Vertebral Bone Marrow Transplant from a Deceased Lung Transplant Donor: Durable Hematopoiesis and Immune Tolerance
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PROVIDER: PRJNA1307505 | ENA |
REPOSITORIES: ENA
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Project description:Background: Primary immunodeficiency patients are ineligible for lung transplant (LTX) due to futility and bone marrow transplant (BMT) for lung failure. We hypothesized that using marrow extracted from the vertebral bodies (VB) of a deceased lung donor with partial HLA-match would be able to establish persistent hematopoiesis and generate immunity and tolerance. Methods: A teenager with severe combined immunodeficiency in lung failure due to recurrent pneumonias underwent LTX in 2016 from a 1/8 HLA allele-matched unrelated donor followed by reduced intensity conditioning and infusion of T cell/B cell-depleted cryopreserved VB marrow 4 months later. Results: Immune competence and donor-derived thymopoiesis were evident by six months post-BMT, while immunosuppression was withdrawn at 16-month post-BMT. Donor T cell (>95%) and myeloid chimerism (7-10%) have persisted for over nine years. At two years post-BMT, circulating donor-derived T cells were hyporesponsive to host dendritic cells in vitro. T-cell receptor clonotyping revealed the disappearance of host-reactive clones identifiable in the marrow graft, while circulating donor T cells exhibited downmodulation of signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, circulating predominantly host monocytes upregulated signaling pathways compared to their donor-derived counterparts, indicating active interactions between post-thymic donor T cells and host monocytes. Conclusion: In summary, durable hematopoietic engraftment and protective immunity were demonstrable for the first time in a patient receiving deceased donor vertebral bone marrow graft. Moreover, tolerance exceeding 8-years without immunosuppression was attainable.
2025-09-01 | GSE305710 | GEO
Project description:Because of inherent differences between deceased donor (DD) and living donor (LD) liver grafts, we hypothesize that the molecular signatures will be unique, correlating with specific biologic pathways and clinical patterns. Following reperfusion, 579 genes in DD grafts and 1324 genes in LDs were differentially expressed (p<0.005). Many up-regulated LD genes were related to regeneration, biosynthesis and cell cycle, and a large number of down-regulated genes were linked to hepatic metabolism and energy pathways correlating with post-transplant clinical laboratory findings. There was significant up-regulation of inflammatory/immune genes in both DD and LD, each with a distinct pattern. Gene expression patterns of select genes associated with inflammation and regeneration in LD and DD grafts correlated with protein expression. Unique patterns of early gene expression are seen in LD and DD liver grafts, correlating with protein expression and clinical results, demonstrating distinct inflammatory profiles and significant down-regulation of metabolic pathways in LD grafts. Keywords: liver transplantation, live donor transplantation, liver regeneration, microarrays, mRNA expression, reperfusion injury
2009-06-11 | GSE12720 | GEO
Project description:Because of inherent differences between deceased donor (DD) and living donor (LD) liver grafts, we hypothesize that the molecular signatures will be unique, correlating with specific biologic pathways and clinical patterns. Following reperfusion, 579 genes in DD grafts and 1324 genes in LDs were differentially expressed (p<0.005). Many up-regulated LD genes were related to regeneration, biosynthesis and cell cycle, and a large number of down-regulated genes were linked to hepatic metabolism and energy pathways correlating with post-transplant clinical laboratory findings. There was significant up-regulation of inflammatory/immune genes in both DD and LD, each with a distinct pattern. Gene expression patterns of select genes associated with inflammation and regeneration in LD and DD grafts correlated with protein expression. Unique patterns of early gene expression are seen in LD and DD liver grafts, correlating with protein expression and clinical results, demonstrating distinct inflammatory profiles and significant down-regulation of metabolic pathways in LD grafts. Experiment Overall Design: Microarray profiles of 63 biopsies in 13 DD and 8 LD liver grafts done at serial time points (procurement - No Manipulation, backbench - Cold Preservation, and 1-hour post-reperfusion - Post reperfusion) were compared between groups using class comparisons, network and biological function analyses. Specific genes were validated by quantitative PCR and immunopathology. Clinical findings were also compared.
2009-06-23 | E-GEOD-12720 | biostudies-arrayexpress
Project description:This prospective, single-center study (NCT06171438) included 276 kidneys from 174 deceased donors. Donor procurement biopsies were performed on the backtable and part of the biopsy was stored for future RNA extraction and molecular profiles analysis using Affymetrix microarrays. Three molecular classifiers (the logistic regression model, the Poisson regression and the extreme gradient boosting) with 10-fold cross validation were employed to identify donor categories based on clinical variables (age, BMI, hypertension, marginal kidney) and histological biopsy scores (the vascular fibrous intimal thickening (cv), interstitial fibrosis (ci) and tubular atrophy (ct) and arteriolar hyaline thickening (ah). Archetypal analysis was applied to determine molecular phenotypes and their association with short- and long-term transplant outcomes. Three donor molecular archetypes were identified. Marginal archetype was characterized by older age (median 68 years), extensive chronic morphological changes (IFTA>0 in 66%, ah>1 in 59%, cv>1 in 36%), and the highest Kidney Donor Risk Index (KDRI). Ideal archetype was associated with young age (median 42 years), low KDRI, minimal chronic histological changes (IFTA>0 in 39%, ah>1 in 33%, cv>1 in 13%) and the highest posttransplant eGFR at 12 months (p<0.001). Intermediate archetype 3 was associated with older age (median 63 years) however better eGFR at 12 months follow-up despite similar chronic histological changes (IFTA>0 in 73%, ah>1 in 63%, cv>1 in 56%). Molecular profiling outperforms histology in procurement biopsies and enables the identification of ECD kidneys with better posttransplant kidney allograft function.
