The goal of this study was to identify immunological markers for use in antigen-specific assays that predict long-term survival after renal allograft and distinguish stable-functioning (SP) patients from poorly functioning (PP) patients. For this prospective study, 20 patients were enrolled. Eight SP and six PP patients were enrolled in this study. Serum cytokine/chemokine levels were analyzed by the Luminex multiplex assay. To detect indirect alloreactive T cells, we performed indirect mixed lymphocyte reaction using donor-antigen-pulsed autologous dendritic cells as stimulators. Serum induced protein-10 levels were significantly higher in the serum of PP patients, whereas sCD40L levels were higher in SP patients. The PP patients had significantly higher numbers of donor-specific CD4+CD43highCD45RO+ T cells after indirect allostimulation, whereas this cell population was unchanged in SP patients. The donor-specific CD4+CD43highCD45RO+ T cells had the effector memory T cell phenotype. Prospectively, we studied whether these cells influence graft outcome and found that their strong proliferation in pre-transplant patients is related to a poorly functioning graft. Indirectly allostimulated CD4+CD43highCD45RO+ T cells may not only contribute to chronic allograft nephropathy development but may also have a role in the progression of acute rejection. Thus, these cells may have potential use as immune-monitoring markers in a noninvasive in vitro assay that predicts graft outcome.
de FijterJW. Rejection and function and chronic allograft dysfunction. Kidney Int2010; 78: S38–41.
3.
NickelPBestardOVolkHDReinkeP. Diagnostic value of T-cell monitoring assays in kidney transplantation. Curr Opin Organ Transplant2009; 14: 426–31.
4.
BrehmMAMangadaJMarkeesTGPearsonTDanielsKAThornleyTBWelshRNRossiniAAGreinerDL. Rapid quantification of naive alloreactive T cells by TNF-alpha production and correlation with allograft rejection in mice. Blood.2007; 109: 819–26.
5.
BrouardSMansfieldEBraudCLiLGiralMHsiehSCBaetenDZhangMAshton-ChessJBraudeauCHsiehFDupontAPallierAMoreauALouisSRuizCSalvatierraOSoulillouJPSarvalM. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A2007; 104: 15448–53.
6.
WallgrenACAnderssonBBackerAKarlsson-ParraA. Direct allorecognition promotes activation of bystander dendritic cells and licenses them for Th1 priming: a functional link between direct and indirect allosensitization. Scand J Immunol2005; 62: 234–42.
7.
van BesouwNMZuijderwijkJMVaessenLMBalkAHMaatAPvan der MeidePHWeimarW. The direct and indirect allogeneic presentation pathway during acute rejection after human cardiac transplantation. Clin Exp Immunol2005; 141: 534–40.
8.
OkumiMFishbeinJMGriesemerADGianelloPRHirakataANoboriS. Role of persistence of antigen and indirect recognition in the maintenance of tolerance to renal allografts. Transplantation2008; 85: 270–80.
9.
FordMLKirkADLarsenCP. Donor-reactive T-cell stimulation history and precursor frequency: barriers to tolerance induction. Transplantation2009; 87: S69–74.
10.
LechlerRIGardenOATurkaLA. The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol2003; 3: 147–58.
11.
BakerRJHernandez-FuentesMPBrookesPAChaudhryANCookHTLechlerRI. Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy. J Immunol2001; 167: 7199–206.
12.
SchliengerKCraigheadNLeeKPLevineBLJuneCH. Efficient priming of protein antigen-specific human CD4(+) T cells by monocyte-derived dendritic cells. Blood2000; 96: 3490–8.
13.
WaandersMMHeidtSKoekkoekKMZoetYMDoxiadisIIAmirAHeemskerkMHMulderABrandARoelenDLClaasFH. Monitoring of indirect allorecognition: wishful thinking or solid data?Tissue Antigens2008; 71: 1–15.
14.
TamburAR. Monitoring indirect presentation of alloantigens by utilizing the autologous processing machinery of dendritic cells in-vitro. J Immunol Methods2003; 283: 215–23.
15.
LeePCZhuLTerasakiPIEverlyMJ. HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation2009; 88: 568–74.
16.
HornickPIMasonPDBakerRJHernandez-FuentesMFrascaLLombardiGTaylorKWengLToseMLYacoubMHBatchelorRLechlerRI. Significant frequencies of T cells with indirect anti-donor specificity in heart graft recipients with chronic rejection. Circulation2000; 101: 2405–10.
17.
BestardONickelPCruzadoJMSchoenemannCBoenischOSefrinAGrinyoJMVolkHDReinkeP. Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients. J Am Soc Nephrol2008; 19: 1419–29.
18.
JerasMBergantMRepnikU. In vitro preparation and functional assessment of human monocyte-derived dendritic cells-potential antigen-specific modulators of in vivo immune responses. Transplant Immunol2005; 14: 231–44.
19.
BenderASappMSchulerGSteinmanRMBhardwajN. Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods1996; 196: 121–35.
20.
