Abstract
Transplantation is the only cure for end-stage organ failure. Current immunosuppressive drugs have two major limitations: 1) non antigen specificity, which increases the risk of cancer and infection diseases, and 2) chronic toxicity. Cell therapy appears to be an innovative and promising strategy to minimize the use of immunosuppression in transplantation and to improve long-term graft survival. Preclinical studies have shown efficacy and safety of using various suppressor cells, such as regulatory T cells, regulatory B cells and tolerogenic dendritic cells. Recent clinical trials using cellbased therapies in solid organ transplantation also hold out the promise of improving efficacy. In this review, we will briefly go over the rejection process, current immunosuppressive drugs, and the potential therapeutic use of regulatory cells in transplantation.
Keywords: Cell therapy, immune suppression, solid organ transplant, chronic toxicity, antigen specificity, DAMP.
Graphical Abstract
[http://dx.doi.org/10.1016/j.trim.2012.04.002] [PMID: 22549100]
[http://dx.doi.org/10.1097/MOT.0000000000000216] [PMID: 26132735]
[http://dx.doi.org/10.1097/00007890-200210150-00003] [PMID: 12394831]
[http://dx.doi.org/10.1172/JCI62970] [PMID: 22706307]
[http://dx.doi.org/10.1159/000347132] [PMID: 23486162]
[http://dx.doi.org/10.1038/ki.2014.430] [PMID: 25629552]
[http://dx.doi.org/10.1034/j.1600-6143.2003.00054.x] [PMID: 12614275]
[http://dx.doi.org/10.1097/00007890-200003150-00063] [PMID: 10755571]
[http://dx.doi.org/10.1016/j.healun.2010.04.012] [PMID: 20591689]
[http://dx.doi.org/10.1038/sj.embor.7400205] [PMID: 15272298]
[http://dx.doi.org/10.3109/08916934.2012.750302] [PMID: 23194089]
[http://dx.doi.org/10.4049/jimmunol.174.12.7506] [PMID: 15944249]
[http://dx.doi.org/10.1084/jem.20070247] [PMID: 17984303]
[http://dx.doi.org/10.3389/fimmu.2015.00614] [PMID: 26697010]
[http://dx.doi.org/10.1172/JCI58344] [PMID: 22156194]
[http://dx.doi.org/10.1111/j.1600-6143.2007.01734.x] [PMID: 17331117]
[http://dx.doi.org/10.1038/nrneph.2016.41] [PMID: 27026348]
[http://dx.doi.org/10.1097/TP.0000000000000427] [PMID: 25286058]
[http://dx.doi.org/10.1097/00007890-200201151-00011] [PMID: 11810059]
[http://dx.doi.org/10.1615/CritRevImmunol.v18.i5.10] [PMID: 9784967]
[http://dx.doi.org/10.1111/j.1600-065X.1996.tb00921.x] [PMID: 9010720]
[http://dx.doi.org/10.1002/eji.200636138] [PMID: 17039566]
[http://dx.doi.org/10.4049/jimmunol.1100056] [PMID: 21697455]
[http://dx.doi.org/10.1002/eji.200324804] [PMID: 14991590]
[http://dx.doi.org/10.1038/ni.2849] [PMID: 24633226]
[http://dx.doi.org/10.1007/s12026-012-8327-1] [PMID: 22477527]
[http://dx.doi.org/10.1002/jemt.1090] [PMID: 11340669]
