Tackling Chronic Kidney Rejection: Challenges And Promises
Feb 03, 2022
Xingqiang Laj1,2,3, Xin Zheng4, James M. Mathew 1,2, Lorenzo Gallon1,5, Joseph R. Leventhal1,2thiab Zheng Jenny Zhang1,2*
Txawm hais tias muaj kev nce qib hauv kev tswj hwm tom qab hloov pauv, qhov kev muaj sia nyob ntev ntawm lub raum grafts thiab cov neeg mob tsis tau zoo dua li kwv yees li plaub caug feem pua ntawm kev hloov pauv tsis pub dhau kaum xyoo tom qab hloov pauv. Ob qho tib si immunologic thiab non-immunologic yam tseem ceeb ua rau kev poob allograft lig. Ntevhloov raumKev tsis lees paub (CKTR) feem ntau yog ib qho chaw kho mob uas ntsiag to tsis tau muaj cov txheej txheem tiv thaiv kab mob allogeneic uas ua rau muaj kev raug mob graft, deterioration ntawm graft function. Chronic active T cell-mediated rejection (TCMR) thiab chronic active antibody-mediated rejection (ABMR) yog muab faib ua ob hom tseem ceeb ntawm CKTR. Txawm hais tias kev txhim kho tseem ceeb tau ua rau kev nkag siab zoo dua ntawm cov xov tooj ntawm tes thiab cov txheej txheem molecular thiab kev kuaj mob ntawm CKTR, qhov tsis muaj kev tshawb pom ntxov, kev kuaj mob sib txawv, thiab cov kev kho mob zoo txuas ntxiv ua teeb meem loj rau kev tswj xyuas mus sij hawm ntev. Txoj kev loj hlob tsis ntev los no ntawm high throughput cellular thiab molecular biotechnologies tau tso cai rau txoj kev loj hlob sai ntawm cov biomarkers tshiab cuam tshuam nrog rau lub raum raug mob, uas tsis yog tsuas yog muab kev nkag siab rau hauv pathogenesis ntawm kev tsis lees paub ntev tab sis kuj tso cai rau kev tshawb pom ntxov. Nyob rau tib lub sijhawm, ntau lub tswv yim kho tshiab tau tshwm sim uas yuav tuav tau cov lus cog tseg zoo rau kev txhim kho cov khoom siv mus sij hawm ntev thiab cov neeg mob muaj sia nyob. Nrog rau cov ntsiab lus luv luv ntawm kev nkag siab tam sim no ntawm pathogenesis, tus qauv kuaj mob, thiab cov teeb meem hauv cov ntsiab lus ntawm CKTR, qhov kev tshuaj xyuas me me no yog lub hom phiaj los muab cov kev hloov kho tshiab thiab kev nkag siab rau qhov kev txhim kho tshiab ntawm kev cog lus tshiab biomarkers rau kev kuaj mob thiab kev kho tshiab los tiv thaiv thiab kho. CKTR.
Ntsiab lus:tsis kam lees allograft ntev,hloov raum, biomarkers, IFTA, T cell mediated rejection
Hu rau:joanna.jia@wecistanche.com
hloov raum thiabcistanche Cov tshuaj ntxiv tuaj yeem txo qhov kev tsis lees txais allograft
Taw qhia
Mob raum hloovKev tsis lees paub (CKTR) yog tus cwj pwm los ntawm kev txo qis ntawm lub raum graft ua haujlwm uas pib tshwm sim ib xyoos tom qab hloov pauv thiab feem ntau yog nrog ntshav siab thiab proteinuria (1). CKTR feem ntau tshwm sim hauv cov neeg mob uas muaj kev tiv thaiv kab mob tsis txaus lossis tshuaj tsis ua raws li (2). Txawm hais tias Kev Tiv Thaiv Kab Mob Tsis Txaus Siab tseem yog qhov ua rau tseem ceeb (3, 4), ntau yam kev pheej hmoo, xws li kev raug mob ischemia-reperfusion thaum ntxov, mob tsis txaus ntseeg, thiab hloov cov kab mob sib kis, tuaj yeem pab txhawb kev loj hlob thiab kev loj hlob ntawm CKTR. Histologically, muaj ob lub ntsiab lus tseem ceeb ntawm CKTR, uas yog cov tshuaj tiv thaiv kab mob ntev ntev (ABMR) thiab mob ntev T cell-mediated rejection (TCMR) raws li kev hloov kho Banff cov qauv (5, 6). Nws tsis yog qhov tsis tshua muaj tshwm sim uas ob qho tib si ua haujlwm ntev TCMR / ABMR sib koom ua ke thiab ua rau poob ntawm kev ua haujlwm sai sai (7-9).
Kev kho mob zoo thiab kev kwv yees ntawm CKTR feem ntau yog nyob ntawm qhov hnyav thiab kev thim rov qab ntawm kev tsis lees paub thaum lub sijhawm kuaj mob. Txawm li cas los xij, nws tseem yog ib qho kev sib tw loj los txheeb xyuas cov kev hloov pauv thaum ntxov ua ntej qhov kev puas tsuaj tsis tuaj yeem tshwm sim. Tam sim no, tsis muaj cov tshuaj tiv thaiv kab mob hauv tsev kho mob tau pom zoo los tiv thaiv thiab kho CKTR, tshwj xeeb yog ABMR. Kev nce qib tsis ntev los no hauv cov xov tooj ntawm tes thiab molecular biotechnologies tau tso cai rau qhov kev soj ntsuam tob ntawm cov txheej txheem ntawm tes thiab cov txheej txheem molecular thiab deconvolutions ntawm cov txheej txheem hauv qab CKTR thiab tau coj mus rau kev txheeb xyuas thiab siv tau ntawm cov tshiab molecular thiab cellular biomarkers los ntawm tsis-invasive lossis tsawg-invasive. txoj hauv kev. Qhov kev tshawb pom ntawm cov biomarkers no tau cog lus zoo heev rau kev tshawb pom ntxov thiab kev txhim kho ntawm kev cog lus tshiab kho tshiab rau kev txhim kho.hloov raumqhov tshwm sim. Qhov kev tshuaj xyuas no yuav xub muab cov ntsiab lus luv luv ntawm kev nkag siab tam sim no ntawm cov kab mob pathogenesis thiab cov qauv mothed cov teeb meem rau kev kuaj mob ntawm CKTR, thiab tom qab ntawd, tsom mus rau ntau qhov kev sib tham hauv qhov tob hauv thaj tsam ntawm biomarker nrhiav pom thiab cov kev kho tshiab tshiab los txhim kho kev hloov mus sij hawm ntev. qhov tshwm sim.
