RESUMO
BACKGROUND: The actual prognostic impact of prior lupus nephritis (LN) diagnosis on end-stage kidney disease (ESKD) patients remains questionable, especially in relation to outcomes of kidney transplantation (KTx) We aim to determine the survival of the graft and recipient after the KTx procedure among patients with ESKD due to LN in comparison to non-LN. METHODS: This meta-analysis included retrospective studies from the last two decades, focusing on the KTx's outcomes among ESKD due to LN in comparison to non-LN. We establish the graft/recipient survival rate at different follow-up intervals as the primary outcome, and acute graft rejection and pooled graft failure rate as secondary outcomes. All analyses were performed with the random-effect model (REM) and were presented as odd ratio (OR; within 95% confidence interval (CI)). The protocol of this study was registered in PROSPERO: CRD42023394310. RESULTS: A total of 1,299 KTx (368 LN patients) from 10 studies with >10 years of follow-up were thoroughly reviewed. All checkpoints (at 1-, 5-, 10, and 15-year post-KTx) on graft survival rate demonstrated comparable outcomes in either LN or non-LN (e.g., at 10-year follow up (OR, 1.08 [0.40, 2.91]; p = 0.88). Similar findings at all checkpoints for recipient survival rate were also observed without statistically significant difference between LN and non-LN arm (e.g., at 10-year checkpoint; OR, 0.99 [0.68, 1.46]; p = 0.98). Both of our secondary analyses also presented insignificant differences (p = 0.70 and = 0.16, respectively). CONCLUSIONS: Our findings suggested that prognosis of ESKD due to complicated LN is equal compared to ESKD associated with non-LN etiologies, suggesting the impact of LN as the inducing cause of ESKD on KTx outcome is relatively neglectable.
Assuntos
Sobrevivência de Enxerto , Falência Renal Crônica , Transplante de Rim , Nefrite Lúpica , Humanos , Nefrite Lúpica/cirurgia , Falência Renal Crônica/cirurgia , Adulto , Rejeição de Enxerto , Fatores de Tempo , Estudos Retrospectivos , PrognósticoRESUMO
Importance: Low socioeconomic status (SES) has been associated with higher risk of rejection and graft loss in pediatric heart transplant (HT) recipients. The association of SES with other posttransplant morbidities is unknown. Objective: To assess whether low SES is associated with higher risk of a major adverse transplant event (MATE) among pediatric HT recipients. Design, Setting, and Participants: Retrospective single-center cohort study at a children's hospital in Boston with consecutive primary HT recipients from 2006 to 2019 and follow-up through 2022. Data were analyzed from June 2023 to March 2024. Exposure: Very low or low, moderate, and high or very high Childhood Opportunity Index (COI) for neighborhood (census tract) of patient residence. Main Outcomes and Measures: Primary outcome was 3-year MATE-6 score assessed in 6-month survivors as cumulative burden of acute cellular rejection, antibody-mediated rejection, coronary vasculopathy, lymphoproliferative disease, kidney dysfunction, and infection, each as an ordinal score from 0 to 4 (24 for death or retransplant). Secondary outcomes were freedom from rejection during first 6 months, freedom from death or retransplant, MATE-3 score for events 1 to 3 (under immune suppression) and events 4 to 6 (chronic immune suppression effects), and each MATE component. Results: Of 153 children analyzed, the median (IQR) age at HT was 7.2 (1.5-14.8) years, 99 (65%) were male, 16 (10%) were Black, 17 (11%) were Hispanic, and 106 (69%) were White. Fifty patients (33%) lived in very low or low, 17 (11%) in moderate, and 86 (56%) in high or very high COI neighborhoods. There was no significant group difference in mean (SD) 3-year MATE-6 score (very low or low COI, 3.4 [6.5]; moderate COI, 2.4 [6.3]; and high or very high COI, 4.0 [6.9]). Furthermore, there was no group difference in mean (SD) MATE-3 scores for underimmune suppression (very low or low COI, 1.9 [3.5]; moderate COI, 1.2 [3.2]; and high or very high COI, 2.2 [3.6]), chronic immune suppression effects (very low or low COI, 1.6 [3.3]; moderate COI, 1.1 [3.2]; and high or very high COI, 1.8 [3.6]), individual MATE components, rejection during the first 6 months, or death or retransplant. Conclusions and relevance: In this cohort study of pediatric HT recipients, there was no difference in posttransplant outcomes among recipients stratified by SES, a notable improvement from prior studies. These findings may be explained by state-level health reform, standardized posttransplant care, and early awareness of outcome disparities.