[http://dx.doi.org/10.1002/1521-4141(200104)31:4<1150:AID-IMMU1150>3.0.CO;2-V] [PMID: 11298340]
[http://dx.doi.org/10.1084/jem.20081937] [PMID: 19047438]
[http://dx.doi.org/10.1038/nri1027] [PMID: 12658268]
[http://dx.doi.org/10.1253/circj.CJ-08-0292] [PMID: 19088395]
[http://dx.doi.org/10.1007/s00467-008-1020-x] [PMID: 21476231]
[http://dx.doi.org/10.1111/j.1600-6143.2011.03926.x] [PMID: 22300494]
[http://dx.doi.org/10.1111/j.1600-6143.2011.03754.x] [PMID: 21929642]
[http://dx.doi.org/10.1517/17425255.2011.544249] [PMID: 21241200]
[http://dx.doi.org/10.1101/cshperspect.a015487] [PMID: 24003247]
[http://dx.doi.org/10.1097/00007890-199807150-00005] [PMID: 9679818]
[http://dx.doi.org/10.1097/00007890-199904150-00013] [PMID: 10221486]
[http://dx.doi.org/10.1016/S1053-2498(99)00100-X] [PMID: 10612381]
[http://dx.doi.org/10.1053/jlts.2001.26353] [PMID: 11510013]
[http://dx.doi.org/10.1097/01.tp.0000295420.49063.b1]
[http://dx.doi.org/10.1097/01.TP.0000109643.32659.C4] [PMID: 14742976]
[http://dx.doi.org/10.1002/14651858.CD003897.pub3] [PMID: 20091551]
[http://dx.doi.org/10.1056/NEJMoa1009546] [PMID: 21591943]
[http://dx.doi.org/10.2165/00002018-199513030-00002] [PMID: 7495501]
[http://dx.doi.org/10.1172/JCI16432] [PMID: 12697733]
[http://dx.doi.org/10.4103/0971-4065.85483] [PMID: 22022086]
[http://dx.doi.org/10.1097/00075198-200112000-00003] [PMID: 11805539]
[http://dx.doi.org/10.2165/00003495-200565050-00004] [PMID: 15748097]
[PMID: 18217899]
[http://dx.doi.org/10.1016/0065-2571(83)90007-9] [PMID: 6152730]
[http://dx.doi.org/10.1016/j.transproceed.2007.11.066] [PMID: 18261583]
[http://dx.doi.org/10.1111/ijcp.12661] [PMID: 26176940]
[http://dx.doi.org/10.1007/s13318-015-0262-9] [PMID: 25663618]
[http://dx.doi.org/10.1097/00007890-199707150-00007] [PMID: 9233697]
[http://dx.doi.org/10.1097/00007890-199707150-00008] [PMID: 9233698]
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[http://dx.doi.org/10.1111/ajt.12669] [PMID: 24580843]
[http://dx.doi.org/10.1111/j.1600-6143.2009.03005.x] [PMID: 20415897]
[http://dx.doi.org/10.1111/j.1600-6143.2011.03785.x] [PMID: 21992533]
[http://dx.doi.org/10.1056/NEJMoa1506027] [PMID: 26816011]
[http://dx.doi.org/10.1111/ajt.14377] [PMID: 28556519]
[http://dx.doi.org/10.1097/TP.0000000000001755] [PMID: 28403127]
[http://dx.doi.org/10.1681/ASN.2009101043] [PMID: 20431040]
[http://dx.doi.org/10.4103/0971-4065.73431] [PMID: 21206677]
[http://dx.doi.org/10.2215/CJN.04410512] [PMID: 22977217]
[http://dx.doi.org/10.4103/2321-3868.126086] [PMID: 27574642]
[http://dx.doi.org/10.1038/77513] [PMID: 10888927]
[http://dx.doi.org/10.1097/TP.0000000000002225] [PMID: 29757906]
[http://dx.doi.org/10.1111/imm.12600] [PMID: 26924728]
[http://dx.doi.org/10.3389/fimmu.2018.00035] [PMID: 29441062]
