Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin ...C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Identifying the cause of renal allograft dysfunction is important for the clinical management of kidney transplant recipients.
Purpose
To evaluate the diagnostic efficiency of diffusion ...tensor imaging (DTI) for identifying allografts with acute rejection (AR) and chronic allograft nephropathy (CAN).
Study Type
Prospective.
Subjects
Seventy‐seven renal transplant patients (aged 42.5 ± 9.5 years), including 29 patients with well‐functioning stable allografts (Control group), 25 patients diagnosed with acute rejection (AR group), and 23 patients diagnosed with chronic allograft nephropathy (CAN group).
Field Strength/Sequence
1.5 T/T2‐weighted imaging and DTI.
Assessment
The serum creatinine, proteinuria, pathologic results, and fractional anisotropy (FA) values were obtained and compared among the three groups.
Statistical Test
One‐way analysis of variance; correlation analysis; independent‐sample t‐test; intraclass correlation coefficients and receiver operating characteristic curves. Statistical significance was set to a P‐value <0.05.
Results
The AR and CAN groups presented with significantly elevated serum creatinine as compared with the Control group (191.8 ± 181.0 and 163.1 ± 115.8 μmol/L vs. 82.3 ± 20.9 μmol/L). FA decreased in AR group (cortical/medullary: 0.13 ± 0.02/0.31 ± 0.07) and CAN group (cortical/medullary: 0.11 ± 0.02/0.27 ± 0.06), compared with the Control group (cortical/medullary: 0.15 ± 0.02/0.35 ± 0.05). Cortical FA in the AR group was higher than in the CAN group. The area under the curve (AUC) for identifying AR from normal allografts was 0.756 and 0.744 by cortical FA and medullary FA, respectively. The AUC of cortical FA and medullary FA for differentiating CAN from normal allografts was 0.907 and 0.830, respectively. The AUC of cortical FA and medullary FA for distinguishing AR and CAN from normal allografts was 0.828 and 0.785, respectively. Cortical FA was able to distinguish between AR and CAN with an AUC of 0.728.
Data Conclusion
DTI was able to detect patients with dysfunctional allografts. Cortical FA can further distinguish between AR and CAN.
Evidence Level
2
Technical Efficacy
Stage 2
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Single‐antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts ...have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor‐specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single‐antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third‐party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death‐censored graft survival (DCGS) and risk factors for rejection. Antibody‐mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell‐mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization.
When stratifying kidney transplant recipients by sensitization history and day of transplant serum analysis, univariate and multivariate analysis reveals donor‐specific sensitization to be the most important risk factor for rejection.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), ...neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.
Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.
In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute antibody-mediated rejection (AAMR) is an important cause of cardiac allograft dysfunction, and more effective strategies need to be explored to improve allograft prognosis. Interleukin ...(IL)-6/IL-6R signaling plays a key role in the activation of immune cells including B cells, T cells and macrophages, which participate in the progression of AAMR. In this study, we investigated the effect of IL-6/IL-6R signaling blockade on the prevention of AAMR in a mouse model. We established a mouse model of AAMR for cardiac transplantation
presensitization of skin grafts and addition of cyclosporin A, and sequentially analyzed its features. Tocilizumab, anti-IL-6R antibody, and recipient IL-6 knockout were used to block IL-6/IL-6R signaling. We demonstrated that blockade of IL-6/IL-6R signaling significantly attenuated allograft injury and improved survival. Further mechanistic research revealed that signaling blockade decreased B cells in circulation, spleens, and allografts, thus inhibiting donor-specific antibody production and complement activation. Moreover, macrophage, T cell, and pro-inflammatory cytokine infiltration in allografts was also reduced. Collectively, we provided a highly practical mouse model of AAMR and demonstrated that blockade of IL-6/IL-6R signaling markedly alleviated AAMR, which is expected to provide a superior option for the treatment of AAMR in clinic.
Introduction: Identification of allograft injury, including acute clinical and subclinical injury, is vital in increasing the longevity of the transplanted organ. Acute rejection, which occurs as a ...result of a variety of immune and non-immune factors including the infiltration of immune cells and antibodies to the donor specific epitopes, poses a significant risk to the organ. Recent years have marked an increase in the discovery of new genomic, transcriptomic, and proteomic biomarkers in molecular diagnostics, which offer better potential for personalized management of the transplanted organ by providing earlier detection of rejection episodes.
