Mesenchymal stem cells avoid allogeneic rejection

BioMed Cen al Page 1 o 11 (page numbe no o ci a ion pu poses) Jou nal o In lamma ion Open Access Re iew Mesenchymal s em cells a oid allogeneic ejec ion Jenni e M Ryan1, F ank P Ba y2, J Ma y Mu phy2 and Be na d P Mahon*1 Add ess: 1Ins i u e o Immunology, Na ional Uni e si y o I eland, Maynoo h, Co. Kilda e I eland and 2Regene a i e Medicine Ins i u e (REMEDI), Na ional Cen e o Biomedical Enginee ing Science, Na ional Uni e si y o I eland, Galway, I eland Email: Jenni e M Ryan - [email protected]; F ank P Ba y - [email p o ec ed]; J Ma y Mu phy - ma y.mu [email protected]; Be na d P Mahon* - [email p o ec ed] * Co esponding au ho Abs ac Adul bone ma ow de i ed mesenchymal s em cells o e he po en ial o open a new on ie in medicine. Regene a i e medicine aims o eplace e e e cells in a b oad ange o condi ions associa ed wi h damaged ca ilage, bone, muscle, endon and ligamen . Howe e he no mal p ocess o immune ejec ion o misma ched allogeneic issue would appea o p e en he ealisa ion o such ambi ions. In ac mesenchymal s em cells a oid allogeneic ejec ion in humans and in animal models. These inding a e suppo ed by in i o co-cul u e s udies. Th ee b oad mechanisms con ibu e o his e ec . Fi s ly, mesenchymal s em cells a e hypoimmunogenic, o en lacking MHC-II and cos imula o y molecule exp ession. Secondly, hese s em cells p e en T cell esponses indi ec ly h ough modula ion o dend i ic cells and di ec ly by dis up ing NK as well as CD8+ and CD4+ T cell unc ion. Thi dly, mesenchymal s em cells induce a supp essi e local mic oen i onmen h ough he p oduc ion o p os aglandins and in e leukin-10 as well as by he exp ession o indoleamine 2,3,-dioxygenase, which deple es he local milieu o yp ophan. Compa ison is made o ma e nal ole ance o he e al allog a , and con as ed wi h he immune e asion mechanisms o umo cells. Mesenchymal s em cells a e a highly egula ed sel - enewing popula ion o cells wi h po en mechanisms o a oid allogeneic ejec ion. Re iew In oduc ion: Wha a e S em Cells? The e m "s em cell" can be applied o a ema kably di e se g oup o cells. These cells, ega dless o hei sou ce, sha e wo cha ac e is ic p ope ies. Fi s ly, hey ha e he capaci y o p olonged o unlimi ed sel - enewal unde con olled condi ions, and secondly hey e ain he po en ial o di e en ia e in o a a ie y o mo e specialized cell ypes [1,2]. The s em cells ha a ise du ing he i s days o mammalian emb yonic de elopmen a e plu ipo- en and a e e e ed o as emb yonic s em (ES) cells. These a e usually de i ed om he inne cell mass o he p e-implan a ion emb yo, a he blas ocys s age[3]. How- e e s em cells a e no con ined o issues o ea ly de elop- men , bu can also be ound a a ious si es in he adul mammal. Adul s em cells a e mo e di e en ia ed hen ES cells bu can s ill gi e ise o specialized lineages[1,2]. The bes -desc ibed popula ions o da e a e he hema opoie ic s em cells (HSC) o he bone ma ow ha can gene a e a ious blood cells[4]. Howe e he bone ma ow also con ains a popula ion o mesenchymal s em cells (MSC) [1,2]. These cells, i s cha ac e ized by F iedens ein and colleagues mo e han hi y yea s ago, a e mul ipo en cells capable o di e en ia ing in o se e al lineages including; ca ilage, bone, muscle, endon, ligamen and adipose issue[2,5,6]. In hei undi e en ia ed s a e, MSC Published: 26 July 2005 Jou nal o In lamma ion 2005, 2:8 doi:10.1186/1476-9255-2-8 Recei ed: 01 Ap il 2005 Accep ed: 26 July 2005 This a icle is a ailable om: h p://www.jou nal-in lamma ion.com/con en /2/1/8 © 2005 Ryan e al; licensee BioMed Cen al L d. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 2 o 11 (page numbe no o ci a ion pu poses) a e spindle-shaped and esemble ib oblas s[5,6] (Fig 1). The e a e no cell su ace ma ke s ha speci ically and uniquely iden i y MSC, and hei cha ac e iza ion in he li e a u e lacks consis ency. The di e si y o cha ac e is ics associa ed wi h MSC can be explained by di e ences in issue o igin, isola ion me hods and cul u e condi ions be ween labo a o ies, in addi ion he e appea o be s ain- o-s ain di e ences in mu ine de i ed MSC[2,7-9]. Whils he e is an ob ious need o s anda diza ion be ween esea ch g oups, some consensus can be ound among