[http://dx.doi.org/10.3389/fimmu.2015.00171] [PMID: 25926835]
[http://dx.doi.org/10.3389/fimmu.2015.00494] [PMID: 26539191]
[http://dx.doi.org/10.1016/j.transproceed.2003.08.030] [PMID: 14611991]
[http://dx.doi.org/10.1016/j.it.2015.05.005] [PMID: 26091728]
[PMID: 7636184]
[http://dx.doi.org/10.1126/science.1079490] [PMID: 12522256]
[http://dx.doi.org/10.1038/ni904] [PMID: 12612578]
[http://dx.doi.org/10.1002/eji.200425274] [PMID: 15307180]
[http://dx.doi.org/10.1038/ni1536] [PMID: 17982458]
[http://dx.doi.org/10.3389/fimmu.2016.00315] [PMID: 27621729]
[http://dx.doi.org/10.4049/jimmunol.177.10.6780] [PMID: 17082591]
[http://dx.doi.org/10.1084/jem.20062512] [PMID: 17502665]
[http://dx.doi.org/10.4049/jimmunol.166.6.3789] [PMID: 11238621]
[http://dx.doi.org/10.1038/nature06306] [PMID: 18033300]
[http://dx.doi.org/10.1084/jem.20020590] [PMID: 12119348]
[http://dx.doi.org/10.1016/j.immuni.2007.08.014] [PMID: 17919943]
[http://dx.doi.org/10.1002/1521-4141(200006)30:6<1538:AID-IMMU1538>3.0.CO;2-X] [PMID: 10898488]
[http://dx.doi.org/10.1002/eji.201242909] [PMID: 23749427]
[http://dx.doi.org/10.1016/j.bbmt.2006.01.005] [PMID: 16503495]
[http://dx.doi.org/10.1016/j.transci.2012.06.007] [PMID: 22795999]
[http://dx.doi.org/10.1101/cshperspect.a015552] [PMID: 24186492]
[http://dx.doi.org/10.1126/scitranslmed.3001809] [PMID: 21593401]
[http://dx.doi.org/10.3324/haematol.2012.074088] [PMID: 23242600]
[http://dx.doi.org/10.1111/ajt.12433] [PMID: 24102808]
[http://dx.doi.org/10.1016/j.clim.2009.06.001] [PMID: 19559653]
[http://dx.doi.org/10.1002/hep.28459] [PMID: 26773713]
[http://dx.doi.org/10.1177/2040620719841581] [PMID: 31019670]
[http://dx.doi.org/10.1056/NEJMc1901464] [PMID: 30995383]
[http://dx.doi.org/10.1093/nar/gku1166] [PMID: 25414323]
[http://dx.doi.org/10.3389/fimmu.2016.00575] [PMID: 28003816]
[http://dx.doi.org/10.1172/JCI82771] [PMID: 26999600]
[http://dx.doi.org/10.1111/ajt.14175] [PMID: 27997080]
[http://dx.doi.org/10.1038/nbt0714-604] [PMID: 25004212]
[http://dx.doi.org/10.1016/j.blre.2018.11.002] [PMID: 30528964]
[http://dx.doi.org/10.1016/S1074-7613(02)00274-1] [PMID: 11869683]
[http://dx.doi.org/10.1038/251550a0] [PMID: 4547522]
[PMID: 4279260]
[http://dx.doi.org/10.1111/ajt.13483] [PMID: 26552037]
[http://dx.doi.org/10.1186/ar3736] [PMID: 22315945]
[http://dx.doi.org/10.1126/scitranslmed.3005407] [PMID: 23427243]
[http://dx.doi.org/10.4049/jimmunol.181.12.8278] [PMID: 19050244]
[http://dx.doi.org/10.1007/s00262-011-0972-z] [PMID: 21253724]
[http://dx.doi.org/10.1038/nature11501] [PMID: 23064231]
[http://dx.doi.org/10.4049/jimmunol.178.6.3447] [PMID: 17339439]
[http://dx.doi.org/10.1016/j.molimm.2014.01.014] [PMID: 24556109]
[http://dx.doi.org/10.4049/jimmunol.1100284] [PMID: 21464089]
[http://dx.doi.org/10.1038/nature12979] [PMID: 24572363]