PATHOGENESIS NTAWM CHRONIC ACTIVE ABMR thiab CHRONIC TCMR
Kev ua haujlwm ntev ABMR sawv cev rau feem ntau ntawm CKTR (2), featuring transplant glomerupathies nrog rau mob hnyav peritubular capillary hauv qab daus membrane multilayering thiab tshiab-pib arterial intimal fibrosis. Nyob rau hauv sib piv, TCMR active ingredient yog txiav txim raws li nyob rau hauv cov cheeb tsam ntawm lub cortex nrog interstitial fibrosis thiab tubular atrophy (i-IFTA), ib tug feature ntawm CKTR ntxiv rau tubulitis. Cov txheej txheem tshiab Banff hloov tshiab ntawm kev ua haujlwm ntev ntev TCMR paub txog cov kab mob tseem ceeb ntawm TCMR hauv kev txhim kho cov kab mob sib kis mob ntev ua rau i-IFTA, txawm li cas los xij, nws tsis cais cov kab mob alloimmune-mediated cov ntaub so ntswg raug mob los ntawm 'tsis yog tshwj xeeb kev raug mob, tshwj xeeb tshaj yog calcineurin inhibitor ( CNI) mediated nephrotoxicities (10, 11).
Thaum cov txheej txheem meej hauv qab ABMR tseem tsis pom, nws ntseeg tau tias kev sib cuam tshuam ntawm tus neeg pub dawb tshwj xeeb alloantibodies (DSAs) tawm tsam tus neeg pub HLA antigens, tshwj xeeb tshaj yog HLA class II antigens qhia los ntawm cov hlwb endothelial ntawm microvascular ncig, pib ABMR (12). DSAs khi rau cov hlwb endothelial ua rau muaj kev cuam tshuam ntawm cov xwm txheej molecular, suav nrog kev ua kom muaj zog ntxiv uas tuaj yeem ua rau endothelial dysfunction, microvascular o, thiab kho dua tshiab, thiab thaum kawg ua rau cov nqaij mos raug mob (13). B cell deficiency ua rau txo qis kev hloov pauv hauv glomerulopathy, txo qis microvascular inflammation, txo cov macrophage infilltration, thiab IFNg cov ntaub ntawv hauv allograft (14), uas qhia txog qhov tseem ceeb ntawm B hlwb hauv pathogenesis ntawm ABMR. Ntxiv rau qhov tsis muaj kev tswj hwm lub cev tiv thaiv kab mob vim tsis muaj kev tiv thaiv kab mob tsis txaus lossis tsis muaj kev tiv thaiv, cov xwm txheej thaum ntxov xws li mob TCMR thiab kab mob kis tau pom tias yog qhov muaj feem cuam tshuam rau DSA (dnDSA) ntau lawm (15-17). Ua ntej TCMR tau pom tias muaj kev sib raug zoo nrog kev txhim kho ntawm kev ua haujlwm ntev ABMR dnDSA (7). Tsis tas li ntawd, nws tau pom nyob rau hauv biopsy-proven chronic active ABMR mob uas T hlwb (tshwj xeeb tshaj yog CD8 ntxiv rau T hlwb) thiab macrophages yog cov tseem ceeb infilltrating cell hom nyob rau hauv lub glomerulus, whereas B hlwb feem ntau pom nyob rau hauv lub tubulointerstitial compartment, qhia tau hais tias ob leeg. T hlwb thiab macrophages ua lub luag haujlwm tseem ceeb hauv lub raum mob ABMR (18). Kev koom tes ntawm NK hlwb hauv ABMR tau txais kev mloog tsis ntev los no. Cov kev tshawb fawb tsis ntev los no tau qhia tias NK hlwb koom nrog ABMR ntawm CD16a Fc receptors (19, 20). Kev txo qis ntawm NK hlwb tseem ceeb txo qis DSA-induced chronic allograft vasculopathy (CAV) (21). NK hlwb nce IFNg ntau lawm tom qab raug rau alloantigens los ntawm antibody-dependent cellular cytotoxicity-zoo li mechanisms, uas yog txuam nrog kev pheej hmoo rau ABMR (22) thiab NK cell infilltration kwv yees qhov tshwm sim tsis zoo tom qab.hloov raum (23).
Kev raug mob tsis tu ncua T cell-mediated tuaj yeem ua rau mob ntev TCMR (24). Alloreactive effector nco T Cells (Tem), tshwj xeeb tshaj yog CD8 ntxiv rau Tem subsets (qhia ntau ntxiv CD44hi, CD45RO ntxiv, OX40, KLRG-1, thiab BLIMP-1), muaj feem cuam tshuam rau kev txhim kho TCMR (25) . Tsis zoo li naïve T hlwb, Tem hlwb paub txog lawv qhov pib ua kom qis, muaj zog effector ua haujlwm, thiab tsis kam tiv thaiv kev tiv thaiv kab mob thiab costimulation blockade (26). Nco T hlwb yog los ntawm ib puag ncig antigens los yog tsim los ntawm yav dhau los rejection ntu thiab ib zaug qhib, lawv nkag mus rau hauv lub raum interstitium thiab secrete ntau cytokines xws li IFNg thiab TGFb, thiab tom qab ntawd ua rau ib tug cascade ntawm inflammation ua rau tubulitis (27). TCMR ntev kuj ua rau mob raum vasculature, xws li arterial o thiab intimal fibrosis (6). Hauv kev tshawb fawb tsis ntev los no, Claudia thiab cov npoj yaig (25) tau pom tias CD8 ntxiv rau lub cim xeeb T hlwb sib kho los ntawm OX40 gene pathway ua lub luag haujlwm tseem ceeb hauv kev tsim cov kab mob TCMR.
