Dataset Information

Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages in a Rat Kidney Transplant Model.

ABSTRACT: BACKGROUND:Increasingly, it is being appreciated that B cells have broad roles beyond the humoral response and are able to contribute to and regulate inflammation. The specific role of B cells in the pathogenesis of early allograft inflammation remains unclear. METHODS:To address this question, we generated B cell-deficient (B) Lewis rats via clustered regularly interspaced short palindromic repeats (CRISPR) technology. In a full mismatch transplant model, kidneys from Brown Norway donors were transplanted into B Lewis recipients or wild type Lewis recipients. T cell-mediated rejection was attenuated with cyclosporine. RESULTS:Renal inflammation was reduced at 1 week after transplant (Banff scores for interstitial inflammation, microvascular inflammation, glomerulitis, and C4d) in allografts from B recipients. The reduction in interstitial inflammation was predominantly due to a decline in graft infiltrating macrophages. Intragraft T-cell numbers remained unchanged. In addition, B-cell deficiency was associated with increased T regulatory cells and reduced splenic T follicular helper cells at baseline; and significantly increased intragraft and splenic IL-10 mRNA levels after transplant. In vitro, B and wild type splenic T cells produced similar levels of IFN-? in response to T cell-specific activation. CONCLUSIONS:B-cell deficiency in this model produced an anti-inflammatory phenotype with a shift toward regulatory T-cell populations, production of anti-inflammatory cytokines (IL-10), and a reduction in allograft inflammation. These findings define a role for B cells to influence the cell populations and mediators involved in the pathogenesis of early allograft inflammation.

SUBMITTER: Panzer SE

PROVIDER: S-EPMC5820216 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages in a Rat Kidney Transplant Model.

Panzer Sarah E SE Wilson Nancy A NA Verhoven Bret M BM Xiang Ding D Rubinstein C Dustin CD Redfield Robert R RR Zhong Weixiong W Reese Shannon R SR

Transplantation 20180301 3

<h4>Background</h4>Increasingly, it is being appreciated that B cells have broad roles beyond the humoral response and are able to contribute to and regulate inflammation. The specific role of B cells in the pathogenesis of early allograft inflammation remains unclear.<h4>Methods</h4>To address this question, we generated B cell-deficient (B) Lewis rats via clustered regularly interspaced short palindromic repeats (CRISPR) technology. In a full mismatch transplant model, kidneys from Brown Norwa ...[more]

PMID: 29215459

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Project description:Long-term kidney transplant (KT) allograft outcomes have not improved as expected despite a better understanding of rejection and improved immunosuppression. Previous work had validated a computed rejection score, the tissue common rejection module (tCRM), measured by amplification-based assessment of 11 genes from formalin-fixed paraffin-embedded (FFPE) biopsy specimens, which allows for quantitative, unbiased assessment of immune injury. We applied tCRM in a prospective trial of 124 KT recipients, and contrasted assessment by tCRM and histology reads from 2 independent pathologists on protocol and cause biopsies post-transplant. Four 10-?m shaves from FFPE biopsy specimens were used for RNA extraction and amplification by qPCR of the 11 tCRM genes, from which the tCRM score was calculated. Biopsy diagnoses of either acute rejection (AR) or borderline rejection (BL) were considered to have inflammation present, while stable biopsies had no inflammation. Of the 77 biopsies that were read by both pathologists, a total of 40 mismatches in the diagnosis were present. The median tCRM scores for AR, BL, and stable diagnoses were 4.87, 1.85, and 1.27, respectively, with an overall significant difference among all histologic groups (Kruskal-Wallis, p < 0.0001). There were significant differences in tCRM scores between pathologists both finding inflammation vs. disagreement (p = 0.003), and both finding inflammation vs. both finding no inflammation (p < 0.001), along with overall significance between all scores (Kruskal-Wallis, p < 0.001). A logistic regression model predicting graft inflammation using various clinical predictor variables and tCRM revealed the tCRM score as the only significant predictor of graft inflammation (OR: 1.90, 95% CI: 1.40-2.68, p < 0.0001). Accurate, quantitative, and unbiased assessment of rejection of the clinical sample is critical. Given the discrepant diagnoses between pathologists on the same samples, individuals could utilize the tCRM score as a tiebreaker in unclear situations. We propose that the tCRM quantitative score can provide unbiased quantification of graft inflammation, and its rapid evaluation by PCR on the FFPE shave can become a critical adjunct to help drive clinical decision making and immunosuppression delivery.