PeiRLeeJHShihNJChenMTerasakiPI. Single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen antibody specificities. Transplantation2003; 75: 43–9.
21.
ThakkerPLeachMWKuangWBenoitSELeonardJPMarusicS. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J Immunol2007; 178: 2589–98.
22.
FamulskiKSEineckeGReeveJRamassarVAllanachKMuellerTHidalgoLGZhuLFHalloranPF. Changes in the transcriptome in allograft rejection: IFN-gamma-induced transcripts in mouse kidney allografts. Am J Transplant2006; 6: 1342–54.
23.
AharinejadSKrennKZuckermannASchaferRGmeinerMThomasAAliabadiASchneiderBGrimmM. Serum matrix metalloprotease-1 and vascular endothelial growth factor–a predict cardiac allograft rejection. Am J Transplant2009; 9: 149–59.
24.
GorielySGoldmanM. The interleukin-12 family: new players in transplantation immunity?Am J Transplant2007; 7: 278–84.
25.
GiavedoniLD. Simultaneous detection of multiple cytokines and chemokines from nonhuman primates using luminex technology. J Immunol Methods2005; 301: 89–101.
26.
SallustoFGeginatJLanzavecchiaA. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol2004; 22: 745–63.
27.
ZhouLToungouzMDonckierVAndrienMTroisiRde HemptinneBLe MoineADupontEGoldmanMStordeurP. A rapid test to monitor alloreactive responses in whole blood using real-time polymerase chain reaction. Transplantation2005; 80: 410–3.
28.
GuitardJRibesDKamarNCointaultOLavayssiereLEspositoLRostaingLMuscariFSucBPeronJM. Predictive factors for chronic renal failure one year after orthotopic liver transplantation. Ren Fail2006; 28: 419–25.
29.
PengWChenJJiangYShouZChenYWangH. Non-invasive detection of acute renal allograft rejection by measurement of vascular endothelial growth factor in urine. J Int Med Res2007; 35: 442–9.
30.
SlavcevAHonsovaELodererovaAPavlovaYSajdlovaHVitkoSSkibovaJStrizIViklickyO. Soluble CD30 in patients with antibody-mediated rejection of the kidney allograft. Transpl Immunol2007; 18: 22–7.
31.
SawitzkiBBushellAStegerUJonesNRischKSiepertALehmannMSchmitt-KnosallaIVogtKGebuhrIWoodKVolkHD. Identification of gene markers for the prediction of allograft rejection or permanent acceptance. Am J Transplant2007; 7: 1091–102.
32.
LachmannNTerasakiPIBuddeKLiefeldtLKahlAReinkePPratschkeJRudolphBSchmidtDSalamaASchronemannC. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation2009; 87: 1505–13.
33.
RiethmullerSFerrari-LacrazSMullerMKRaptisDAHadayaKRusiBLaubeGSchneiterGFehrTVillardJ. Donor-specific antibody levels and three generations of crossmatches to predict antibody-mediated rejection in kidney transplantation. Transplantation2010; 90: 160–7.
34.
JordanSCVoAA. Donor-specific antibodies in allograft recipients: etiology, impact and therapeutic approaches. Curr Opin Organ Transplant2014; 19: 591–7.
35.
HidalgoLGCampbellPMSisBEineckeGMengelMChangJSellaresJReveJHalloranPF. De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant2009; 9: 2532–41.
36.
Filippone EJ, Farber JL. Humoral immune response and allograft function in kidney transplantation. Am J Kidney Dis. Epub ahead of print 2015.
JonesND. Memory T cells: how might they disrupt the induction of tolerance?Transplantation2009; 87: S74–7.
39.
Yang J, Brook MO, Carvalho-Gaspar M, Zhang J, Ramon HE, Sayegh MH, Wood KH, Turka LA, Jones ND. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A. Epub ahead of print 2007.
40.
SeoWZiltenerHJ. CD43 processing and nuclear translocation of CD43 cytoplasmic tail are required for cell homeostasis. Blood2009; 114: 3567–77.
41.
OharaTKoyamaKKusunokiYHayashiTTsuyamaNKuboYKyoizumiS. Memory functions and death proneness in three CD4+CD45RO+ human T cell subsets. J Immunol2002; 169: 39–48..
42.
HikonoHKohlmeierJETakamuraSWittmerSTRobertsADWoodlandDL. Activation phenotype, rather than central- or effector-memory phenotype, predicts the recall efficacy of memory CD8+ T cells. J Exp Med2007; 204: 1625–36.
43.
TsudaKYamanakaKKitagawaHAkedaTNakaMNiwaKNakanishiTKakedaMGabazzaECMizutaniH. Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naive T cells into cytokine-producing mature T cells. PloS One2012; 7: e31465–e31465.
44.
KoenenHJMichielsenECVerstappenJFasseEJoostenI. Superior T-cell suppression by rapamycin and FK506 over rapamycin and cyclosporine A because of abrogated cytotoxic T-lymphocyte induction, impaired memory responses, and persistent apoptosis. Transplantation2003; 75: 1581–90.