he con lic ing da a. In b oad e ms, MSC expanded in i o do no exp ess he hema opoie ic o endo helial su ace ma ke s CD11b, CD14, CD31, CD34 o CD45 bu s ain posi i e o CD29, CD44, CD73, CD105, CD106 and CD166 [2,5,10]. The non-emb yonic sou ce o his popula ion, he educed likelihood o neo- plasia, and he mo e limi ed di e en ia ion po en ial, ha e made hese cells a ac i e candida es o applica ion in cell based he apies usually e med " egene a i e med- icine"[2]. The e is one con ounding in luence on his app oach; whils sel de i ed MSC pose ew immunologi- cal p oblems, in p ac ice egene a i e medicine is likely o ely on misma ched (allogeneic) cells o epai o eplace damaged issue. No mally, allogeneic cells a e dele ed by hos immune esponses. The majo su p ise o Immunol- ogis s wo king in his ield ha e been indings ha sugges ha MSC do no obey he no mal " ules" o allogeneic ejec ion. This e iew will su ey ecen da a, which con- incingly indica e he mechanisms by which MSC escape he no mal p ocess o alloan igen ecogni ion. MSC e ade allo ejec ion The majo limi o solid o gan g a su i al is T cell ecog- ni ion by he ecipien o alloan igen (domina ed by, bu no con ined o MHC/HLA an igens)[11]. The e a e wo mechanisms media ing his powe ul ejec ion esponse; "di ec " ecogni ion, in ol ing ecogni ion by ecipien CD8+ o CD4+ T cells o dono MHC class I and class II molecules; and "indi ec " mechanisms in ol ing ecogni- ion o pep ides om he allogeneic issue[11]. Recipien an igen p esen ing cells (APC) such as dend i ic cells (DC) p ocess alloan igen in o pep ides and p esen hese o nai e T cells on sel -MHC molecules [12]. Howe e he e a e no able excep ions o hese allo ejec ion p oc- esses; he e al allog a e ades ejec ion by he mo he h ough a complex se ies o ac ions ( e iewed in[13]), simila ly issue which has limi ed lympha ic d ainage is less p one o allo ejec ion[14]. In e es ingly umo cells, whils no allogeneic, a e in many cases bo h "al e ed-sel " and immunogenic bu o en ac i ely modula e immune esponsi eness o e ade immune su eillance[15]. Thus mechanisms o umo e asion o he immune sys em may p o ide insigh in o how allogeneic MSC a e ole a ed by he misma ched hos . The e is suppo ing e idence o he use o allogeneic MSC om bo h in i o and in i o s udies ha show MSC a oid no mal allo esponses. A small numbe o in- i o s udies sugges ha MSC play a ole in enabling alloan i- gen ole ance. Koc e al, showed no e idence o allo eac- i e T cells and no incidence o g a hos disease when allogeneic MSC we e in used in o pa ien s wi h Hu le 's synd ome o me ach oma ic leukodys ophy[16]. In a p e ious s udy by he same g oup, au ologous cul u e- expanded MSC we e in used o b eas cance pa ien s o in es iga e whe he MSC would enhance he eng a men o pe iphe al blood s em cells a e myeloabla i e he apy [17]. Resul s showed apid hema opoie ic eco e y and no signs o oxici y om MSC in usion[17]. Ho wi z and col- leagues, epo ed ha dono MSC con ibu ed o bone emodelling a e allogeneic s em cell ansplan a ion in h ee child en wi h os eogenesis impe ec a (OI)[18], a a e gene ic diso de o ype I collagen. This is suppo ed by da a om Ba holomew e al who showed ha in- i o adminis a ion o allogeneic MSC p olonged 3 d pa y skin g a su i al in animal models[19]. Fu he mo e, Sai o e al, demons a ed ha MSC unde going di e en i- a ion o a ca diac pheno ype we e ole a ed in a xenoge- neic en i onmen , e aining hei abili y o be ec ui ed o he inju ed myoca dium[20]. Mo e ecen wo k by Agga - wal and Pi enge suppo ed he easibili y o MSC- ans- plan a ion showing ha MSC al e ed he pheno ypes o speci ic immune cell sub ypes he eby c ea ing a ole ogenic en i onmen [21]. These epo s sugges ha ansplan a ion o MSC could be bene icial in pa ien s wi h a ious diso de s equi ing issue egene a ion, and Human mesenchymal s em cells (MSC) a e spindle shaped, ib oblas -like cellsFigu e 1 Human mesenchymal s em cells (MSC) a e spindle shaped, ib oblas -like cells. O iginal magni ica ion × 100, phase-con- as ligh mic oscopy, scale ba ep esen s 50 µm. Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 3 o 11 (page numbe no o ci a ion pu poses) p o ide e idence suppo ing he ole ance o allogeneic MSC by ecipien s. Da a suppo ing he con en ion ha MSC a oid alloge- neic esponses has also come om a la ge body o in i o expe imen s, usually in ol ing co-cul u e o mixed lym- phocy e eac ions (MLR). E idence om hese s udies indica e ha he use o misma ched MSC does no p o- oke a p oli e a i e T cell esponse in allogeneic MLR, hus sugges ing an immunosupp essi e ole o MSC[19,22- 26]. Le Blanc e al, showed ha MSC ailed o elici p oli - e a ion o allogeneic lymphocy es[27]. Addi ionally, hey demons a ed ha MSC emained immunosupp essi e e en a e IFN-γ s imula ion[27]. E idence om K ampe a e al con i ms hese indings, hey showed ha mu ine MSC lack MHC class II and inhibi ed T cell p oli e a- ion[25]. Tse e al, also showed ha human MSC ail o elici allogeneic T cell esponse in a MLR e en when MHC class II was up egula ed[28]. Consis en wi h hese s ud- ies, Ba holomew e al showed ha allogeneic baboon MSC supp essed he p oli e a i e ac i i y o lymphocy es in i o and p olonged g a su i al[19]. These indings suppo he iew ha MSC can be ansplan ed be ween MHC-incompa ible indi iduals. Al hough hese da a show ha success ul use o allogeneic MSC in egene a i e he apy is possible, such app oaches a e unlikely o be b oadly accep able un il i is unde s ood why MSC a e no ejec ed. This ques ion has been he subjec o in ense ecen s udy and h ee candida e mechanisms a e eme g- ing. MSC appea o e ade allogeneic ejec ion by a) being hypoimmunogenic; b) modula ing T cell pheno ype and c) c ea ing an immunosupp essi e local milieu. These mechanisms a e in e - ela ed and will in ol e cell con ac dependen and independen in e ac ions. The challenge acing he ield is o un a el he con ibu ion o hese di e se in e ac ions. MSC a e hypoimmunogenic The e is con o e sy su ounding he cell su ace exp es- sion o MHC alloan igens by MSC. Al hough con lic ing e idence exis s, mos s udies desc ibe human MSC as MHC class I posi i e and MHC class II nega i e (Fig 2). The da a con lic ing wi h hese indings may ep esen di - e en s em cell lineages o be he esul o he ecen ly desc ibed p ocess o cell-cell ans e [29-31]. The exp es- sion o MHC class I by MSC is impo an because exp es- sion p o ec s MSC om ce ain NK cell mechanisms o dele ion. Fo ins ance, a majo unc ion o NK and NK- like cells is o kill umo cells ha ha e down egula ed class I [32]. HLA-G is an MHC-like p o ein ha is known o p o ec he e al allog a agains NK media ed ejec- ion[33,34]. This p o ein has been shown o bind o he wo majo inhibi o y NK ecep o s, KIR1 and KIR2, and o inhibi NK killing [35-37]. Howe e no s udies o HLA-G exp ession by MSC ha e been epo ed o da e. As MHC class II p o eins a e po en alloan igens, he exp ession by MSC is ano he impo an ac o . Again he e is some con o e sy o e exp ession, which may be explained by he di e si y o models desc ibed abo e. Howe e he e a e widesp ead obse a ions ha unde non-in lamma o y condi ions, human MSC a e MHC-II Human MSC cul u ed acco ding o [106, 107] a e A) MHC-I posi i e (HLA-A,B,C, an ibody W6/32-FITC), B) MHC class II nega i e (HLA-DR, an ibody LN-3-PE); C) CD14 nega i e (an ibody MEM-18-FITC), D) CD86 nega i e (an ibody IT2.2-PE); and E) CD40L/ CD154 (an ibody 24-31-FITC), F) CD95L (FasL) nega i e (an ibody NOK-1-PE)Figu e 2 Human MSC cul u ed acco ding o [106, 107] a e A) MHC-I posi i e (HLA-A,B,C, an ibody W6/32-FITC), B) MHC class II nega i e (HLA-DR, an ibody LN-3-PE); C) CD14 nega i e (an ibody MEM-18-FITC), D) CD86 nega i e (an ibody IT2.2- PE); and E) CD40L/ CD154 (an ibody 24-31-FITC), F) CD95L (FasL) nega i e (an ibody NOK-1-PE). Iso ype ma ched con ol an ibody labelling a e shown as unshaded plo s, FITC conjuga es a e shown in blue, PE conjuga es shown in pink. Flow cy ome y pe o med acco ding o me hods p e iously desc ibed [108-110]. Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 4 o 11 (page numbe no o ci a ion pu poses) nega i e, suppo ing a ole o MSC as ha ing educed immunogenici y h ough he con ol o alloan igen exp ession [38-40]. The absence o MHC class II gi es MSC he po en ial o escape ecogni ion by allo eac i e CD4+ T cells. In addi ion o being MHC II nega i e, MSC do no appea o exp ess he co-s imula o y molecules CD40, CD40L, CD80 o CD86 equi ed o e ec o T cell induc ion[28,39]. The absence o co-s imula o y mole- cules is a signi ican obse a ion. I implies ha any esid- ual engagemen o he T cell ecep o on Th cells would esul in ane gy and con ibu e o ole ance a he han allogeneic esponses. Al hough his is a com o ing sce- na io, based la gely on in i o s udies, i canno ully explain he e asion o allo eac i i y demons a ed by MSC. Expe imen s in ol ing allogeneic co-cul u es o MLR ha e demons a ed ha bo h cell-cell con ac and ac ion by soluble ac o s con ibu e o he immunomod- ula o y unc ion o MSC[25,41-43]. Thus i is likely ha e asion o allo eac i i y is a esul o bo h MSC hypoim- munogenici y, modula ion o T cell immune induc ion and he c ea ion o a supp essi e milieu a ound MSC. Al hough he mechanisms go e ning he supp essi e e ec a e no ully unde s ood, se e al s udies ha e gi en indica o s o he p ocesses in ol ed. MSC in e e e wi h DC ma u a ion and unc ion Dend i ic cells (DC) a e he mos in luen ial APC, playing a key ole in di ec ing cellula and humo al immune esponses agains sel and non-sel an igens [44]. DC con- ibu e o he es ablishmen o ole ance, especially in he pe iphe y[45]. Imma u e DC a e no ully di e en ia ed o ca y ou hei known oles as induce s o immu- ni y[45]. Despi e his, imma u e DC ci cula e h ough is- sues and he lymph sys em, cap u ing sel and non-sel an igens[45]. Imma u e DC ha a e loaded wi h an igen can silence T cells by dele ion o by expanding egula o y T cell popula ions[45,46]. I has long been belie ed ha his p ocess con ibu es o g a su i al du ing ansplan- a ion [14]. The capaci y o DC o induce pe iphe al ole - ance is a po en ial mechanism by which MSC could manipula e immuni y in o de o escape T cell ecogni- ion. Thus MSC could p e en no mal allogeneic esponses ei he h ough modula ion o DC unc ion o by di ec e ec s on T cells. Indica ions om di e en s ud- ies encou age his hypo hesis. Zhang e al [24] p o ides e idence ha MSC in e e e wi h DC ma u a ion. Co-cul- u e expe imen s showed ha MSC down- egula e CD1a, CD40, CD80, CD86, and HLA-DR exp ession du ing DC ma u a ion[24]. This is also shown by Bey h e al. [42], who sugges ha human MSC con e ed APC in o an inhibi o y o supp esso pheno ype ia cell- o-cell con- ac , hus locking DC in o a semi-ma u e s a e and he eby inducing pe iphe al ole ance. Thei indings also show educed IFN-γ, IL-12 and TNF-α in human MSC/mono- cy e co-cul u e [42]. Simila ly Jiang e al epo ed ha MSC main ain DC in an imma u e s a e[26] and show ha MSC inhibi up egula ion o IL-12p70 [26]. These esul s sugges ha MSC media e allogeneic ole ance by di ec ing APC owa ds a supp esso o inhibi o y pheno- ype ha esul s in an a enua ed o egula o y T cell esponse. MSC modula e CD4+ T cell esponses E idence has eme ged ha MSC in e ac di ec ly wi h T cells o supp ess allo ea i i y[25]. K ampe a e al showed ha MSC impai T cell con ac wi h APC in a non-cogna e bu ansien ashion[25]. This suppo ed wo k om Ba - holomew e al showing ha he addi ion o IL-2 o MLR/ MSC co-cul u es educed MSC supp ession and es o ed T cell p oli e a ion[19]. Taken oge he , hese esul s s ongly suppo a ole o ei he a di ec (T cell pheno- ype) o indi ec (DC pheno ype) mechanism o immune modula ion di ec ed by MSC. MSC modula ion o CD4+ T cell esponses is mo e ex en- si e han he s aigh o wa d e ec desc ibed abo e. The egula p ocess o an igen speci ic CD4+ T cell induc ion equi es an igen cap u e and p ocessing by DC (o o he amenable cells), ollowed by a p ocess o ma u a ion and a icking o local lymph nodes[14,47-49]. The e is e i- dence ha MSC p e en no mal allogeneic esponses by di ec ing CD4+ T cells o a supp essi e o coun e - egula- o y pheno ype[46,50]. Di Nicola e al, showed ha MSC s ongly supp essed CD4+ (and CD8+) T cells in MLR[43], indings suppo ed by Tse e al, who showed ha MSC supp ess he p oli e a ion o T-cell subse s[28]. S udies o T cell di e en ia ion ha e shown ha in he p esence o human MSC, Th1 cell sec e ion o IFN-γ d opped by 50% compa ed o cul u es wi hou MSC. Con e sely, e ec o T cells unde going Th2 di e en ia ion when co-cul u ed wi h human MSC showed a signi ican inc ease in IL-4 p oduc ion compa ed o con ols[21]. These indings sugges ha MSC exe a coun e egula- o y, an i-in lamma o y ole by di ec ing cy okine-medi- a ed