Project description:Rationale & objectiveThe Kidney Failure Risk Equation (KFRE) is a simple widely validated prediction model using age, sex, estimated glomerular filtration rate, and urinary albumin-creatinine ratio to predict the risk for end-stage kidney disease. Data are limited for its applicability to kidney transplant recipients.Study designValidation study of the KFRE as a post hoc analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial.Setting & participantsAdult kidney transplant recipients with functioning kidney allografts at least 6 months posttransplantation from 30 centers in the United States, Canada, and Brazil. Participants with estimated glomerular filtration rates < 60 mL/min/1.73 m2 at study entry were included.Predictor2- and 5-year kidney failure risk predicted by the KFRE using variables at study entry.OutcomeGraft loss, defined by initiation of dialysis.Analytical approachDiscrimination of the KFRE was assessed using C statistics; calibration was assessed by plotting predicted risk against observed cumulative incidence of graft loss.Results2,889 participants were included. Within 2 years, 98 participants developed graft loss, 107 participants died with a functioning graft, and 129 participants were lost to follow-up, and by 5 years, 252 had developed graft loss, 265 died with a functioning graft, and 1,543 were lost to follow-up. The KFRE demonstrated accurate calibration and discrimination (C statistic, 0.85 [95% CI, 0.81-0.88] at 2 years and 0.81 [95% CI, 0.78-0.84] at 5 years); performance was similar regardless of donor type (living vs deceased) and graft vintage, with the noted exception of poorer calibration for graft vintage less than 2 years.LimitationsUnavailable cause of graft loss.ConclusionsThe KFRE accurately predicted the risk for graft loss among adult kidney transplant recipients with graft vintage longer than 2 years and may be a useful prognostic tool for nephrologists caring for kidney transplant recipients.

Project description:Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury.Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each); a cross-sectional cohort with preimplantation biopsy specimens (n=82); and a cross-sectional cohort with postreperfusion biopsy specimens (n=46).Results Analysis of the paired preischemia and postischemia specimens revealed that methylation increased drastically in all allografts on ischemia. Hypermethylation was caused by loss of 5-hydroxymethylcytosine, the product of TET activity, and it was stable 1 year after transplant. In the preimplantation cohort, CpG hypermethylation directly correlated with ischemia time and for some CpGs, increased 2.6% per additional hour of ischemia. Hypermethylation preferentially affected and reduced the expression of genes involved in suppressing kidney injury and fibrosis. Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant. This finding was validated in the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables.Conclusions We highlight a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential.

Project description:ImportanceIn the United States, substantial disparities in access to kidney transplant exist for wait-listed candidates with end-stage renal disease. The implications of transplant centers' willingness to accept kidney offers for access to transplant and mortality outcomes are unknown.ObjectiveTo determine the outcomes for wait-listed kidney transplant candidates after the transplant center's refusal of a deceased donor kidney offer.Design, setting, and participantsThis cohort study obtained data from the United Network for Organ Sharing Potential Transplant Recipient data set on all deceased donor kidney offers in the United States made between January 1, 2008, and December 31, 2015. The final study cohort included adult patients who were wait-listed for kidney transplant and received at least 1 allograft offer during the study period (N?=?280?041). Data analysis was conducted from June 1, 2018, to March 30, 2019.ExposureCandidate state of residence.Main outcomes and measuresWaiting list outcome event groups included received deceased donor allograft, received living donor allograft, died while on the waiting list, removed from the waiting list without a transplant, or still on the waiting list at the end of follow-up.ResultsAmong the 280?041 kidney transplant candidates included in the study, the mean (SD) age at wait-listing was 51.1 (13.1) years, and male patients were predominant (171 517 [61.2%]). In this cohort, 81 750 candidates (29.2%) received a deceased donor kidney allograft, 30 870 (11.0%) received a living donor allograft, 25 967 (9.3%) died while on the waiting list, and 59 359 (21.2%) were removed from the waiting list. Overall, 10 candidates with at least 1 previous allograft offer died each day during the study period. Time to first offer was similar for candidates who received deceased donor kidney allograft compared with those who died while waiting (median [interquartile range {IQR}] time, 79 [16-426] days vs 78 [17-401] days, respectively). Deceased donor allograft recipients had a median of 17 offers (IQR, 6-44) over 422 days (IQR, 106-909 days), whereas candidates who died while waiting received a median of 16 offers (IQR, 6-41) over 651 days (IQR, 304-1117 days). Most kidneys (84%) were declined on behalf of at least 1 candidate before being accepted for transplant. As reported by centers, organ or donor quality concerns accounted for 8 416 474 (92.6%) of all declined offers, whereas offers were infrequently refused because of patient-related factors (232 193 [2.6%]), logistical limitations (49 492 [0.5%]), or other concerns. The odds of death after an offer and the median number of offers received prior to death varied considerably by state.Conclusions and relevanceThis study found that transplant candidates appeared to receive a large number of viable deceased donor kidney offers that were refused on their behalf by transplant centers, potentially exacerbating the detrimental consequences of the organ shortage; increased transparency in organ allocation process and decisions may improve patient-centered care and access to kidney transplant.

Project description:BackgroundAcute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients.MethodsThe cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant.ResultsIn analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60; P = 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (P = 0.32).ConclusionsThese results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.

Dataset Information

Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages in a Rat Kidney Transplant Model.

Publications

Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages in a Rat Kidney Transplant Model.

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