[http://dx.doi.org/10.1038/nm.3554] [PMID: 24743305]
[http://dx.doi.org/10.4049/jimmunol.167.2.1081] [PMID: 11441119]
[http://dx.doi.org/10.4049/jimmunol.170.12.5897] [PMID: 12794116]
[http://dx.doi.org/10.1016/j.immuni.2012.02.008] [PMID: 22406267]
[http://dx.doi.org/10.1111/j.1600-6143.2010.03336.x] [PMID: 21114655]
[http://dx.doi.org/10.4049/jimmunol.1500429] [PMID: 26432892]
[http://dx.doi.org/10.1002/eji.201445082] [PMID: 25408265]
[http://dx.doi.org/10.1172/JCI46274] [PMID: 21821911]
[http://dx.doi.org/10.1073/pnas.1120914109] [PMID: 22773818]
[http://dx.doi.org/10.4049/jimmunol.1402632] [PMID: 25582854]
[http://dx.doi.org/10.1111/ajt.13087] [PMID: 25645598]
[http://dx.doi.org/10.1038/s41467-017-00838-4] [PMID: 28959012]
[http://dx.doi.org/10.1371/journal.pone.0178765] [PMID: 28570665]
[http://dx.doi.org/10.1056/NEJMc0808481] [PMID: 19535812]
[http://dx.doi.org/10.1681/ASN.2013080837] [PMID: 24610932]
[http://dx.doi.org/10.1681/ASN.2014040404] [PMID: 25644114]
[http://dx.doi.org/10.4049/jimmunol.1600218] [PMID: 28087671]
[http://dx.doi.org/10.1084/jem.137.5.1142] [PMID: 4573839]
[http://dx.doi.org/10.1182/blood-2005-10-4190] [PMID: 16410444]
[http://dx.doi.org/10.1146/annurev.immunol.21.120601.141040] [PMID: 12615891]
[http://dx.doi.org/10.3389/fimmu.2012.00274] [PMID: 22969767]
[http://dx.doi.org/10.1186/2047-1440-1-14] [PMID: 23369527]
[http://dx.doi.org/10.1016/j.bj.2017.01.002] [PMID: 28521905]
[http://dx.doi.org/10.1016/j.stemcr.2017.03.020] [PMID: 28434942]
[http://dx.doi.org/10.1002/eji.201445217] [PMID: 25820702]
[http://dx.doi.org/10.1189/jlb.0613336] [PMID: 24108704]
[http://dx.doi.org/10.3389/fimmu.2015.00569] [PMID: 26617604]
[http://dx.doi.org/10.2337/dc11-0472] [PMID: 21680720]
[http://dx.doi.org/10.1038/nri2132] [PMID: 17627284]
[http://dx.doi.org/10.1189/jlb.1102582] [PMID: 12949248]
[http://dx.doi.org/10.3389/fimmu.2012.00218] [PMID: 22908013]
[http://dx.doi.org/10.1111/j.1600-6143.2004.00683.x] [PMID: 15643985]
[http://dx.doi.org/10.1182/blood-2009-10-251058] [PMID: 20576812]
[http://dx.doi.org/10.1097/00007890-199912270-00001] [PMID: 10628758]
[http://dx.doi.org/10.1093/ecco-jcc/jjv144] [PMID: 26303633]
[http://dx.doi.org/10.1136/annrheumdis-2015-208456] [PMID: 27117700]
[http://dx.doi.org/10.3389/fimmu.2018.00274] [PMID: 29520275]
[http://dx.doi.org/10.3389/fimmu.2016.00015] [PMID: 26858719]
[http://dx.doi.org/10.1182/blood-2007-02-075481] [PMID: 17684157]
[http://dx.doi.org/10.1097/TP.0b013e318298f9fa] [PMID: 23759879]
[http://dx.doi.org/10.1001/jama.2012.316] [PMID: 22436957]
[http://dx.doi.org/10.1038/mt.2012.168] [PMID: 22929659]
[http://dx.doi.org/10.4049/jimmunol.1100762] [PMID: 21804023]
[http://dx.doi.org/10.1038/nri2506] [PMID: 19197294]