DAIM NTAWV THOV KEV PAB CUAM THIAB KEV PAB CUAM
Early diagnosis of CKTR determines successful therapeutic interventions and prognosis. CKTR is a slowly progressive process in which pathologic changes as such vascular inflammation and i-IFTA do not have clinical manifestations until late stages. In addition, differential diagnosis is extremely important to distinguish CKTR from late graft dysfunction caused by other complications including CNI toxicity, BK- virus-associated nephropathy, and recurrent renal diseases, each of which requires different treatment. Transplant patients are subjected to routine laboratory tests for continuous graft monitoring. Serum creatinine (sCr), blood urea nitrogen (BUN), and cystatin C are commonly used to evaluate graft function. The estimated glomerular filtration rate (eGFR), calculated based on sCr level, age, weight, and gender, is considered as an accurate indicator and predictor for graft function and long-term graft survival (28). Proteinuria>500 mg / hnub kuj tseem suav tias yog tus cim ntawm lub raum tsis ua haujlwm ntev (29). Txawm li cas los xij, vim tias qhov kev tsis lees paub ntev ntev yog ib qho txheej txheem tsis txaus ntseeg nrog kev hloov pauv qeeb hauv cov kab mob pathologic (30), cov kev ntsuam xyuas tau hais los saum no tsis yog tshwj xeeb, feem ntau tsis pom lub raum puas thaum ntxov thiab yooj yim cuam tshuam los ntawm lwm yam kev raug mob uas tsis muaj zog tiv thaiv kab mob tuaj yeem cuam tshuam cov txiaj ntsig. . Qhov tshwm sim ntawm circulating de novo DSAs yog txuam nrog kev pheej hmoo ntxiv rau kev ua txhaum cai tsis ua haujlwm raws li kev ua haujlwm ntev ABMR (31, 32). Kev saib xyuas yav tom ntej rau DSAs tuaj yeem qhia tau rau kev kho mob ntxov ua ntej kev raug mob tsis zoo (33, 34), txawm li cas los xij, tsis yog txhua tus DSAs raug puas tsuaj los ua kab mob (35) thiab DSA qib yuav tsis cuam tshuam nrog cov ntaub so ntswg raug mob (15). Kev yees duab yees xws li Doppler ultrasonography (Asmeskas), Contrast-enhanced ultrasound (CEUS), thiab Sib Nqus Resonance Imaging (MRI) yog cov txheej txheem uas tsis yog-invasive complementary methodologies siv los pab rau kev kuaj mob ntxov ntawm ob qho tib si mob thiab mob tsis zoo los ntawm kev ntsuam xyuas lub raum vasculature kuj. (Asmeskas) (36, 37), graft blood perfusion (CEUS) (38), thiab anatomical pauv (MRI) xws li fibrosis (39). Txawm li cas los xij, kev tshawb nrhiav los ntawm cov kev ntsuam xyuas no feem ntau tsis yog tshwj xeeb nrog tus nqi tsawg hauv kev coj ua kev kho mob.
Tam sim no, graft biopsies tseem yog tus qauv kub rau kev kuaj mob graft rejection. Graft histology muab cov pov thawj pom pom ntawm lub hauv paus pathology thiab pathogenesis ntawm graft dysfunction. Tsis ntev los no, kev tshuaj ntsuam genetic tsom xam ntawm cov ntaub so ntswg biopsy tau siv los pab hauv kev kuaj mob sib txawv ntawm allograft rejection nrog rau histology thiab immunohistochemistry. Banff kev faib tawm, nrhiav tau nyob rau hauv 1991, tau tsim cov txheej txheem tshwj xeeb rau kev kuaj mob raum allograft rejection. Nws tau hloov kho ntau zaus hauv ob xyoos dhau los (5). C4d complement fragment deposition nyob rau hauv peritubular capillaries raug suav hais tias yog ib qho cim rau ABMR (40) tab sis raug tshem tawm raws li kev kuaj mob hauv qhov tseeb Banff (2019) Classification Criteria rau ABMR active vim qhov tshwm sim ntawm C4d tsis zoo ABMR (41). Txawm hais tias kev kuaj mob histological los ntawm lub raum biopsy tseem yog qhov ntsuas kub ntsuas, nws tsis tuaj yeem ua tiav ntau dhau vim nws qhov cuam tshuam. Ib tug graft koob biopsy tuaj yeem ua rau muaj ntau yam kev phais mob, xws li perinephric hematoma, arteriovenous fistula, los ntshav, kis kab mob. Tsis tas li ntawd, muaj lwm yam kev txwv uas cuam tshuam nrog kev soj ntsuam histological, piv txwv li tsis muaj cov qauv kev ntsuas thiab qhov ntau, qhov ua piv txwv tsis raug, thiab kev kuaj pom tseeb feem ntau vam khom rau cov kws kho mob cov txuj ci (42). Yog li ntawd, cov uas tsis yog-/yam tsawg-invasive thiab kwv yees biomarkers yog heev xav tau rau kev kuaj mob thaum ntxov thiab tsim tsim kom ncua los yog tiv thaiv CKTR thiab txhim kho graft ntev.
