Increased Complement Gene Expression in Circulating B Cells From Kidney Transplant Recipients With Chronic Antibody-Mediated Rejection.
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SUBMITTER: Cravedi P
PROVIDER: S-EPMC9727519 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Increased Complement Gene Expression in Circulating B Cells From Kidney Transplant Recipients With Chronic Antibody-Mediated Rejection.
Cravedi Paolo P Bruschi Maurizio M Pontrelli Paola P Grandaliano Giuseppe G Zaza Gianluigi G Fribourg Miguel M
Kidney international reports 20220930 12
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Project description:The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.
| S-EPMC4483591 | biostudies-literature
Project description:Complement activation is an important cause of tissue injury in patients with Ab-mediated rejection (AMR) of transplanted organs. Complement activation triggers a strong inflammatory response, and it also generates tissue-bound and soluble fragments that are clinically useful markers of inflammation. The detection of complement proteins deposited within transplanted tissues has become an indispensible biomarker of AMR, and several assays have recently been developed to measure complement activation by Abs reactive to specific donor HLA expressed within the transplant. Complement inhibitors have entered clinical use and have shown efficacy for the treatment of AMR. New methods of detecting complement activation within transplanted organs will improve our ability to diagnose and monitor AMR, and they will also help guide the use of complement inhibitory drugs.
| S-EPMC4672393 | biostudies-literature
Project description:There is limited information on the value of short-term invasive and noninvasive monitoring in kidney transplant recipients (KTR) undergoing therapy for chronic active antibody-mediated rejection (cAMR).MethodsWe describe response rates in patients with cAMR receiving pulse steroids/IVIG ± rituximab 3-mo after index biopsy.ResultsThe study included 82 consecutive KTR. Mean time from transplant to cAMR was 10 y. Mean peritubular capillaritis (ptc), glomerulitis (g), microvascular inflammation (MVI), C4d, and cg Banff scores were 1.1, 2.1, 3.2, 0.2, and 2, respectively. Mean estimated glomerular filtration rate (eGFR) and urine protein creatinine (UPC) ratio were 38 mL/min and 1.6 g/g, respectively. Thirty (37%) patients lost their allograft during the mean follow-up of 2.4 y. In patients treated with pulse steroids/IVIG (n = 41), response rates for eGFR, UPC, donor-specific antibodies (DSAs), and MVI were 27%, 49%, 7%, and 19%, respectively. In the pulse steroids/IVIG/rituximab group, response rates were 66%, 61%, 20%, and 69%, respectively. Univariate analysis identified response in eGFR (HR = 0.03; P = 0.001; 95% CI, 0.004-0.26), UPC (HR = 0.38; P = 0.01; 95% CI, 0.18-0.82), and DSA (HR = 0.11; P = 0.004; 95% CI, 0.02-0.49) as predictors of graft survival. Multivariate analysis only retained eGFR response (HR = 0.12; P = 0.01; 95% CI, 0.02-0.64).ConclusionsIn cAMR, short-term response to treatment for kidney function and DSA was associated with graft survival, but the role of early surveillance biopsies needs further evaluation.
| S-EPMC9355109 | biostudies-literature
Project description:Antibody mediated transplant rejection (AMR) is a major cause of long-term allograft failure, and currently available treatments are of limited efficacy for treating the disease. AMR is caused by donor specific antibodies (DSA) that bind to antigens within the transplanted organ. DSA usually activate the classical pathway of complement within the allograft, and complement activation is believed to be an important cause of tissue injury in AMR. Several new clinical assays may improve our ability to identify patients at risk of AMR. Complement inhibitory drugs have also been tested in selected patients and in small series. Better understanding of the role of complement activation in the pathogenesis of AMR will likely improve our ability to diagnose the disease and to develop novel treatments.