Assuntos
Rejeição de Enxerto , Transplante de Coração , Classe Social , Humanos , Transplante de Coração/efeitos adversos , Transplante de Coração/estatística & dados numéricos , Masculino , Feminino , Criança , Estudos Retrospectivos , Rejeição de Enxerto/epidemiologia , Pré-Escolar , Adolescente , Complicações Pós-Operatórias/epidemiologia , Boston/epidemiologia , Lactente , Transplantados/estatística & dados numéricos , Fatores de RiscoRESUMO
Haploidentical hematopoietic cell transplantation (haplo-HCT) is associated with an increased risk of allograft rejection. Here, we employed a major histocompatibility complex (MHC)-mismatched allogeneic HCT (allo-HCT) murine model to better understand the role of Gal-1 in immune tolerance. Transplanted mice were classified into either rejected or engrafted based on donor chimerism levels. We noted significantly higher frequencies of CD4+ T cells, CD8+ T cells, natural killer cells, IFN-γ and TNF-α producing CD4+ T cells, and IFN-γ producing dendritic cells and macrophages in rejected mice. Conversely, we found significantly increased frequencies of regulatory T cells (Tregs), predominantly Helios+, IL-10-producing CD4+ T cells, type 1 regulatory (Tr1) cells, and the proportion of Tr1+Gal-1+ cells in engrafted mice. Further, Gal-1 specific blockade in Tregs reduced suppression of effector T cells in engrafted mice. Lastly, effector T cells from engrafted mice were more prone to undergo apoptosis. Collectively, we have shown that Gal-1 may favor HSC engraftment in an MHC-mismatched murine model. Our results demonstrate that Gal-1-expressing Tregs, especially at earlier time points post-transplant, are associated with inducing immune tolerance and stable mixed chimerism after HCT.
Assuntos
Galectina 1 , Transplante de Células-Tronco Hematopoéticas , Linfócitos T Reguladores , Animais , Camundongos , Galectina 1/imunologia , Galectina 1/metabolismo , Linfócitos T Reguladores/imunologia , Camundongos Endogâmicos C57BL , Rejeição de Enxerto/imunologia , Transplante Homólogo , Complexo Principal de Histocompatibilidade/imunologia , Sobrevivência de Enxerto/imunologia , Camundongos Endogâmicos BALB C , Tolerância ImunológicaRESUMO
BACKGROUND: Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. AIM: To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. METHODS: A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. RESULTS: Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. CONCLUSION: Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.
Assuntos
Rejeição de Enxerto , Sobrevivência de Enxerto , Antígenos HLA , Teste de Histocompatibilidade , Isoanticorpos , Transplante de Fígado , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/epidemiologia , Feminino , Criança , Antígenos HLA/imunologia , Isoanticorpos/sangue , Isoanticorpos/imunologia , Brasil/epidemiologia , Pré-Escolar , Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade/métodos , Incidência , Lactente , Adolescente , Fígado/imunologia , Fígado/patologia , Biópsia , Estudos Retrospectivos , Doadores Vivos , Transplantados/estatística & dados numéricosRESUMO
BACKGROUNDS: Acute transplant rejection is a major component of poor prognoses for organ transplantation. Owing to the multiple complex mechanisms involved, new treatments are still under exploration. Endometrial regenerative cells (ERCs) have been widely used in various refractory immune-related diseases, but the role of ERC-derived exosomes (ERC-Exos) in alleviating transplant rejection has not been extensively studied. Signaling lymphocyte activation molecule family 6 (SLAMF6) plays an important role in regulating immune responses. In this study, we explored the main mechanism by which ERC-Exos loaded with siSLAMF6 can alleviate allogeneic transplant rejection. METHODS: C57BL/6 mouse recipients of BALB/c mouse kidney transplants were randomly divided into four groups and treated with exosomes. The graft pathology was evaluated by H&E staining. Splenic and transplanted heart immune cell populations were analyzed by flow cytometry. Recipient serum cytokine profiles were determined by enzyme-linked immunosorbent assay (ELISA). The proliferation and differentiation capacity of CD4+ T cell populations were evaluated in vitro. The α-2,6-sialylation levels