POTENTIAL BIOMARKERS rau kev kuaj pom ntxov thiab kev tshaj tawm
Txoj kev loj hlob tsis ntev los no ntawm cov khoom siv cellular thiab molecular biotechnologies tau ua rau muaj kev vam meej loj heev hauv biomarker nrhiav pom hauv thaj tsam ntawm kev hloov pauv, nrog kev cog lus zoo rau kev nkag siab zoo dua thiab kev tswj hwm ntawm CKTR. Kev koom tes ntawm kev tshawb fawb biomarker muaj ntau yam, suav nrog 1) tsim kev pom tshiab rau hauv cov txheej txheem molecular ntawm CKTR, 2) tso cai rau kev kuaj mob ntxov thiab txawv txav, 3) muab kev ntsuam xyuas ntawm kev kho mob, thiab 4) kev kwv yees kwv yees. Cov yam ntxwv tseem ceeb ntawm biomarkers tau raug tshuaj xyuas zoo nyob rau lwm qhov (42–44). Txawm hais tias feem ntau cov kev tshawb fawb tau tsom mus rau kev tshawb nrhiav cov biomarkers uas tsis yog-invasive rau ischemia / reperfusion raug mob thiab mob allograft rejection nyob rau hauv cov ntshav thiab zis (42), ntau yam biomarkers yog tsim los ntawm cov kev tshawb fawb nyob rau hauv lub raum raws tu qauv biopsies thiab cov ntshav thiab zis kuaj yog qhia rau kev kuaj mob thiab prognosticator rau CKTR. Raws li cov yam ntxwv ntawm biomarkers thiab thev naus laus zis siv, biomarkers hais txog CKTR tuaj yeem muab faib ua tsib pawg: transcriptomic biomarkers, Epigenetic biomarkers, Proteomic biomarkers, thiab Metabolomic biomarkers, thiab cellular biomarkers, uas tau sau tseg hauv Table 1, thiab tau tham hauv nqe lus hauv qab no.
Transscriptomic Biomarkers
Cov biomarkers no yog tsim los ntawm high-throughput gene los yog transcriptome profiling, kuj hu ua transcriptomics, siv microarray thiab tiam tom ntej gene sequencing technologies. Cov kev tshawb fawb no tau ua ntau dua ntawm kev kuaj lub raum biopsy raws li lawv muab cov khoom txaus rau RNA rho tawm. Raws li tau teev nyob rau hauv Table 1, cov cim kos npe cuam tshuam nrog fibrosis, i-IFTA, kev tsis lees paub ntev (ABMR thiab TCMR), thiab kev ua tsis tiav tuaj yeem raug txheeb xyuas los ntawm kev txiav txim siab txog cov noob caj noob ces (45–53). Qhov tseem ceeb, cov noob txheej muaj peev xwm kwv yees ntau dua li ntawm cov kev hloov pauv hauv lub hauv paus thiab kev kho mob thiab cov kab mob pathological. Ib qho kev xav los ntawm cov kev tshawb fawb no yog qhov zoo sib xws cov npe kos npe rau kev tsis lees paub mob hnyav kuj yog qhov qhia txog CKTR. Piv txwv li, kev kawm los ntawm Khatri et al. (85) tau nthuav tawm 11 cov noob caj noob ces cuam tshuam nrog kev tsis lees paub thoob plaws cov ntaub so ntswg sib txawv, ntawm cov 7 cov noob (CD6, INPP5D, ISG20, NKG7, PSMB9, RUNX3, thiab TAP1) tau txheeb pom tias yog cov kwv yees rau kev loj hlob ntawm i-IFTA ntawm 24 lub hlis. posttransplant (45) . Qhov zoo tshaj plaws, cov txheej txheem ntawm plaub lub cim cim (vimentin, NKCC2, E-cadherin, thiab 18S rRNA) hauv cov zis kuaj tau raug txheeb xyuas tias yog cov biomarkers uas tsis muaj kev cuam tshuam rau i-IFTA (46).
Epigenetic Biomarkers
Epigenetic modifications thiab regulators tswj cov gene qhia thiab muaj nuj nqi nyob rau hauv cov lus teb rau cov kev hloov ntawm biological txheej txheem thiab li no yuav siv tau raws li tus kab mob biomarkers (86). Kev hloov pauv ntawm Epigenetic suav nrog cytosine methylation ntawm DNA ntawm cytosine-phosphate diester-guanine dinucleotides, microRNA kev cuam tshuam, kev hloov kho histone, thiab chromatin remodeling complexes (87), uas tshwm sim rau genome yam tsis muaj kev hloov pauv ntawm DNA ib ntus. Epigenetics yog ib thaj chaw tshiab ntawm kev tshawb fawb hauvhloov raum. Feem ntau cov kev tshawb fawb tau ua nyob rau hauv cov ntsiab lus ntawm ischemia thiab reperfusion raug mob thiab mob heev rejection, qhia qhov cuam tshuam ntawm aberrant DNA methylation (88). Cov kev tshawb fawb tsis ntev los no hauv tib neeg thiab tsiaj txhu (54, 89) tau pom tias kev hloov pauv hloov pauv hloov pauv, tshwj xeeb yog DNA methylation, cuam tshuam rau kev ua kom muaj zog, kev loj hlob, kev sib txawv, thiab kev tsiv teb tsaws ntawm ntau hom cell, xws li pab T hlwb (90, 91) lossis regulatory T hlwb (54) thiab fibroblast (92), uas muaj feem xyuam rau allograft ciaj sia taus thiab raum fibrosis. Piv txwv li, Foxp3 demethylation ntawm T(reg)-qhov tshwj xeeb demethylation cheeb tsam muaj txiaj ntsig zoo nrog cov lej ntawm intragraft Foxp3- qhia T hlwb hauv cov neeg mob uas tsis lees paub subclinical nrog i-IFTA los ntawm cov txheej txheem biopsies; Yog li ntawd, cov neeg mob uas muaj ntau dua Foxp3 ntxiv rau T(reg) hlwb nyob rau hauv graft infilltrates pom tau tias zoo dua 5-xyoo graft function evolution dua li cov