| S-EPMC6646053 | biostudies-literature
Project description:In this study, we investigated whether CD161+CD4+ T cells can reflect the Th17 pathway in kidney transplant recipients (KTRs) and investigated the clinical significance of this cell type in chronic antibody-mediated rejection (cAMR) in KT. First, we investigated the relationship between CD161+CD4+ T and Th17 cells by flow cytometry and microarray analysis in an in vitro study. Second, we compared the proportion of T cell subsets including CD161+CD4+ T cells in cAMR (n = 18), long-term graft survival (LTGS) (n = 46), and interstitial fibrosis/tubular atrophy (IF/TA) (n = 22). We compared CD161+ cell infiltration between cAMR and IF/TA and also examined the effect of CD161+ T cells on human renal proximal tubular epithelial cells (HRPTEpiC). In flow cytometry, the proportion of CD161+CD4+ T cells showed a significant correlation with the proportion of Th17 cells. In microarray analysis, transcripts associated with the Th17 pathway such as IL18RAP, IL-18R1, IL23R, IL12RB2, RORC, TBX21, and EOMES were upregulated in CD161+ cells compared with CD161- cells. In an ex vivo study, only CD161+CD4+ T cells showed a significant increase in the cAMR group compared with IF/TA and LTGS groups. In allograft tissue, CD161+ cells showed a higher level of infiltration in the cAMR group than the IF/TA group. Lastly, CD161+ T cells increased the production of inflammatory cytokines from HRPTEpiC in a dose-dependent manner. This study suggests that monitoring of CD161+ T cells can be useful to detect the progression of cAMR.
| S-EPMC6047803 | biostudies-literature
Project description:BackgroundElevated levels of donor-derived cell-free DNA (dd-cfDNA) in the plasma of renal allograft recipients indicates organ injury and an increased probability of active rejection. Donor-specific antibodies (DSA) to HLA antigens are associated with risk of antibody-mediated rejection (ABMR). This study assessed the combined use of dd-cfDNA and DSA testing to diagnose active ABMR.MethodsDonor-derived cell-free DNA was assayed in 90 blood samples with paired DSA and clinically indicated biopsies from 87 kidney transplant patients. Sixteen cases met criteria for active ABMR. Performance characteristics of dd-cfDNA for diagnosis of active ABMR were determined for samples with prior or current positive DSA (DSA+, n = 33).ResultsThe median level of dd-cfDNA (2.9%) in DSA+ patients with active ABMR was significantly higher than the median level (0.34%) in DSA+ patients without ABMR (P < 0.001). The median level of dd-cfDNA in DSA- patients was 0.29%. The positive predictive value of dd-cfDNA (at 1%) to detect active ABMR in DSA+ patients was 81%, whereas the negative predictive value was 83%. The positive predictive value for DSA+ alone was 48%.ConclusionsThe combined use of dd-cfDNA and DSA testing may improve the noninvasive diagnosis of active ABMR in kidney transplant patients. Patients with dd-cfDNA+/ DSA+ results have a high probability of active ABMR.
| S-EPMC6133406 | biostudies-literature
Project description:BackgroundCorrelation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved.MethodsWe retrospectively assessed patients with transplant biopsies scored following Banff'15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (AT1R)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMRh) with and without HLA-DSA.ResultsOne-hundred eighteen patients with normal histology (n = 19), ABMRh (n = 52) or IFTA (n = 47) were studied. ABMRh patients were HLA-DSApos (n = 38, 73%) or HLA-DSAneg (n = 14, 27%). Pre-transplant HLA-DSA and AT1R-Ab were more frequent in ABMRh compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRhDSAneg cases showed non-HLA antibodies. ABMRhDSAneg and ABMRhDSApos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRhDSApos but not with ABMRhDSAneg. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31-10.37], p = 0.013) and AT1R-Ab (OR: 5.47 [1.78-16.76], p = 0.003) were independent predictors of ABMRhDSApos.ConclusionsIn conclusion, pre-transplant AT1R-Ab is frequently found in ABMRhDSApos patients. However, AT1R-Ab, MICA-Ab, ETAR-Ab or EC-XM+ are rarely found among ABMRhDSAneg patients. Pre-transplant AT1R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMRhDSApos but not ABMRhDSAneg. HLA epitope mismatch associates with ABMRhDSApos compared with ABMRhDSAneg, suggesting factors other than HLA are responsible for the damage.
