Anti-C4d chimeric antigen receptor regulatory T cells suppressed allograft rejection in ABO-incompatible heart transplantation.
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SUBMITTER: Lee SK
PROVIDER: S-EPMC8720693 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation. During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier. In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations. Desensitization is usually achieved by apheresis and B cell-depleting therapies that are accompanied by powerful immunosuppression. Anti-A/B antibodies are aimed to be below a certain threshold at the time of ABOi kidney transplantation and during the first 2 weeks after surgery. Thereafter, even a rebound of anti-A/B antibodies does not appear to harm the kidney transplant, a phenomenon that is called accommodation, but is poorly understood. There is still concern, however, that infectious complications such as viral disease, Pneumocystis jirovecii pneumonia, and severe urinary tract infections are increased after ABOi transplantations. Recent data from the Collaborative Transplant Study show that during the first year after kidney transplantation, one additional patient death from an infectious complication occurs in 100 ABOi kidney transplant recipients. Herein, we review the recent evidence on ABOi kidney transplantation with a focus on desensitization strategies and respective outcomes.
| S-EPMC5338156 | biostudies-literature
Project description:BackgroundABO incompatible kidney transplantation (ABOi-KT) is an important approach for overcoming donor shortages. We evaluated the effect of ABOi-KT on living donor KT.MethodsTwo nationwide transplantation databases were used. We evaluated the impact of ABOi-KT on overall living donor transplant activity and spousal donation as subgroup analysis. In addition, we compared the clinical outcome between ABOi-KT and ABO compatible KT (ABOc-KT) from spousal donor, and performed a Cox proportional hazards regression analysis to define the risk factors affecting the allograft outcomes.ResultThe introduction of ABOi-KT increased overall living donor KT by 12.2% and its portion was increased from 0.3% to 21.7% during study period. The ABOi-KT in living unrelated KT was two times higher than that of living related donor KT (17.8 vs.9.8%). Spousal donor was a major portion of living unrelated KT (77.6%) and ABOi-KT increased spousal donation from 10% to 31.5% in living donor KT. In addition, increasing rate ABOi-KT from spousal donor was 10 times higher than that of living related donor. The clinical outcome (incidence of acute rejection, allograft function, and allograft and patient survival rates) of ABOi-KT from spousal donor was comparable to that of ABOc-KT. Neither ABO incompatibility nor spousal donor was associated with acute rejection or allograft failure on multivariate analysis.ConclusionsABOi-KT increased overall living donor KT, and ABOi-KT from spousal donor is rapidly increasing with favorable clinical outcomes.
| S-EPMC5360260 | biostudies-literature
Project description:BackgroundEndothelial cells are vital in the transplant immune system as semiprofessional antigen-presenting cells. Few studies have investigated the importance of anti-endothelin subtype A receptor (ETAR) antibodies in kidney transplantation. Here, we aimed to analyze the association between anti-angiotensin II type I receptor (AT1R) and anti-ETAR antibodies and the association between the presence of anti-endothelial antibodies and the risk of allograft rejection in kidney transplantation.MethodsIn total, 252 patients who underwent kidney transplantation were enrolled in this study. Antibodies for human leukocyte antigens (HLAs) and non-HLAs were analyzed immediately before transplantation. Patients were categorized based on the occurrence of antibody-mediated rejection (AMR) or T-cell-mediated rejection (TCMR) by 2017 Banff classification. All p-values were two-tailed, and statistical significance was set at p < 0.05.ResultsPatients with anti-AT1R antibodies had a 3.49-fold higher risk of TCMR than those without anti-AT1R antibodies. Patients with anti-ETAR antibodies had a 5.84-fold higher risk of AMR than those without anti-ETAR antibodies. The hazard ratio of AMR in patients with both HLA DSAs and anti-ETAR antibodies, relative to patients without anti-ETAR antibodies and HLA DSAs, was 32.85 (95% CI = 1.82-592.91).ConclusionOur findings indicated that anti-ETAR antibodies are associated with AMR, and patients with both anti-ETAR antibodies and de novo HLA DSAs were at a high risk of AMR.
| S-EPMC10561590 | biostudies-literature
Project description:We performed a single-center retrospective cohort study of 66 consecutive ABO incompatible kidney transplants (ABOiKT) performed without B-cell depleting therapy. Outcomes were compared to an earlier era performed with rituximab (n = 18) and a contemporaneous cohort of ABO compatible live donor transplants (ABOcKT). Acute rejection within 3 months of transplant was significantly more common after rituximab-free ABOiKT compared to ABOiKT with rituximab (OR 8.8, p = 0.04) and ABOcKT (OR 2.9, p = 0.005) in adjusted analyses. Six recipients of rituximab-free ABOiKT experienced refractory antibody mediated rejection requiring splenectomy, and a further two incurred early graft loss with no such episodes amongst ABOiKT with rituximab or ABOcKT cohorts. Patient and graft survival were similar between groups over a median follow-up of 3.1 years. This observational evidence lends strong support to the continued inclusion of rituximab in desensitization protocols for ABOiKT.