Areas covered: This review was compiled from key word searches of full-text publications relevant to the field.
Expert commentary: Many of the recent advancements in the molecular diagnostics of allograft injury show much promise, but before they can be fully realized further validation in larger sample sets must be conducted. Additionally, for better informed therapeutic decisions, more work must be completed to differentiate between different causes of injury. Moreover, the diagnostics field is looking at methodologies that allow for multiplexing, the ability to identify multiple targets simultaneously, in order to provide more robust biomarkers and better understanding.
CTLA4Ig has been shown to improve kidney allograft function, but an increased frequency of early rejection episodes poses a major obstacle for more widespread clinical use. The deleterious effect of ...CTLA4Ig on Treg numbers provides a possible explanation for graft injury. Therefore, we aimed at improving CTLA4Ig's efficacy by therapeutically increasing the number of Tregs. Murine cardiac allograft transplantation (BALB/c to B6) was performed under CTLA4Ig therapy modeled after the clinically approved dosing regimen and Tregs were transferred early or late after transplant. Neither early nor late Treg transfer prolonged allograft survival. Transferred Tregs were traceable in various lymphoid compartments but only modestly increased overall Treg numbers. Next, we augmented Treg numbers in vivo by means of IL2 complexes. A short course of IL2/anti‐IL2‐complexes administered before transplantation reversed the CTLA4Ig‐mediated decline in Tregs. Of note, the addition of IL2/anti‐IL2‐complexes to CTLA4Ig therapy substantially prolonged heart allograft survival and significantly improved graft histology on day 100. The depletion of Tregs abrogated this effect and resulted in a significantly diminished allograft survival. The increase in Treg numbers upon IL2 treatment was associated with a decreased expression of B7 on dendritic cells. These results demonstrate that therapy with IL2 complexes improves the efficacy of CTLA4Ig by counterbalancing its unfavorable effect on Tregs.
In vivo expansion of Tregs by IL‐2 complexes acts synergistically with CTLA4Ig therapy to down regulate available B7 on antigen‐presenting cells.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features.
We performed a ...retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction.
We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days.
Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR.
In kidney transplantation, the use of minimally invasive damage biomarkers that are more sensitive and specific than plasma creatinine will be crucial to enable early, actionable detection or ...exclusion of structural kidney damage due to acute or chronic rejection. Donor-derived cell-free DNA (dd-cfDNA), which can be quantified, for example, through next-generation sequencing, droplet digital PCR and quantitative PCR, is a candidate biomarker with great potential for enabling comprehensive monitoring of allograft injury. dd-cfDNA has a favourable overall diagnostic performance for the detection of rejection and its high negative predictive value might be especially useful for avoiding unnecessary biopsies. Elevated dd-cfDNA levels have been shown to be detectable before graft injury can be clinically identified using current diagnostic methods. Moreover, dd-cfDNA falls rapidly to baseline levels after successful treatment for rejection owing to its short half-life. dd-cfDNA can detect graft injury caused by immune activation owing to insufficient immunosuppression and might therefore also help guide immunosuppression dosing. The fractional abundance of dd-cfDNA can be affected by changes in the recipient cfDNA (for example, due to infection or physical exercise) but the use of absolute quantification of dd-cfDNA overcomes this limitation. Serial dd-cfDNA determinations might therefore facilitate cost-effective personalized clinical management of kidney transplant recipients to reduce premature graft loss.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Single-center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute rejection.
The goal of this study was to validate ...whether IMR measured early after transplantation can predict subsequent acute rejection and long-term outcome in a large multicenter cohort.
From 5 international cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was acute allograft rejection (AAR) within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE) (the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission) at 10 years.
IMR was measured at a median of 7 weeks (interquartile range: 3-10 weeks) post-transplantation. At 1 year, the incidence of AAR was 14.4%. IMR was associated proportionally with the risk of AAR (per increase of 1-U IMR; adjusted hazard ratio aHR: 1.04; 95% confidence interval CI: 1.02-1.06; p < 0.001). The incidence of AAR in patients with an IMR ≥18 was 23.8%, whereas the incidence of AAR in those with an IMR <18 was 6.3% (aHR: 3.93; 95% CI: 1.77-8.73; P = 0.001). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-U IMR; aHR: 1.02; 95% CI: 1.01-1.04; P = 0.005).
IMR measured early after heart transplantation is associated with subsequent AAR at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized posttransplantation management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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