in the CD4+ T cells were determined by SNA blotting. RESULTS: In vivo, mice treated with ERC-siSLAMF6 Exo achieved significantly prolonged allograft survival. The serum cytokine profiles of the recipients were significantly altered in the ERC-siSLAMF6 Exo-treated recipients. In vitro, we found that ERC-siSLAMF6-Exo considerably downregulated α-2,6-sialyltransferase (ST6GAL1) expression in CD4+ T cells, and significantly reduced α-2,6-sialylation levels. Through desialylation, ERC-siSLAMF6 Exo therapy significantly decreased CD4+ T cell proliferation and inhibited CD4+ T cell differentiation into Th1 and Th17 cells while promoting regulatory T cell (Treg) differentiation. CONCLUSIONS: Our study indicated that ERC-Exos loaded with siSLAMF6 reduce the amount of sialic acid connected to α-2,6 at the end of the N-glycan chain on the CD4+ T cell surface, increase the number of therapeutic exosomes endocytosed into CD4+ T cells, and inhibit the activation of T cell receptor signaling pathways, which prolongs allograft survival. This study confirms the feasibility of using ERC-Exos as natural carriers combined with gene therapy, which could be used as a potential therapeutic strategy to alleviate allograft rejection.
Assuntos
Endométrio , Exossomos , Rejeição de Enxerto , Transplante de Coração , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Animais , Exossomos/metabolismo , Rejeição de Enxerto/imunologia , Feminino , Camundongos , Endométrio/metabolismo , Aloenxertos , Citocinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Sobrevivência de EnxertoRESUMO
OBJECTIVES: Chronic rejection remains the leading cause of progressive decline in graft function. Accumulating evidence indicates that macrophages participate in chronic rejection dependent on CD40-CD40L. The FOS family members are critical in inflammatory and immune responses. However, the mechanisms underlying the role of FOS family members in chronic rejection remain unclear. In this study, we aimed to elucidate the role and underlying mechanisms of FOS-positive macrophages regulated by CD40 that mediate chronic allograft rejection. MATERIALS AND METHODS: We downloaded publicly accessible chronic rejection kidney transplant single-cell sequencing datasets from the gene expression omnibus database. Differentially expressed genes between the CD40hi and CD40low macrophage chronic rejection groups were analyzed. We established a chronic rejection mouse model by using CTLA-4-Ig. We treated bone marrow-derived macrophages with an anti-CD40 antibody. We assessed expression of the FOS family by flow cytometry, real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. We identified altered signaling pathways by using RNA sequencing analysis. We detected DNA specifically bound to transcription factors by using ChIP-sequencing, with detection of the degree of graft fibrosis and survival. RESULTS: FOS was highly expressed on CD40hi macrophages in patients with chronic transplantrejection. Mechanistically, we showed that CD40 activated NF-κB2 translocation into the nucleus to upregulate c-Fos and FosB expression, thus promoting chronic rejection of cardiac transplant.We showed thatNF-κB2 regulated c-Fos and FosB expression by binding to the c-fos and fosb promoter regions. Inhibition of c-Fos/activator protein-1 decreased graft fibrosis and prolonged graft survival. CONCLUSIONS: CD40 may activate transcription factor NF-κB2 translocation into the nucleus of macrophages to upregulate c-Fos and FosB expression, thus promoting chronic rejection of cardiac transplant. Inhibition of c-Fos/activator protein-1 decreased grafts fibrosis and prolonged graft survival.
Assuntos
Antígenos CD40 , Modelos Animais de Doenças , Rejeição de Enxerto , Transplante de Coração , Macrófagos , Proteínas Proto-Oncogênicas c-fos , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Antígenos CD40/metabolismo , Antígenos CD40/genética , Células Cultivadas , Doença Crônica , Bases de Dados Genéticas , Fibrose , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/genética , Sobrevivência de Enxerto , Transplante de Coração/efeitos adversos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Fator de Transcrição AP-1/metabolismoRESUMO
Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept.