neeg mob uas tsis muaj Foxp3 ntxiv rau T(reg) cell infiltration (54). Boer et al. (55) kawm DNA methylation (DNAm) ntawm pro-inflammatory cytokine interferon g (IFNg) thiab inhibitory receptor programmed tuag 1 (PD1) hauv naïve thiab nco CD8 ntxiv rau T cell subsets hauvhloov raumcov neeg txais. Kev nce DNAm ntawm IFN-g thiab PD1 tau pom hauv nco CD8 ntxiv rau T hlwb hauvhloov raumCov neeg tau txais 3 lub hlis tom qab hloov pauv, tsis hais qhov kev tsis lees paub qhov rov qab los yog tsis, qhia tias nws yog qhov tsis muaj kev hloov pauv cuam tshuam nrog kev hloov pauv lossis siv tshuaj tiv thaiv kab mob. Txawm li cas los xij, PD1 methylation hauv CD27- nco CD8 ntxiv rau T hlwb tau nce ntxiv hauv cov neeg tau txais kev tsis lees paub ntau dua li cov tsis muaj. Hauv kev tshawb fawb tsis ntev los no hais txog lub luag haujlwm ntawm DNAm nyob rau hauv kev loj hlob ntawm IFTA hauv lub raum biopsies, ib txwm allograft biopsies ntawm 2- xyoo tom qab hloov pauv tau pom cov qauv DNAm zoo sib xws piv rau preimplantation biopsies, whereas persistent differential methylation yog txuam nrog kev loj hlob ntawm allografts rau mob raum tsis ua haujlwm allograft (93). Cov txheej txheem Epigenetic xws li hypomethylation tuaj yeem txhawb nqa ncaj qha thiab tsis ncaj qha hloov lawv cov kev qhia los ntawm kev tswj cov miRNAs (93). Cov kev tshawb fawb tsis ntev los no tau qhia tias mi- R21 thiab miR200b qhia hauv cov zis yog txuam nrog IFTA thiab CAD (56) thaum ncig miR-150, miR192, miR-200b, thiab miR-423-3p hauv plasma muaj feem xyuam rau IFTA (57). Lub caij no, kev qhia ntawm miR21, miR-155, thiab miR-142-3p tau nce- tswj hauv cov ntshav ntawm cov neeg mob nrog IFTA (58), thaum miR- 145-5p, thiab miR{24 }}a raug tswj tsis tau (59, 60). Lwm txoj kev tshawb fawb tau pom tias kev qhia ntawm miR-142-3p tau nce- tswj, whereas miR-204 thiab miR-211 tau txo qis- tswj ob qho tib si hauv cov zis thiab lub raum graft ntawm cov neeg tau txais nrog CAD-IFTA (61 ). Tsis tas li ntawd, nce-txoj cai ntawm miR142-5p, thiab kev tswj qis ntawm miR-486-5p tuaj yeem ua haujlwm biomarkers rau kev tshawb pom ntxov ntawm ABMR (62). Cov cim no tuaj yeem, yog li, suav tias yog cov cim muaj peev xwm rau CAD.
Proteomic Biomarkers
Cov qhab nia ntawm non-invasive proteomic biomarkers ntawm CKTR yog tsim los siv high-throughput proteomic cov tswv yim, xws li kua chromatography-mass spectrometry (LC-MS), isobaric tag rau cov txheeb ze thiab tag nrho quantitation (iTRAQ), protein microarray, thiab hlaws-raws li immunoassay . Cov kev tshawb fawb soj ntsuam cov biomarkers tsis-invasive proteomic hauv cov zis thiab ntshav (94), tau pom cov protein tshwj xeeb uas muaj txiaj ntsig zoo rau kev kuaj mob sib txawv. Piv txwv li, ib txoj kev tshawb fawb ntawm 245 cov zis kuaj los ntawm ib tus menyuam yaus thiab cov neeg laus lub raum allograft tau txais kev sib koom ua ke, txheeb xyuas 35 cov proteins uas tuaj yeem cais peb hom kev raug mob graft, 11 peptides rau kev tsis pom zoo, 12 urinary peptides rau mob nephropathy, 12 peptides rau BK virus nephritis (63). Metzger et al. (95) validated ib tug multi-marker urinary peptide classifer tsim los ntawm capillary electrophoresis mass spectrometry (CE-MS) peptide spectra ntawm cov zis los ntawm ib tug kev cob qhia set ntawm 39 allograft cov neeg mob kom cais TCMR los ntawm noj qab haus huv allografts. Srivastava et al. (64, 65) tau txheeb xyuas tias qhov kev nthuav tawm ntawm cov zis ANXA11, Integrin a3, Integrin b3 thiab TNF-a, thiab kev txo qis ntawm cov ntshav PARP1 tuaj yeem siv los ua tus neeg sib tw proteomic biomarkers rau lub raum allograft rejection. Tsis tas li ntawd, ntau cov proteins, qee cov tshuaj chemokines, thiab cytokines hauv cov ntshav thiab cov zis kuj raug txheeb xyuas tias yog biomarkers rau kev kuaj mob CKTR thiab kwv yees qhov tshwm sim ntawm graft (66-71). Ntau qhov kev siv zog tsis ntev los no tau tsim cov zis CXC motif chemokine 9 (CXCL9) thiab CXCL10 ua cov biomarkers txhim khu kev qha rau subclinical allograft rejection thiab rau kev coj noj coj ua tom qab hloov pauv (66, 67). Ib txoj kev tshawb fawb tsis ntev los no qhia tau hais tias platelets muaj ntau yam ntawm cov neeg kho kom haum xeeb uas tuaj yeem txhawb nqa tus mob ABMR (96, 97). Qhov tseeb, platelet yam 4 (PF4, tseem hu ua CXCL4), feem ntau platelet-txog tus neeg nruab nrab uas kuaj pom nyob rau hauv allograft nrog ntau ntau, muaj ntau yam tshwm sim ntawm allografts, ib qho yog los txhawb monocytes ciaj sia thiab macrophage sib txawv (98) , kwv yees cov txiaj ntsig tsis zoo ntawm kev ua txhaum cai (99).