2025-12-22 | GSE290167 | GEO
Project description:Kidney transplantation is regarded as the best treatment option for patients with end-stage renal disease. However, living-donor recipients (LDRs) and deceased-donor recipients (DDRs) still face challenges in transplant-specific emotional adjustment post-transplantation. Research distinguishing emotional adjustment between transplant groups has been limited to Western settings, with little attention given to Asian populations. As such, documenting and comparing the emotional adjustment of LDRs and DDRs in an ethnically diverse Asian setting in Singapore and identifying factors associated with emotional adjustment are of interest. Methods:One hundred eighty-two kidney transplant patients (106 LDRs and 76 DDRs) completed measures of generic distress (Depression, Anxiety, Stress Scale-21) and transplantation-specific emotional and behavioral outcomes (Transplant Effects Questionnaire). Results:LDRs were significantly younger (P = 0.019) and had higher education levels (P = 0.007), higher personal income (P < 0.001), shorter dialysis vintage (P < .001), and higher estimated glomerular filtration rates (eGFRs) (P = 0.002) compared with DDRs. Generic symptoms of depression and stress were very low; however, 29.2% of LDRs and 19.7% of DDRs experienced moderate to severe symptoms of anxiety. Similarly, 83.0% of LDRs and 72.4% of DDRs reported high levels of transplant-specific worry. Multivariate models showed younger patients expressing greater generic distress, and transplant-specific worry (P < 0.01), despite higher eGFRs (P < 0.05). ANCOVA controlling for casemix differences showed that LDRs experienced higher feelings of guilt (P = 0.004) and greater willingness to disclosure (P = 0.041). Conclusions:Clinicians should be vigilant of younger kidney transplant patients who have greater risk of poorer emotional adjustment. Future interventions should target alleviating anxiety and transplant-specific worry.
| S-EPMC7004627 | biostudies-literature
Project description:The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.
| S-EPMC6175247 | biostudies-literature
Project description:The clear benefits of ischemic preconditioning (IPC) in reducing ischemia reperfusion injury (IRI) remain indistinct in human liver transplantation. To further understand the mechanistic aspects of IPC in human deceased donor liver transplantation (DDLT), we performed microarray analyses to determine global gene expression profiles associated with IPC administration. Donor and recipient characteristics in both groups were comparable. Clinical data from our study subset and larger trial were similar. IPC increased expression of 10 transcripts at either time point with roles in: antioxidant defenses, immunological response, lipid biosynthesis, and xenobiotic metabolism. IPC decreased the expression of 1 cell development related transcript. Conclusions: 1) IPC in DDLT increased the expression of antioxidant transcripts similar to studies in animal IPC, anesthetic, and remote IPC. 2) IPC increased expression of lipogenic transcripts, which may be relevant to the clinically observed increased IRI in our IPC group. 3) Our microarray findings support our clinical observations and are compatible with the varied outcomes of hepatic IPC studies in human liver transplantation.
2009-04-01 | GSE15480 | GEO
Project description:IntroductionTransplant clinicians may disagree on whether or not to accept a deceased donor kidney offer. We investigated the interobserver variability between transplant nephrologists regarding organ acceptance and whether the use of a prediction model impacted their decisions.MethodsWe developed an observational online survey with 6 real-life cases of deceased donor kidneys offered to a waitlisted recipient. Per case, nephrologists were asked to estimate the risk of adverse outcome and whether they would accept the offer for this patient, or for a patient of their own choice, and how certain they felt. These questions were repeated after revealing the risk of adverse outcome, calculated by a validated prediction model.ResultsSixty Dutch nephrologists completed the survey. The intraclass correlation coefficient of their estimated risk of adverse outcome was poor (0.20, 95% confidence interval [CI] 0.08-0.62). Interobserver agreement of the decision on whether or not to accept the kidney offer was also poor (Fleiss kappa 0.13, 95% CI 0.129-0.130). The acceptance rate before and after providing the outcome of the prediction model was significantly influenced in 2 of 6 cases. Acceptance rates varied considerably among transplant centers.ConclusionIn this study, the estimated risk of adverse outcome and subsequent decision to accept a suboptimal donor kidney varied greatly among transplant nephrologists. The use of a prediction model could influence this decision and may enhance nephrologists' certainty about their decision.
| S-EPMC10577326 | biostudies-literature
Project description: Not available
| S-EPMC7710837 | biostudies-literature
Project description:Assessment of deceased-donor organ quality is integral to transplant allocation practices, but tools to more precisely measure donor kidney injury and better predict outcomes are needed. In this study, we assessed associations between injury biomarkers in deceased-donor urine and the following outcomes: donor AKI (stage 2 or greater), recipient delayed graft function (defined as dialysis in first week post-transplant), and recipient 6-month eGFR. We measured urinary concentrations of microalbumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) from 1304 deceased donors at organ procurement, among whom 112 (9%) had AKI. Each biomarker strongly associated with AKI in adjusted analyses. Among 2441 kidney transplant recipients, 31% experienced delayed graft function, and mean±SD 6-month eGFR was 55.7±23.5 ml/min per 1.73 m(2) In analyses adjusted for donor and recipient characteristics, higher donor urinary NGAL concentrations associated with recipient delayed graft function (highest versus lowest NGAL tertile relative risk, 1.21; 95% confidence interval, 1.02 to 1.43). Linear regression analyses of 6-month recipient renal function demonstrated that higher urinary NGAL and L-FABP concentrations associated with slightly lower 6-month eGFR only among recipients without delayed graft function. In summary, donor urine injury biomarkers strongly associate with donor AKI but provide limited value in predicting delayed graft function or early allograft function after transplant.
| S-EPMC4849827 | biostudies-literature