Assuntos
Abatacepte , Inibidores de Calcineurina , Imunossupressores , Transplante de Rim , Torque teno virus , Carga Viral , Humanos , Transplante de Rim/efeitos adversos , Abatacepte/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Inibidores de Calcineurina/administração & dosagem , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Torque teno virus/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Adulto , Infecções por Vírus de DNA/tratamento farmacológico , Infecções por Vírus de DNA/virologia , Idoso , Transplantados , Rejeição de Enxerto/prevenção & controleRESUMO
PURPOSE: Evaluate cytomegalovirus (CMV) post-prophylaxis surveillance in high-risk (D+/R-) kidney and liver transplant recipients. METHODS: Adult D+/R- patients were included if transplanted between 6/1/15 and 11/30/22 and divided into a pre-CMV-stewardship-era (6/1/15-5/31/18), CMV-stewardship-era (6/1/18-6/30/20), and a surveillance-era (7/1/2020-11/30/2022) then followed through 12 months. The primary objective was to evaluate CMV-related outcomes. The secondary objective was to assess graft and patient survival by era. RESULTS: There were 328 patients in the study period; 133 in the pre-stewardship-era, 103 in the stewardship-era, and 92 in the surveillance-era. Replication rates in the surveillance-era were significantly higher, as anticipated due to increased sampling (pre 38.4%, stewardship 33.0%, surveillance 52.2%, p = 0.02). Time from transplant to first replication was similar (pre 214.0 ± 79.0 days, stewardship 231.1 ± 65.5, surveillance 234.9 ± 61.4, p = 0.29). CMV viral load (VL) at first detection, maximum-VL, and incidence of VL > 100 000 IU/mL were numerically lower in the surveillance era, although not statistically significant. CMV end-organ disease (p < 0.0001) and ganciclovir-resistance (p = 0.002) were significantly lower in the surveillance era than in both previous eras. Rejection was not different between eras (p = 0.4). Graft (p = 0.0007) and patient survival (p = 0.008) were significantly improved in the surveillance era. CONCLUSIONS: Post-prophylaxis surveillance significantly reduced CMV end-organ disease and resistance. Despite observing increased replication rates in the surveillance era, rejection was not significantly different and there was no graft loss or patient mortality at 12 months.
Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Farmacorresistência Viral , Ganciclovir , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Rim , Transplante de Fígado , Humanos , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Citomegalovirus/isolamento & purificação , Citomegalovirus/efeitos dos fármacos , Antivirais/uso terapêutico , Ganciclovir/uso terapêutico , Seguimentos , Transplante de Fígado/efeitos adversos , Fatores de Risco , Transplante de Rim/efeitos adversos , Prognóstico , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/virologia , Complicações Pós-Operatórias/prevenção & controle , Adulto , Taxa de Sobrevida , Estudos Retrospectivos , Transplantados/estatística & dados numéricosRESUMO
Although kidney transplantation from living donors (LD) offers better long-term results than from deceased donors (DD), elderly recipients are less likely to receive LD transplants than younger ones. We analyzed renal transplant outcomes from LD versus DD in elderly recipients with a propensity-matched score. This retrospective, observational study included the first single kidney transplants in recipients aged ≥65 years from two European registry cohorts (2013-2020, n = 4,257). Recipients of LD (n = 408), brain death donors (BDD, n = 3,072), and controlled cardiocirculatory death donors (cDCD, n = 777) were matched for donor and recipient age, sex, dialysis time and recipient diabetes. Major graft and patient outcomes were investigated. Unmatched analyses showed that LD recipients were more likely to be transplanted preemptively and had shorter dialysis times than any DD type. The propensity score matched Cox's regression analysis between LD and BDD (387-pairs) and LD and cDCD (259-pairs) revealing a higher hazard ratio for graft failure with BDD (2.19 [95% CI: 1.16-4.15], p = 0.016) and cDCD (3.38 [95% CI: 1.79-6.39], p < 0.001). One-year eGFR was higher in LD transplants than in BDD and cDCD recipients. In elderly recipients, LD transplantation offers superior graft survival and renal function compared to BDD or cDCD. This strategy should be further promoted to improve transplant outcomes.