immuni y[21]. A s a egy o egula ion and dele ion o speci ic T cells is an e ec i e con ol agains unwan ed immune espon- si eness especially a e ansplan ion[51]. Consequen ly, eno mous in e es has ocused on he possibili y o T eg cells as a ma ke o T cell ole ance du ing ansplan a- ion. T eg can ac di ec ly on o he T cells o indi ec ly h ough APC[46]. Agg awal e al, demons a ed ha CD4+ CD25+ T eg popula ions inc eased signi ican ly in MLR when MSC we e p esen compa ed o con ols[21]. Howe e , da a exis s showing ha human MSC-media ed inhibi ion is no supp essed by emo ing T eg cells om co-cul u es [25,42]. Ne e heless a ole o hese cells can no be excluded, i is possible ha an incomple e eplica- ion o he supp essi e mic oen i onmen in i o o Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 5 o 11 (page numbe no o ci a ion pu poses) indeed he di e si y o T eg cell popula ions mean ha hese s udies do no ully explo e he po en ial ole o sup- p essi e o egula o y T cells in p omo ing MSC ole ance. MSC in luence con ol o e cell di ision cycle pa hways in cells o immunological ele ance. Glennie e al ha e shown ha T cells s imula ed in co-cul u es wi h MSC exhibi an ex ensi e inhibi ion o cyclin D2 and up egula- ion o he cyclin dependen kinase inhibi o p27kip1 [52]. As T cell inhibi ion could no be e e sed, hese cells we e no in e p e ed as ane gic in he classical sense. The au ho s sugges ha MSC a e mos likely inducing he al e na i e condi ion o di isional a es ane gy in T cells, an occu ence usually associa ed wi h CTLA-4 signal- ling[53]. In addi ion, emo al o MSC om he sys em only es o ed IFN-γ p oduc ion bu no T cell p oli e a- ion[52]. This sugges s ha MSC induce a condi ion simi- la o spli ane gy[54] o spli ole ance[55,56]. The key poin is ha his wo k demons a es ha MSC exe e o e ec s on T cells and i is signi ican in demons a ing ha he mechanisms inducing MSC ole ance a e no con ined o pa e ns o cy okine sec e ion bu ex end o di ec mod- ula ion o T cell di ision. MSC modula e CD8+ T cell and NK cell ac i i y The impac o MSC on CD8+ CTL and NK cells has also been add essed. CTL can lyse allogeneic cells a e ecog- ni ion o cogna e alloan igen, by he elease o cy o oxic e ec o s such as, pe o ins, se ine es e ases, IFN-γ and TNF-α [57] whe eas NK cells do no equi e an igen p ocessing[58]. Consequen ly bo h e ec o cells can ope - a e in andem, wi h NK cells p o iding a i s line de ence killing a ge cells ha escape CTL ecogni ion o show inadequa e exp ession o sel -MHC[58]. The e is e idence ha MSC inhibi he o ma ion o CTL and appea o e ade NK cell a ge ing mechanisms. Djouad e al showed ha CD8+ cells a e supp essed by MSC in MLR[41]. Ras- musson suppo ed hese indings and u he showed ha NK cells in co-cul u e did no ecognize MSC al hough ly ic capabili y was s ill p esen [59]. This e ec appea ed o be media ed by soluble ac o s[50,59]. Thus MSC in e - ac and supp ess cell-media ed immune esponses di ec ly and h ough soluble ac o s. The a ge s o his supp es- sion a e DC, CD4+ Th, CD8+ CTL and NK cells; in e ec MSC silence each aspec o he cellula ejec ion p ocess. MSC sec e e soluble ac o s o c ea e an immunosupp essi e milieu The cha ac e isa ion o cy okines p oduced by MSC is s ill p o isional and is hinde ed by he lack o s anda disa ion in isola ion and cul u e condi ions, which ha e gi en ise o mul iple indings and in e p e a ions. I is e iden ha MSC do no cons i u i ely exp ess IL-2, IL-3, IL-4 and IL- 5[60,61]. Howe e some epo s show ha MSC do con- s i u i ely exp ess mRNA o cy okines such as in e leukin (IL)-6, -7, -8, -11, -12, -14, -15, -27, leukaemia inhibi o y ac o , mac ophage colony-s imula ing ac o , and s em cell ac o [62,63]. Some o hese cy okines p o ide c i ical cell-cell in e ac ions and p omo e HSC di e en ia ion, howe e cau ion should be exe cised be o e o e in e - p e ing hese indings. P o ein sec e ion does no always mi o mRNA le els and mos wo ke s in he ield would adop a mo e conse a i e p o ile o cy okine and g ow h ac o p oduc ion by MSC. Despi e hese ca ea s, ce ain MSC sec e ed p oduc s such as Hepa ocy e g ow h ac o , (HGF) a e likely o con ib- u e o c ea ing a local immunosupp essi e en i onmen . HGF induces mi ogenic and an iapop o ic ac i