Metabolomic Biomarkers
Metabolomics yog qhov kev tshawb fawb tawm sai sai uas suav nrog kev tshuaj xyuas tag nrho ntawm cov metabolites hauv ib qho qauv lom neeg (100) thiab tsis ntev los no tau txais txiaj ntsig zoo heev hauv kev tshawb fawb biomarker hauv kev hloov pauv hauv nruab nrog cev. Piv nrog rau cov cim proteomic lossis cov cim transcriptomic, cov kab mob metabolomic biomarkers yuav muaj tseeb dua hauv kev cuam tshuam cov haujlwm ntawm tes (101). Metabolomics tuaj yeem siv tau ob txoj hauv kev: kev tshuaj xyuas thiab txheeb xyuas tus kheej cov metabolites; los yog siv tus qauv lees paub los sau cov qauv spectral thiab siv zog es tsis txhob sau cov molecules ntawm tus kheej (100, 102). Cov kws tshawb fawb pom zoo tias cov cim metabolomic txhim kho kev soj ntsuam kev tsis lees paub thiab lwm yam kev raug mob ntawm lub cev (103). Hauv cov menyuam yaus, cov tshuaj urinary metabolomics txhim kho kev kuaj pom ntawm ciam teb TCMR thiab pom cov lus cog tseg hauv ABMR (104). Ntsuas adenosine triphosphate (ATP) tiam los ntawm mitogen-stimulated CD4 lymphocytes (ImmuKnow assay) yog FDA-pom zoo biomarker muaj peev xwm ua tau zoo rau cov neeg tau txais kev hloov pauv (72). Hauv txoj kev tshawb fawb randomized, raws li kev tiv thaiv kab mob qhov tseem ceeb tau txiav txim siab los ntawm ImmuKnow qhov kev ntsuam xyuas, ib xyoos tus neeg mob muaj sia nyob tau zoo zuj zus tuaj thiab kev kis tus kab mob tau txo qis hauv pab pawg tau txais ATP tso tawm biomarker-guided immunosuppressant regulation (105). Hauv kev tshawb fawb tsis ntev los no, ib lub vaj huam sib luag ntawm cuaj qhov sib txawv ntawm cov metabolites hauv cov zis tau txheeb xyuas tias muaj peev xwm metabolite biomarkers tshiab ntawm TCMR (73). Cov metabolomic biomarkers uas suav tias yog cov cim muaj peev xwm rau kev tsis lees paub lub sijhawm muaj npe nyob rau hauv Table 1 (72–78).
Cellular Biomarkers
Muaj cov kev saib xyuas tseem ceeb uas tau kos los txhawm rau txheeb xyuas cov alloreactive CD8 ntxiv rau T hlwb raws li cov cellular biomarkers ntawm kev tsis lees paub (25, 79, 106), lossis kam rau ua (107). Ashokkumar et al. (80) pom tias allospecific CD154 ntxiv rau T-cytotoxic nco hlwb tau cuam tshuam nrog kev pheej hmoo ntawm kev tsis lees paub hauv daim siab hloov pauv. Cov ntaub ntawv txwv tsis pub pom tias qhov nce hauv CD154 ntxiv rau subset cuam tshuam rau qhov mob hnyavhloov raumkev tsis lees paub (81). Cov kev tshawb fawb tsis ntev los no tau pom tias kev saib xyuas cov cim xeeb alloreactive IFN-g- tsim T hlwb tuaj yeem soj ntsuam subclinical TCMR thiab kwv yees de novo DSA (82), thaum qhov piv ntawm T follicular pab hlwb thiab T follicular regulatory hlwb (Tfc / Tfr) yog ib qho kev pheej hmoo ntawm kev ywj pheej. rau CAD (83). Txawm li cas los xij, ntau qhov kev lees paub ntawm nws qhov kev kuaj mob / prognostic biomarker utility hauv CKTR tseem yuav txiav txim siab (108). Ob leeg macrophages thiab NK hlwb cuam tshuam nrog kev tsis lees paub ntev (21, 109-111). Txawm li cas los xij, nws tseem yuav tau txiav txim siab seb puas muaj ib qho tshwj xeeb ntawm macrophages lossis NK hlwb tuaj yeem ua haujlwm ua cov cim cellular rau CKTR. Tsis ntev los no, ib leeg-cell sequencing technologies tau tsim sai heev thiab tau hloov zuj zus raws li ib tug haib cuab tam rau unbiased kev ntsuam xyuas ntawm genomic, epigenomic, thiab transcriptomic profilling nyob rau hauv ib-cell theem. Piv nrog rau cov txheej txheem kev sib txuas ib txwm siv, cov thev naus laus zis ib leeg muaj qhov zoo ntawm kev tshawb xyuas qhov sib txawv ntawm cov tib neeg lub hlwb, paub qhov txawv ntawm cov cell me, thiab delineating cell maps (112, 113). Siv cov txheej txheem scRNA-seq, Liu et al. tau nthuav tawm ntau yam tshiab ntawm cov kab mob tiv thaiv kab mob, suav nrog tsib pawg ntawm NKT hlwb, ob hom subtypes hauv lub cim xeeb B hlwb, pawg CD14 ntxiv rau classic, thiab pawg CD16 ntxiv rau cov neeg mob monocytes, hauv cov neeg mob CKTR. Lawv kuj tau txheeb xyuas qhov tshiab subpopulation [myofibroblasts (MyoF)] hauv fibroblasts, uas qhia txog collagen thiab extracellular matrix Cheebtsam hauv pawg CKTR (84). Thaum tseem nyob rau hauv nws cov me nyuam mos thaum ntxov, scRNA-seq yog suav tias yog ib qho kev kuaj mob rau kev txheeb xyuas cov cellular thiab molecular biomarkers tshwj xeeb rau CKTR. Nrog rau kev nkag siab zoo dua ntawm cov txheej txheem ntawm tes hauv qab CKTR thiab kev nce qib hauv ntau cov xim ntws cytometry kev soj ntsuam ua ke nrog kev txhim kho tsis ntev los no ntawm ib leeg-cell genomics cov kev tshawb fawb, nws pom tau tias cov cellular biomarkers ntau dua yuav raug txheeb xyuas rau CKTR.
Ntau qhov kev txiav txim siab yuav tsum tau hais kom txaus ua ntej cov biomarkers tuaj yeem siv tsis tu ncua hauv kev kho mob rauhloov raum(114–116). Ua ntej, rhiab heev, qhov tshwj xeeb, qhov zoo thiab qhov tsis zoo ntawm qhov kev kwv yees yuav tsum raug txiav txim siab, thiab tus neeg txais kev ua haujlwm yam ntxwv (ROC) nkhaus yuav tsum tau soj ntsuam kom zoo rau lawv cov khoom siv kho mob. Qhov thib ob, kev sib koom ua ke ntawm cov biomarkers sib txawv yog qhov tsim nyog rau kev kuaj mob kom raug. Thib peb, kev tshawb fawb txog kev siv tau zoo thiab kev ntsuas kev ntsuas yuav tsum tau txheeb xyuas cov biomarkers tshiab. Thaum kawg, lub sijhawm xav tau los tsim cov txiaj ntsig thiab tus nqi ntawm kev ntsuas yuav tsum tsim nyog.