Assuntos
Sobrevivência de Enxerto , Transplante de Rim , Doadores Vivos , Pontuação de Propensão , Sistema de Registros , Humanos , Transplante de Rim/estatística & dados numéricos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Europa (Continente) , Doadores de Tecidos , Fatores Etários , Rejeição de Enxerto , Resultado do Tratamento , Idoso de 80 Anos ou maisRESUMO
AIMS: This study aims to evaluate the presence of EBV, HCMV, and BKV genomic sequences in the plasma samples (active infection/viremia) of kidney transplant recipients suspected of rejection and to investigate host and risk factors related to the activation of these viruses in these patients. METHODS: In this cross-sectional single-center study, plasma samples were collected from 98 suspected kidney transplant rejection patients at Labafinejad Hospital, Tehran, Iran, between December 2022 and June 2023. Quantitative real-time PCR assays for HCMV, EBV, and BK were performed using GeneProof Real-time PCR kits. ROC curve analysis was used to determine the viral load cutoff point for each virus. FINDINGS: HCMV active viremia was detected in 18 (18.36%) recipients, EBV active viremia in 7 (7.14%), and BKV active viremia in 5 (5.10%). ROC results indicated viral load cutoff points of 778, 661, and 457 points for HCMV, EBV, and BKV, respectively. The duration of time after transplantation significantly differed between active viremia and no viremia groups (120.5 vs. 46 months, P = 0.014). In the BKV active viremia group, the increase in creatinine compared to baseline creatinine was significantly higher than in the no viremia group (2.7 vs. 0.8, P = 0.017). The odds ratio of HCMV active viremia in patients taking tacrolimus was 2.84 times higher, and the odds of HCMV active viremia in patients taking antithymocyte globulin was 3.01 times higher than in patients not taking these drugs. CONCLUSION: Rapid and timely diagnosis of viral active infections in kidney transplant patients is crucial for effective disease management and implementation of appropriate treatment strategies. Identifying potential risk factors, including host and treatment-related factors that influence transplantation, can facilitate the development of suitable preventive strategies.
Assuntos
Vírus BK , Infecções por Citomegalovirus , Citomegalovirus , Infecções por Vírus Epstein-Barr , Rejeição de Enxerto , Herpesvirus Humano 4 , Transplante de Rim , Infecções por Polyomavirus , Carga Viral , Viremia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Vírus BK/isolamento & purificação , Vírus BK/genética , Adulto , Estudos Transversais , Infecções por Polyomavirus/virologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Citomegalovirus/virologia , Citomegalovirus/isolamento & purificação , Citomegalovirus/genética , Rejeição de Enxerto/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Irã (Geográfico)/epidemiologia , Fatores de Risco , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/sangue , Idoso , Adulto Jovem , Transplantados/estatística & dados numéricosRESUMO
Organ transplantation increases life expectancy and improves the quality of life of patients experiencing specific conditions such as terminal organ failure. Despite matching efforts between donor and recipient, immune activation can interfere with allograft survival after transplantation if immunosuppression is not used. With both innate and adaptive responses, this is a complicated immunological process. This can lead to organ rejection, or graft-versus-host disease (GVHD), depending on the origin of the immune response. Inflammatory factors, such as chemokine receptors and their ligands, are involved in a wide variety of immunological processes, including modulating transplant rejection or GVHD, therefore, chemokine biology has been a major focus of transplantation studies. These molecules attract circulating peripheral leukocytes to infiltrate into the allograft and facilitate dendritic and T cell trafficking between lymph nodes and the graft during the allogeneic response. In this chapter, we will review the most relevant chemokine receptors such as CXCR3 and CCR5, among others, and their ligands involved in the process of allograft rejection for solid organ transplantation and graft-versus-host disease in the context of hematopoietic cell transplantation.