i y in di - e en sys ems [64-66] and has a well-cha ac e ized ole in wound epai [66-68], e ec s ha a e consis en wi h a ole o MSC in egene a i e medicine. Al hough some g oups do no de ec HGF in MSC co-cul u es [41] mo e epo s sugges ha HGF is cons i u i ely exp essed by MSC [13,43,69,70]. Indica ions ha MSC p oduce HGF [13,43,69,70] encou age a ole o hese cells in issue epai [70]. S udies by Chunmeng e al, demons a ed ha a de mal de i ed "mul ipo en " cells sec e e HGF and p omo e wound healing[68]. In e es ingly, Azuma e al, showed ha HGF ea men p e en s ch onic allog a neph opa hy in a s[71]. Taken oge he hese esul s sug- ges ha HGF may con ibu e o he abili y o MSC o a oid allo ejec ion. IL-10 has a well-documen ed ole in T cell egula ion and in he p omo ion o a " egula o y" o supp esso pheno- ype. In ou hands human MSC cons i u i ely p oduce IL- 10 whe eas Rasmusson e al and Bey h e al only de ec ed IL-10 in co-cul u e expe imen s [42,72]. In ei he case, IL- 10 is likely o be supp essing po en ial allo- esponsi e- ness because i is a ecognized g ow h ac o o egula o y T cells [73]. IL-10 can an agonize IL-12 du ing induc ion o in lamma o y immune esponses [74-79]. This is sup- po ed by s udies showing ha MSC pa ially media e supp ession h ough IL-10 sec e ion in MLR cul- u es[42,72]. Simila ly ans o ming g ow h ac o (TGF)- β1 also plays a ole in T cell supp ession. This cy okine as well as IL-10 in luences cell lineages b oade han lym- phocy es [74,80,81]. Howe e cons i u i e exp ession o TGF-β1 has no been de ec ed om ou own s udies on human MSC[13]. This is in line wi h Le Blanc who ound no di e ence in TGF-β1 concen a ion in co-cul u es wi h o wi hou MSC [69]. In con as Bey h e al showed ha TGF-β1 was sec e ed in media om co-cul u es o human MSC and immune cells bu again co-cul u e did no aug- men TGF-β1 concen a ion[42]. Al hough a numbe o s udies sugges no ole o TGF-β1 in e asion o allogeneic esponsi eness[42,69,72], i has been sugges ed ha HGF in combina ion wi h TGF-β p omo es he allo-escaping pheno ype[43]. Di Nicola e al showed ha neu alizing Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 6 o 11 (page numbe no o ci a ion pu poses) an ibodies o HGF and TGF-β es o ed he p oli e a i e esponse in MLR, sugges ing ha hese ac o s a e a leas pa ially esponsible[43]. MSC cons i u i ely exp ess he eicosanoid P os aglandin E (PGE)-2 [82]. This may be up egula ed in co-cul- u e[21,28] o down egula ed on di e en ia ion[82]. PGE-2 in luences nume ous immune unc ions including supp ession o B cell ac i a ion[83] and induc ion o eg- ula o y T cells[84]. Al hough he e is e idence o PGE-2 sec e ion by MSC, he e is con o e sy su ounding a ole o PGE-2 as a media o o supp ession o allo esponses in MLR. S udies om Tse, sugges ed ha PGE-2 is no a signi ican componen o supp ession[28]. Suppo ing hese indings Rasmusson e al showed ha blocking PGE- 2 p oduc ion did no es o e allogeneic MLR esponses bu did in luence mi ogen d i en p oli e a ion[72]. Al hough he p esen opinions a e con lic ing, i should be highligh ed ha o he possible p os aglandins and eicosanoids could be in luencing allo esponses[85]. Anal- ysis o hese o he immunomodula o y molecules could p o ide u he clues as o how MSC escape he immune sys em. In con as o immunosupp ession h ough he sec e ion o soluble ac o s, supp ession may be media ed by wi h- d awal o ac o s in he mic o-en i onmen necessa y o ac i e immune esponses. Indoleamine 2,3-dioxygenase (IDO) is an enzyme ha ca abolizes L-T yp ophan, he eby deple ing an essen ial amino acid om he local en i onmen [86-89]. Recen e idence has shown ha his mechanism is exploi ed by he mammalian e al allo- g a o supp esses T cell ac i i y and p e en ejec ion [86- 89]. Al hough no a soluble ac o , he exp ession o IDO may con ibu e o a ole genic en i onmen . This is o g ea ele ance and has ob ious pa allels wi h MSC. Mei- sel e al showed ha IDO is no cons i u i ely exp essed by MSC bu can be induced by IFN-γ[90], he eby inhibi - ing allogeneic T cell esponses by T yp ophan deple- ion[90]. O he indings ha e sugges ed ha IDO- media ed yp ophan deple ion inhibi s allogeneic T-cell esponses by mul iple pa hways[91]. The disco e y o his mechanism, which shows pa