Cistanche tuaj yeem tiv thaivraumkab mob
TSHUAJ TIV THAIV KEV KHO MOB CKTR
Kev ua haujlwm ntev ABMR yog qhov pom dav tshaj plaws ntawm kev ua haujlwm tsis ua haujlwm (117), thaum TCMR feem ntau muaj nyob rau hauv ib qho kev tsis lees paub sib xyaw (118). Muab qhov kev nkag siab tam sim no tias TCMR mob ntev heev feem ntau cuam tshuam nrog kev tiv thaiv kab mob tsis txaus, TCMR kev kho mob tau raug qhia kom nce koob tshuaj thiab hom tshuaj tiv thaiv T cell immunosuppressive xws li kev sib txuas ntawm kev kho mob nrog basiliximab, everolimus ntxiv rau tacrolimus (119). Ntau yam kev kho mob tau siv rau hauv qhov chaw kho mob, feem ntau tsom rau kev mob ABMR. Cov tswv yim muaj xws li plasmapheresis, intravenous immunoglobulin (IVIG), CD20 antibody (rituximab), proteasome inhibitor (bortezomib) (120–122), thiab anti-complement monoclonal antibody (eculizumab), kev kho ib leeg lossis ua ke (123, 124). Lawv cov txiaj ntsig kho tau zoo hauv kev kho mob ntev ntev ABMR tau raug soj ntsuam hauv cov kev sim ntsuas tsis ntev los no thiab cov txiaj ntsig tau raug tshuaj xyuas ntau (125), qhia tias tsis muaj kev vam meej tau ua tiav los ntawm kev siv cov tshuaj no ib leeg lossis ua ke txawm tias lawv muaj txiaj ntsig hauv kev kho mob ABMR. Los ntawm kev tshawb pom biomarker, kev nkag siab ntawm CKTR tau txhim kho zoo heev nyob rau tsib xyoos dhau los. Kev lees paub txog kev lom neeg zoo sib xws los ntawm CKTR, kev tiv thaiv kab mob qog noj ntshav, thiab kab mob autoimmune tau ua rau muaj kev tshawb nrhiav pem hauv ntej hauv kev rov ua dua ntawm ntau cov tswv yim kho mob los ntawm kev kho mob qog noj ntshav lossis kab mob autoimmune rau ABMR. IL-6/IL-6R blockade (Tocilizumab), C1 esterase inhibitor (C1 INH), thiab B-lymphocyte stimulator (BLyS) inhibitor (Belimumab) yog cov uas tau sim rau lawv cov peev xwm kho tau. hauv kev txo qis ABMR thiab tau pom cov txiaj ntsig tau zoo raws li tau piav qhia hauv qab no thiab sau tseg hauv Table 2.
IL-6/IL-6R Blockade
IL-6 yog ib qho pleiotropic cytokine cuam tshuam nrog ntau yam ntawm innate thiab adaptive tiv thaiv kab mob, uas plays lub luag hauj lwm tseem ceeb nyob rau hauv DSA tiam thiab ntev ABMR, nrog rau nws cov teebmeem ntawm B cell tiv thaiv kab mob thiab antibody-tsim plasma hlwb, nrog rau cov Kev sib npaug ntawm effector thiab tswj T hlwb (130). Blockade ntawm IL-6/IL-6R axis nrog Tocilizumab, anti –interleukin-6 receptor monoclonal antibody tau tsim zoo rau kev kho mob rheumatoid mob caj dab (131), thiab tsis ntev los no suav tias yog kev kho tshiab los tiv thaiv ABMR kev loj hlob (126). Nws tau pom tias tocilizumab tau txo qis DSAs thiab ua kom lub raum ua haujlwm ruaj khov ntawm 2 xyoos tom qab hloov pauv, qhia txog kev kho mob ntawm tocilizumab hauv ABMR. Tocilizumab kuj tau raug soj ntsuam ua ke nrog IVIG thiab rituximab rau cov neeg mob uas ua tsis tau raws li tus qauv desensitization, thiab nws tshwm sim tau zoo thiab muaj kev nyab xeeb (132). Txawm li cas los xij, tseem tsis tau muaj kev sim tshuaj ntsuam xyuas los ntsuas qhov ua tau zoo thiab kev nyab xeeb ntawm tocilizumab los txog niaj hnub no. Lwm tus tshiab inhibitor rau IL-6/IL-6R axis yog canakinumab, ib qho tshuaj genetic engineered humanized monoclonal antibody qhia tawm tsam IL-6. Ob qhov kev sim sim (NCT03444103, NCT03380377) (132– 134) thiab ib qho kev sim loj multicenter soj ntsuam canakinumab nyob rau hauv lig / chronic ABMR (NCT03744910) (135) tab tom ua.
