–701.
67.
SayreBL and LewisGS. (1993). Arachidonic acid metabolism during early development of ovine embryos: a possible relationship to shedding of the zona pellucida. Prostaglandins, 45:557–569.
68.
AdaikanGP and KarimSMM. (1974). Effect of prostaglandins A1, A2, B1, B2, E2 and F2α on human umbilical cord vessels. Prostaglandins, 8:411–416.
69.
SullivanMH, RosebladeCK, RendellNB, TaylorGW and ElderMG. (1992). Metabolism of prostaglandins E2 and F2 alpha by human fetal membranes. Biochim Biophys Acta, 1123:342–346.
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