allels o he c ea ion o a "T yp ophan dese " a he ma e no- e al in e ace[13], p o ides a u he easible mechanism by which MSC a oid allo eac i i y. Howe e , IDO exp ession is no essen ial o he main enance o ole ance agains MSC. Tse e al showed ha an IDO inhibi o o supplemen a y T yp ophan addi ion o MLR did no es o e PBMC p oli - e a ion [28]. MSC con ol su ace ma ke exp ession o exhibi a hypoimmunogenic o ole ogenic pheno ype. MSC can also modula e T cell induc ion di ec ly o ia DC and sec e e a ba e y o immunosupp essi e ac o s. I is appa en ha he ques ion acing he applica ion o egen- e a i e medicine is no longe "how do MSC escape allo e- ac i i y?" bu a he "wha is he hie a chy o signals ha con ol immunosupp ession?" In his ega d, esea ch om o he ields has been in o ma i e. We ha e p e i- ously p oposed ha ma e nal accep ance o he e al allo- g a p o ides indica o s o how his p ocess is con olled[13]. Howe e , insigh could also come om ano he a enue o inqui y. The mechanisms o umo e a- sion may e lec he su i al mechanisms o MSC. MSC a oidance o allo eac i i y shows pa allels o umo e asion Escape om immune su eillance is belie ed o be a p i- ma y ea u e o malignan disease in humans. The immune e ec o esponse is sub-op imal because umo s de elop mul i ac o ial s a egies o escape immune dele- ion[92,93]. These s a egies may p o ide clues o how MSC p omo e ole ogenic mechanisms du ing allogeneic eng a men (Fig. 3). Modula ion o umo an igen exp ession, pa icula ly MHC class I and II is a pa icula ly common componen o umo immune e asion[93]. This is o en accompanied by poo o non-exp ession o co- s imula o y molecules, which no only limi s clonal expansion o umo -speci ic CD4+ T cells, bu also hin- de s he p oduc ion o cy okines, and he de elopmen o CTL[44,94,95]. Simila ly MSC show no exp ession o co- s imula o y molecules (Fig. 2) [28,39]. In addi ion o educed immunogenici y, umo cells can di ec ly modu- la e DC and T cell unc ion. S udies om pa ien s wi h hepa ocellula ca cinoma showed ha neoplasia induced a de ec o DC ma u a ion[96]. This pa allels indings by Bey h e al [42] sugges ing ha human MSCs in e e e wi h no mal APC ma u a ion, he eby indi ec ly in luenc- ing T-cell ac i a ion. F eshly isola ed umo -in il a ing T cells a e usually inac i e agains au ologous cance cells bu can be eac i a ed in- i o by he addi ion o IL-2[97]. S udies o MSC by Le Blanc e al showed s iking pa allels o his o m o supp ession[69]. They sugges ha MSC ac by p e en ing exp ession o CD25 (IL-2 ecep o ) he eby limi ing T cell ac i a ion[69]. O he wo k has shown ha exogenous IL-2 addi ion o co-cul u es con aining MSC e e sed he supp essi e e ec [19,69]. Simila ly, an igen- speci ic CD4+ CD25+ egula o y T cells also supp ess umo -speci ic CD8 T cell cy o oxici y al hough his mech- anism elies on TGF-β sec e ion by egula o y cells[98,99]. Tumo s can supp ess CD4+ T cell ac i i y and CTL umo lysis di ec ly h ough sec e ion o immunosupp essi e ac o s including TGF-β1 bu also PGE-2, and IL-10. Van de Pouw K aan e al, showed ha umo -de i ed p os ag- landins inc eased he p oduc ion o inhibi o y cy okines such as IL-10, while supp essing IL-12[100], which is nec- essa y o e ec i e hos -cell-media ed an i- umo immune esponse[75,93]. Likewise, TGF-β p oduc ion has been Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 7 o 11 (page numbe no o ci a ion pu poses) epo ed om a numbe o umo s, con ibu ing o immune e asion. In iguingly in his con ex i also inhib- i s CTL di e en ia ion [101]. Al hough he e is li le e i- dence ha MSC sec e e TGF-β1, he bone ma ow is ich in his cy okine, sugges ing ha MSC eside in a compa - men wi h immunosupp essi e quali ies. Al hough he e a e s iking pa allels be ween MSC and some umo cells, i is no ou con en ion ha hese cells a e di ec ly ela ed. Indeed he e a e dis inc di e ences be ween he popula ions (Table 1). The undamen al di - e ence be ween he cell ypes esides in he con ol o cell di ision and apop osis, which a e igh ly egula ed in MSC bu dys egula ed in ans o med cells. Fu he mo e, i is well documen ed ha some umo s exploi FasL (CD95L) exp ession o acili a e immune escape [102- 104]. Howe e , ou own s udies show ha human MSC do no exp ess FasL (Fig 2) and