C1 Esterase Inhibitor (C1 INH)
Txij li thaum qhov ua tau zoo ntawm C5 blockade nyob rau hauv lig ABMR yog txwv (123, 124), qhov blockade ntawm txoj kev ntxiv thaum ntxov ntawm theem ntawm cov ntsiab lus tseem ceeb C1 tau nyiam ntau yam ntawm kev mloog. Ib lub tswv yim muaj peev xwm tau kawm yog kev siv C1 INH, uas tau siv los tiv thaiv thiab / lossis kho kev tawm tsam ntawm cov kab mob angioedema tau ntau xyoo thiab tau tsim cov ntaub ntawv kev nyab xeeb (136). C1-INH yog cov tshuaj tiv thaiv kab mob ntshav qab zib uas khi covalently thiab inactivates C1r, C1s, thiab mannan-binding protein-associated proteases (136, 137). Hauv ob qhov muag tsis pom RCT, C1-INH raug kuaj raws li kev kho mob rau ABMR. Ob pawg C1-INH thiab cov placebo tau pom tias muaj kev txhim kho hauv kev rov qab kuaj xyuas thaum ntxov. Txawm li cas los xij, hauv ib pawg ntawm cov neeg mob uas muaj kev soj ntsuam kuaj mob lig (6 lub hlis), qhov txo qis ntawm kev hloov pauv hauv glomerulopathy tau pom nyob rau hauv C1-INH pab pawg kho mob, nrog rau kev txhim kho graft muaj nuj nqi, qhia C1- NIH tuaj yeem ua tau zoo los tiv thaiv kev txhim kho ntawm kev raug mob ntev (127). Nyob rau hauv ib tug yav tom ntej, ib leeg-caj npab pilot soj ntsuam sim, C1-INH tau ntxiv rau IVIG los kho refractory mob ABMR. Hauv kev sib piv nrog cov kev tswj xyuas keeb kwm, cov neeg mob kho nrog C1-INH tau pom tias C4d txo qis thiab txhim kho lub raum kev ua haujlwm, qhov kev puas tsuaj microcirculatory tseem pheej muaj (glomerulitis, peritubular capillaritis, thiab allograft glomerulopathy) (128). Tam sim no, ntau qhov chaw kho mob loj loj ntsuas C1-INH ntxiv rau kev kho tus qauv ntawm ABMR (NCT02547220) (138) tab tom tab tom ua, thaum lwm qhov kev sim tshuaj ntsuam xyuas C1-NIH rau kev kho mob ntawm refractory AMR (NCT03221842) Hauv cov neeg tau txais kev hloov pauv lub raum (139) tseem tab tom ua.
Inhibition ntawm B-lymphocyte Stimulator
B-lymphocyte stimulator (BLyS) yog ib qho tseem ceeb cytokine uas txhim kho B cell thiab plasma cell ciaj sia taus (140). Targeting BLyS tsis ntev los no tau ua rau muaj kev txaus siab rau kev hloov pauv los ntawm kev hloov B cell alloimmunity. Belimumab, humanized anti-BLyS antibody, uas tau qhia txog kev kho mob zoo hauv lub cev lupus erythematosus (141), tam sim no tau siv rau hauv kev hloov pauv hauv nruab nrog cev. Hauv ob qhov muag tsis pom kev, randomized, placebo-tswj theem 2 sim, belimumab tau soj ntsuam hauv 28hloov raumcov neeg txais(129). Cov kev tshawb pom tau qhia tias kev kho mob ntawm belimumab tsis cuam tshuam rau kev txo qis ntawm cov hlwb tsis zoo B los ntawm lub hauv paus mus rau 24 lub lis piam tom qab hloov. Txawm li cas los xij, activated memory B hlwb thiab plasmablasts tau txo qis, thiab cov ntaub so ntswg tshwj xeeb cov tshuaj tiv thaiv hauv cov ntshav tau qis dua. Tsis tas li ntawd, kev kho mob nrog belimumab tau hloov kho B cell profile ntawm kev tswj hwm tus lej los ntawm kev hloov pauv IL-10/IL-6 piv. Nyob rau tib lub sijhawm, cov noob coding rau IgG thiab cov cim ntawm T cell proliferation raug txo qis (129). Txog niaj hnub no, tseem tsis tau muaj kev sim tshuaj kho mob siv belimumab los kho qhov tsis lees paub ntev. Hauv murine mob ABMRhloov raumqauv, blockade ntawm APRIL / BLyS los ntawm TAC-Ig ua rau txo qis antinuclear antibody (ANA) thiab cuam tshuam ntawm splenic germinal center architecture, tab sis tsis muaj qhov txawv txav ntawm lymphocyte infiltration thiab lub raum graft pathology piv nrog kev tswj grafts, uas tej zaum yuav yog vim lub tsis muaj T cell immunosuppression (142).
XAIV
Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb yav dhau los yuav tsis tsuas yog tso cai rau kev tsim kho tus kheej rau kev kho mob raws sij hawm tab sis kuj tseem ntxiv kev nkag siab txog cov kab mob ntawm CKTR. Txawm hais tias muaj ntau tus biomarkers teev nyob rau hauv Table 1 tseem xav tau kev lees paub thiab kev tsim qauv hauv ntau pawg neeg ywj pheej, muaj kev vam meej ntau tau ua nyob rau xyoo tas los no (115, 116, 143). Kev tswj hwm ntawm CKTR tseem yog ib txoj haujlwm txaus ntshai vim yog qhov nyuaj ntawm pathogenesis ntawm CKTR thiab nws cov irreversibility thaum lub sijhawm kuaj mob. Txawm li cas los xij, ntau txoj kev kho mob tau zoo tau nyob rau hauv kev cuam tshuam kev sim siab nrog cov txiaj ntsig tau zoo. Nrog rau qhov tshwm sim ntawm cov thev naus laus zis tshiab, xws li ib leeg-cell genomics, kev ua lej biology nrog kev pabcuam kev txawj ntse-raws li kev txawj ntse, nws pom tau tias ntau qhov tshwj xeeb biomarkers thiab cov hom phiaj kho mob rau CKTR yuav raug txheeb xyuas thiab muab txhais rau hauv kev kho mob yav tom ntej.
AUTHOR CONTRIBUTIONS
XL thiab XZ: koom nrog kev npaj thiab sau ntawv. JM, LG, thiab JL: muab tswv yim thiab kho. ZZ conceptualized, sau, thiab kho cov ntawv sau Tag nrho cov kws sau ntawv tau pab txhawb rau tsab xov xwm thiab pom zoo rau cov ntawv xa tawm.
1 Kev Hloov Pauv Hloov Chaw, Northwestern University Feinberg Tsev Kawm Ntawv Tshuaj, Chicago, IL, Tebchaws Asmeskas,
2 Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, Tebchaws Asmeskas,
3 Organ Transplant Center, Lub Tsev Kho Mob Thib Ob ntawm Guangzhou Medical University, Guangzhou, Suav,
4 Department of Urology, Beijing Youan Tsev Kho Mob, Capital Medical University, Beijing, Suav teb,
5 Department of Medicine, Nephrology, Northwestern University Feinberg Tsev Kawm Ntawv Tshuaj, Chicago, IL, United States
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