Assuntos
Rejeição de Enxerto , Doença Enxerto-Hospedeiro , Receptores de Quimiocinas , Humanos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Rejeição de Enxerto/imunologia , Animais , Receptores de Quimiocinas/metabolismoRESUMO
Rationale: Understanding the immune mechanisms associated with liver transplantation (LT), particularly the involvement of tissue-resident memory T cells (TRMs), represents a significant challenge. Methods: This study employs a multi-omics approach to analyse liver transplant samples from both human (n = 17) and mouse (n = 16), utilizing single-cell RNA sequencing, bulk RNA sequencing, and immunological techniques. Results: Our findings reveal a comprehensive T cell-centric landscape in LT across human and mouse species, involving 235,116 cells. Notably, we found a substantial increase in CD8+ TRMs within rejected grafts compared to stable ones. The elevated presence of CD8+ TRMs is characterised by a distinct expression profile, featuring upregulation of tissue-residency markers (CD69, CXCR6, CD49A and CD103+/-,), immune checkpoints (PD1, CTLA4, and TIGIT), cytotoxic markers (GZMB and IFNG) and proliferative markers (PCNA and TOP2A) during rejection. Furthermore, there is a high expression of transcription factors such as EOMES and RUNX3. Functional assays and analyses of cellular communication underscore the active role of CD8+ TRMs in interacting with other tissue-resident cells, particularly Kupffer cells, especially during rejection episodes. Conclusions: These insights into the distinctive activation and interaction patterns of CD8+ TRMs suggest their potential utility as biomarkers for graft rejection, paving the way for novel therapeutic strategies aimed at enhancing graft tolerance and improving overall transplant outcomes.
Assuntos
Linfócitos T CD8-Positivos , Rejeição de Enxerto , Transplante de Fígado , Células T de Memória , Análise de Célula Única , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Rejeição de Enxerto/imunologia , Animais , Camundongos , Células T de Memória/imunologia , Células T de Memória/metabolismo , Análise de Célula Única/métodos , Análise de Sequência de RNA/métodos , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Memória Imunológica , Masculino , Camundongos Endogâmicos C57BL , Antígenos CD/metabolismo , Antígenos CD/genética , Feminino , Pessoa de Meia-Idade , Proteínas com Domínio TRESUMO
Paediatric heart transplant is an established treatment for end stage heart failure in children, however patients have to commit to lifelong medical surveillance and adhere to daily immunosuppressants to minimise the risk of rejection. Compliance with immunosuppressants can be burdensome with their toxic side effects and need for frequent blood monitoring especially in children. Though the incidence of early rejection episodes has significantly improved overtime, the long-term allograft health and survival is determined by Cardiac Allograft Vasculopathy (CAV) which affects a vast number of post-transplant patients. Once CAV has set in, there is no medical or surgical treatment to reverse it and graft survival is significantly compromised across all age groups. Current treatment strategies include novel immunosuppressant agents and drugs to lower blood lipid levels to address the underlying immunological pathophysiology and to manage traditional cardiac risk factors. Translational researchers are seeking novel immunological approaches that can lead to permanent acceptance of the allograft such as using regulatory T cell (Tregs) immunotherapy. Clinical trials in the setting of graft versus host disease, autoimmunity and kidney and liver transplantation using Tregs have shown the feasibility and safety of this strategy. This review will summarise current knowledge of the latest clinical therapies for CAV and pre-clinical evidence in support of Treg therapy for CAV. We will also discuss the different Treg sources and the considerations of translating this into a feasible immunotherapy in clinical practice in the paediatric population.