al hough he e is some e i- dence om immo alized mini-pig de i ed MSC o indi- ca e a ole o FasL in supp ession[105], i seems ha di ec induc ion o apop o ic dele ion is no a ac o in ol ed in MSC in e ac ion wi h T cells in he b oade li - e a u e. The pa allels be ween neoplas ic cells and MSC lie in he exp essed pheno ypes a he han in any di ec lin- eage ela ion. I appea s ha MSC e ain ce ain aspec s o he e al allog a ha p omo e ole ance, some o hese mechanisms may be eac i a ed in neoplasia, he key di - e ence being ha MSC pe o m hese unc ions in an o de ed and con olled way whe eas umo cells do so in a manne ha by de ini ion has escaped no mal con ols on apop osis o cell di ision. Conclusion Cu en esea ch on he in e ac ion be ween MSC and T cells suppo he po en ial use o allogeneic MSC in egen- e a i e medicine. S udies showing enhanced MSC eng a - men o bone, muscle, hea e c encou age he ansla ion o ecen esea ch in o he apy. The u u e holds much p omise o he use o allogeneic MSC and whils obs a- cles exis , he po en ial o allo eac i i y does no seem o be a majo p oblem. F om he esea ch s andpoin , MSC appea o use a su p ising a ay o mechanisms o a oid dele ion by he hos including hypoimmunogenici y, modula ion o DC and T cell unc ion, as well as he c ea- ion o a supp essi e mic oen i onmen . The challenge is now o un a el he iming and con ol o hese mecha- nisms in an in lamma o y si ua ion ypical o he ecipi- en pa ien . Lis o Abb e ia ions APC, an igen p esen ing cells; DC, dend i ic cell; ES, emb yonic s em; HGF, hepa ocy e g ow h ac o ; HSC, hema opoie ic s em cells; IDO, indoleamine 2,3,dioxyge- nase; KIR, kille inhibi o y ecep o ; MLR, mixed lym- phocy e-like eac ion; MSC, mesenchymal s em cells; OI, os eogenesis impe ec a; PBMC, pe iphe al blood mono- nuclea cells; PGE-2, p os aglandin E2. Compe ing in e es s JMR and BPM ha e no compe ing in e es s. FPB and JMM ha e ecei ed sala y om an o ganiza ion and hold s ocks o sha es in an o ganiza ion ha may gain o lose inan- cially om he publica ion o his manusc ip . Au ho s' con ibu ions FPB and BPM concei ed he e iew; JMR pe o med he mic oscopy and low cy ome y. All au ho s p o ided MSC and umo cells c ea e a supp essi e mic oen i onmen Figu e 3 MSC and umo cells c ea e a supp essi e mic oen i on- men . The e a e undamen al di e ences be ween umo cells (A) and MSC (B) wi h espec o con ol o cell di ision, howe e many mechanisms exploi ed by he o me o e ade immune dele ion a e also used by MSC o a oid allogeneic ejec ion. De ails o mechanisms and associa ed e e ences a e supplied in he body o he ex and Table 1. Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8 Page 8 o 11 (page numbe no o ci a ion pu poses) in e p e a ion o published s em cell da a, and ha e made in ellec ual con ibu ions o he con en o he pape . All au ho s ead and app o ed he inal manusc ip . Addi ional ma e ial Acknowledgemen s This wo k was suppo ed by he Science Founda ion I eland Cen es o Science Enginee ing and Technology (CSET) unding o he Regene a i e Medicine Ins i u e (REMEDI). Be na d Mahon is a Wellcome T us /HRB "New Blood" Fellow. Ms Ka en English is hanked o assis ance in p epa- a ion o his manusc ip . Re e ences 1. 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Table 1: Compa ison o MSC and Tumo cellsa Cha ac e is ic MSC Tumo cells Re e ences Cell Di ision Con olled Uncon olled [5, 7, 111] MHC I exp ession + Va iable Fig 2 & [25, 27, 28, 39, 93, 111, 112] MHC II exp ession - Va iable Fig 2 & [2, 25, 27, 39, 93, 111, 112] CD80 exp ession - - [25, 28, 39, 44, 94, 95] CD86 exp ession - - Fig 2 & [25, 28, 39, 44, 94, 95] FasL exp ession - + Fig. 2 & [102-104] P os aglandin sec e ion + + [21, 28, 82, 100] IDO exp ession + Va iable [28, 43, 59, 87, 90] TGF-β sec e ion Va iable + [42, 43, 59, 101, 105] IL-10 sec e ion + + [13, 42, 72, 100] DC modula ion + + [24, 26, 42, 96] Ve o e ec s on T cells + + [23, 112] a Desc ip ions o MSC in he li e a u e a e di e se and many popula ions ha e been desc ibed which show di e en pa e ns o exp ession. In pa icula wo k in mice appea s o be s ain dependen , bu u he a ia ion a ises om di e ences in isola ion, cul u e, iming and me hodology. 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