| S-EPMC8300190 | biostudies-literature
Project description:Current desensitization and maintenance immunosuppression regimens for kidney transplantation in sensitized individuals show limited ability to control the posttransplant humoral response, resulting in high rates of antibody-mediated rejection (ABMR) and graft failure. Here, we showed that anti-CD154 monoclonal antibody (mAb)-based immunosuppression more effectively controlled allograft rejection and humoral rebound in a highly sensitized nonhuman primate kidney transplantation model compared with tacrolimus-based standard-of-care (SOC) immunosuppression. Desensitization with an anti-CD154 mAb (5C8) and a proteasome inhibitor led to decreased donor-specific antibodies (DSAs) and disruption of lymph node germinal centers with reduction of proliferating, memory, and class-switched B cells as well as T follicular helper cells. After transplant, the nonhuman primates maintained on 5C8-based immunosuppression had significantly better survival compared with those maintained on SOC immunosuppression (135.2 days versus 32.8 days, P = 0.013). The 5C8-treated group demonstrated better suppression of DSAs after transplant, more robust suppression of B cell populations, and better induction of regulatory T cells. Fewer infectious and welfare complications, including viral reactivation and weight loss, were also observed with 5C8-based immunosuppression compared with SOC immunosuppression. Therefore, anti-CD154 mAbs may improve kidney transplant outcomes through better control of posttransplant immune responses. The superior efficacy of anti-CD154 mAb-based immunosuppression over tacrolimus-based SOC seen in this highly sensitized NHP transplant model suggests that anti-CD154 mAbs could potentially be used to desensitize and treat highly sensitized patients receiving kidney transplantation.
| S-EPMC11797747 | biostudies-literature
Project description:IntroductionAntibody-mediated rejection (ABMR) impacts kidney allograft outcome. The diagnosis is made based on findings from invasive kidney transplant biopsy specimens. The aim of this study was to identify a noninvasive urinary protein biomarker for ABMR after kidney transplantation.MethodsWe performed a multicenter case-control study to identify a urinary biomarker for ABMR (training cohort, n = 249) and an independent, prospective multicenter cohort study for validation (n = 391). We used concomitant biopsies to classify the samples according to the Banff classification. After untargeted protein identification and quantification, we used a support vector machine to train the model in the training cohort. The primary endpoint was the diagnostic accuracy of the urinary biomarker for ABMR in the validation cohort.ResultsWe identified a set of 10 urinary proteins that accurately discriminated patients with (n = 60) and without (n = 189) ABMR in the training cohort with an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.96-1.00). The diagnostic accuracy was maintained in the validation cohort (AUC, 0.88; 95% CI, 0.8-0.93) for discriminating the presence (n = 43) from the absence (n = 348) of ABMR. The negative predictive value of the 10-protein marker set for exclusion of ABMR was 0.99, and the positive predictive value was 0.33. The diagnostic accuracy was independent of the reason for performing the biopsy, time after transplantation, and better than the accuracy of gross proteinuria (AUC, 0.76).ConclusionsWe identified and validated a urinary protein biomarker set that can be used to exclude ABMR.
| S-EPMC7486186 | biostudies-literature
Project description:Antibody-mediated rejection (ABMR) is an important risk of allograft dysfunction in kidney transplantation. The complement system is considered to be associated with the generation of alloreative antibodies and donor-specific antibodies. However, the association of complement single nucleotide polymorphisms (SNPs) with ABMR still remained unclear. Blood samples of 199 renal transplant recipients containing 68 with ABMR and 131 with stable graft function were collected, and analyzed by next-generation sequencing with an established gene panel. High quality readout was obtained in 18 C3 SNPs, 9 C4 SNPs and 22 C5 SNPs. Concerning C3 gene polymorphisms, after being adjusted with age, sex and immunosuppressive protocols, rs10411506 and rs2230205 were found to be statistically associated with ABMR in dominant model (rs10411506: OR=2.73, 95% CIs: 1.16, 6.68, P=0.028; rs2230205: OR=2.52, 95% CIs: 1.07, 5.92, P=0.034); rs10411506, rs2230205 and rs2230201 were found different in HET model (rs10411506: OR=3.05, 95% CIs: 1.22, 7.64, P=0.017; rs2230205: OR=2.90, 95% CIs: 1.20, 7.00, P=0.018; rs2230201: OR=2.41, 95% CIs: 1.03, 5.64, P=0.042). The linkage analysis showed relatively high linkage disequilibrium among these SNPs. In addition, no significant correlation was found between C4 SNPs, or C5 SNPs, and the development of ABMR. Our study firstly identified the two SNPs (rs10411506 and rs2230205) in C3 gene were statistically correlated with ABMR in kidney transplantation. These findings may have implications for the diagnosis and prevention of ABMR.
| S-EPMC5706894 | biostudies-literature