Assuntos
Rejeição de Enxerto , Transplante de Coração , Linfócitos T Reguladores , Humanos , Transplante de Coração/efeitos adversos , Linfócitos T Reguladores/imunologia , Criança , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Aloenxertos , Animais , Sobrevivência de Enxerto/imunologiaRESUMO
BACKGROUND: Though virtual care was widely adopted during the COVID-19 pandemic, evidence to support its use in kidney transplant recipients early after transplantation is limited. METHODS: We conducted a retrospective cohort study comparing post kidney transplant outcomes in patients who received in-person transplant care before the COVID-19 pandemic with those who received mainly virtual transplant care during the COVID-19 pandemic. The usual-care group included 69 patients who received a kidney transplant from March 1, 2019 to September 1, 2019, and the virtual-care group included 64 patients who received a kidney transplant from September 1, 2020 to March 1, 2021. RESULTS: At 6 months, five patients in the usual-care group and three patients in the virtual-care group died. There was one graft loss and one episode of acute rejection in the usual-care group, and two episodes of acute rejection in the virtual-care group (p = 0.60). Estimated glomerular filtration rate was higher for patients in the virtual-care group (59 mL/min/1.73 m2 vs. 52 mL/min/1.73 m2, p = 0.046) and serum creatinine was not different (138 µmol/L vs. 127 µmol/L, p = 0.27). There was no difference in mean blood pressure or hospitalizations. CONCLUSION: Outcomes were similar among recipients of a kidney transplant prior to the COVID-19 pandemic when care was mainly in person and during the pandemic when care was mainly virtual, without a signal of harm. Patient and donor selection may have led to unmeasured differences between groups.
Assuntos
COVID-19 , Rejeição de Enxerto , Transplante de Rim , SARS-CoV-2 , Humanos , Masculino , Feminino , COVID-19/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Telemedicina , Adulto , Sobrevivência de Enxerto , Prognóstico , Transplantados/estatística & dados numéricos , Taxa de Filtração Glomerular , Falência Renal Crônica/cirurgia , Idoso , SeguimentosRESUMO
BACKGROUND: Tacrolimus blood level variability is associated with reduced graft survival among kidney transplant recipients. To date, no practical approach for reducing variability has been validated. We defined specific tacrolimus blood level patterns correlated with variability and evaluated their independent association with reduced graft survival. METHODS: In this single-center retrospective study, we predefined 12 patterns that exhibited correlation with high tacrolimus blood level variability. Subsequently, we utilized a multivariate Cox proportional hazard model, in conjunction with the Akaike information criteria, to evaluate the association between the predefined patterns and decreased graft survival. RESULTS: Our cohort included 1305 kidney transplant recipients. The primary outcome of this trial was graft loss, defined as the initiation of chronic dialysis or the need for retransplantation. The secondary outcome was the combination of death-censored graft loss and death with a functioning graft. During the study's follow-up period, there were 131 events of graft loss. The number of episodes of subtherapeutic tacrolimus level during the first-year posttransplantation was significantly associated with graft loss (HR 1.208 per episode, 95% CI 1.075-1.356, p = 0.001) and significantly improved the relative likelihood of the model compared to the multivariate model as demonstrated by the delta AIC value (8.256, p = 0.016). CONCLUSION: In addition to increased tacrolimus blood level variability, the number of episodes of subtherapeutic tacrolimus levels is independently associated with decreased graft survival among kidney transplant recipients.
Assuntos
Rejeição de Enxerto , Sobrevivência de Enxerto , Imunossupressores , Transplante de Rim , Tacrolimo , Humanos , Tacrolimo/sangue , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Transplante de Rim/efeitos adversos , Feminino , Masculino , Sobrevivência de Enxerto/efeitos dos fármacos , Estudos Retrospectivos , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Imunossupressores/sangue , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Seguimentos , Prognóstico , Fatores de Risco , Adulto , Taxa de Filtração Glomerular , Testes de Função Renal , Falência Renal Crônica/cirurgia , Falência Renal Crônica/sangue , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/prevenção & controle , Taxa de SobrevidaRESUMO
BACKGROUND: Delayed graft function (DGF) is a common early complication after kidney transplantation (KT) and is associated with various long-term adverse outcomes. Despite numerous studies on hemodynamic management, the optimal hemodynamic goals during KT remain unclear. In this retrospective study, we aimed to investigate if three mean artery pressure (MAP) thresholds (≤75, 80, and 85 mmHg) that were commonly used in clinical practice were associated with DGF in adult patients undergoing KT. METHODS: We extracted de-identified data on adult patients who underwent deceased donor KT from our Discovery Data Repository. DGF was defined as the requirement for dialysis within the first 7 days after transplantation. Three MAP thresholds (≤75, 80, and 85 mmHg) and the duration of pressure below the three thresholds were recorded. Multivariable logistic analysis was used to identify risk factors for DGF. RESULTS: We included 2301 adult KT patients. The mean age was 52.5±12.9 years and 59% were male. DGF occurred in 1066 patients (46.3%). Patients frequently experienced MAP ≤75, 80, and 85 mmHg (approximately 70%, 80%, and 90% of patients experienced 10 min of MAP ≤75, 80, and 85 mmHg, respectively). Patients with DGF spent significantly longer durations below the three MAP thresholds during surgery compared with those without DGF. Further analysis revealed that the minimal time spent on MAP ≤75, 80, and 85 mmHg that were significantly associated with DGF were 6, 23, and 37 min, respectively. After adjusting for non-hemodynamic risk factors (age, basiliximab administration, and urine output), prolonged exposure to the three MAP thresholds remained significant predictors for DGF (for MAP ≤75 mmHg, OR 1.257, 95% CI 1.017-1.554, p = 0.034; MAP ≤80 mmHg, OR 1.220, 95% CI 1.018-1.463, p = 0.031; MAP ≤85 mmHg, OR 1.253, 95% CI 1.048-1.498, p = 0.013). CONCLUSION: Prolonged exposure to the three common MAP thresholds (≤75, 80, and 85 mmHg) occurred frequently during adult deceased donor KT and was associated with DGF.
Assuntos
Pressão Arterial , Função Retardada do Enxerto , Sobrevivência de Enxerto , Transplante de Rim , Complicações Pós-Operatórias , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Função Retardada do Enxerto/etiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Prognóstico , Seguimentos , Complicações Pós-Operatórias/etiologia , Pressão Arterial/fisiologia , Adulto , Falência Renal Crônica/cirurgia , Taxa de Filtração Glomerular , Testes de Função Renal , Rejeição de Enxerto/etiologiaRESUMO
Background: Hematopoietic stem cell transplantation (HSCT) is an approach that has significantly improved the prognosis and survival of hematological patients. However, ovarian dysfunction and infertility following HSCT have gained increasing attention. Live births have been reported following ovarian tissue cryopreservation prior to HSCT and subsequent retransplantation of these tissues. Still, the feasibility of ovarian tissue cryopreservation (OTC) following graft failure (GF) of HSCT remains unknown. In this study, we report the first case of OTC following a GF of allogenic HSCT (allo-HSCT), as well as the cryopreservation of four MII oocytes via in vitro maturation with informed consent. Despite the lack of clinical outcomes after cryopreserved ovarian tissue retransplantation, we documented an interesting case in a woman after GF of allo-HSCT exhibiting functional ovaries and emphasized a clinical dilemma: whether OTC should be offered to women suffering from GF of HSCT. Case presentation: A 22-year-old woman with severe aplastic anemia who had suffered GF of allo-HSCT from her sibling brother [HLA allele match (7/10)] with a reduced dose conditioning regimen including fludarabine, cyclophosphamide, and antithymocyte globulin came to our reproductive center for fertility preservation, as she was about to receive the second allo-HSCT. We evaluated the ovarian reserve of this patient. Hormone assessments showed an anti-Müllerian hormone level of 3.921 ng/mL, a follicle-stimulating hormone level of 5.88 IU/L, a luteinizing hormone level of 10.79 IU/L, and an estradiol level of 33.34 pg/mL. Antral follicle counts accessed transvaginally showed 12-15 follicles. All assessments indicated a well-protected ovarian reserve. Due to the urgency of the second allo-HSCT, the patient decided to undergo ovarian cryopreservation. Laparoscopic surgery proceeded. Ovarian tissues were successfully cryopreserved using vitrification technology, and histologic evaluation demonstrated a follicle density of 20 per 2 × 2 mm2 biopsy with good viability. Four MII oocytes were obtained via in vitro maturation technology and cryopreserved. After the second HSCT, the patient relieved from aplastic anemia but suffered iatrogenic premature ovarian failure as predicted. Conclusion: OTC is applicable to fertility preservation in those undergoing GF of HSCT with benign hematological disorders and especially those who are about to receive the second HSCT.