| S-EPMC10547868 | biostudies-literature
Project description:BackgroundABO blood group antigens in the liver are expressed mainly on endothelial cells or biliary epithelial cells but not on hepatocytes. This suggests that ABO-incompatible hepatocyte transplantation (ABOi-HTx) is theoretically feasible. However, the effects of stress on ABO blood group antigen expression caused by isolation and intraportal infusion require thorough investigation before ABOi-HTx can be implemented in clinical settings.MethodsHuman hepatocytes were isolated from liver tissue obtained from liver resection or deceased donor livers. The expression of blood group antigens on cryopreserved human liver tissues and isolated hepatocyte smear specimens were examined by immunofluorescent staining. The effect of proinflammatory cytokines on blood group antigen expression of hepatocytes was evaluated by flow cytometry. Instant blood-mediated inflammatory reaction after hepatocyte incubation with ABO-incompatible whole blood was examined using the tubing loop model.ResultsBlood group antigens were mainly expressed on vessels in the portal area. In hepatocyte smear specimens, isolated hepatocytes did not express blood group antigens. In contrast, a subset of cells in the smear specimens of nonparenchymal liver cells stained positive. In the flow cytometry analysis, isolated hepatocytes were negative for blood group antigens, even after 4-h incubation with cytokines. Platelet counts and complement activation were not significantly different in ABO-identical versus ABO-incompatible settings in the tubing loop model.ConclusionOur study showed that blood group antigens were not expressed on hepatocytes, even after isolation procedures or subsequent incubation with cytokines. This finding is an important step toward removing the restriction of ABO matching in hepatocyte transplantation. Our results suggest that ABOi-HTx is a feasible therapeutic option, especially in patients who require urgent treatment with freshly isolated hepatocytes, such as those with acute liver failure.
| S-EPMC7068001 | biostudies-literature
Project description:BackgroundABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT.MethodsTwenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 ≤ age < 18; n = 10).ResultsThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection.ConclusionsABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases.
| S-EPMC6166697 | biostudies-literature
Project description:ABO-incompatible liver transplantation (ABO-i LT) is associated with a higher risk of acute kidney injury (AKI) compared to ABO-compatible liver transplantation (ABO-c LT). We compared the risk of AKI associated with transfusion between ABO-c and ABO-i living donor liver transplantation (LDLT). In 885 cases of LDLT, we used a propensity score analysis to match patients who underwent ABO-c (n = 766) and ABO-i (n = 119) LDLT. Baseline medical status, laboratory findings, and surgical- and anesthesia-related parameters were used as contributors for propensity score matching. AKI was defined according to the "Kidney Disease Improving Global Outcomes" criteria. After 1:2 propensity score matching, a conditional logistic regression analysis was performed to evaluate the relationship between the intraoperative transfusion of packed red blood cells (pRBCs) and fresh frozen plasma (FFP) on the risk of AKI. The incidence of AKI was higher in ABO-i LT than in ABO-c LT before and after matching (after matching, 65.8% in ABO-i vs 39.7% in ABO-c, p < 0.001). The incidence of AKI increased in direct proportion to the amount of transfusion, and this increase was more pronounced in ABO-i LT. The risk of pRBC transfusion for AKI was greater in ABO-i LT (multivariable adjusted odds ratio (OR) 1.32 per unit) than in ABO-c LT (OR 1.11 per unit). The risk of FFP transfusion was even greater in ABO-i LT (OR 1.44 per unit) than in ABO-c LT (OR 1.07 per unit). In conclusion, the association between transfusion and risk of AKI was stronger in patients with ABO-i LT than with ABO-c LT. Interventions to reduce perioperative transfusions may attenuate the risk of AKI in patients with ABO-i LT.
| S-EPMC6912207 | biostudies-literature
Project description:BackgroundGraft local infusion and splenectomy in ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) are associated with high rates of operative complications.MethodsConsecutive ABO-I LDLT patients treated at the National Cancer Centre between January 2012 and February 2013 were identified. The protocol for ABO-I LDLT at the study centre included the administration of rituximab (300 mg/m(2)) at 2 weeks preoperatively, followed by plasma exchanges (target isoagglutinin titre: ? 1:8), basiliximab (20 mg on the day of surgery and on postoperative day 4), and i.v. immunoglobulin (0.8 g/kg on postoperative days 1 and 4) without graft local infusion or splenectomy.ResultsFifteen patients (11 men and four women) who underwent transplantation for liver cirrhosis (n = 3) or hepatocellular carcinoma (n = 12) were identified. These included 13 patients with hepatitis B virus infection, one with hepatitis C virus infection and one with alcoholic cirrhosis. The mean age, mean Model for End-stage Liver Disease (MELD) score and mean graft-to-recipient weight ratio (GRWR) of these patients was 51.8 years, 11.5 and 0.84, respectively. The median isoagglutinin titre before plasma exchange was 1:32 (range: 1:4 to 1:256). There were no hyperacute or antibody-mediated rejections. No bacterial or fungal infections were observed. Complications included herpes zoster viral infection in one patient, postoperative bleeding in one patient and extrahepatic biliary stricture in three patients.ConclusionsThis simplified ABO-I LDLT protocol showed good graft outcomes without immunologic failure or serious infections.
| S-EPMC4159453 | biostudies-literature
Project description:BackgroundThere is increasing evidence of good short-term and medium-term outcomes of ABO incompatible (ABOi) and HLA incompatible (HLAi) kidney transplantation with pre-transplant positive crossmatches in paediatric practice. However, there remain concerns regarding the higher risks of infective complications and antibody-mediated rejections. The aim of our study is to show longer-term follow-up on all ABOi and HLAi paediatric kidney transplant recipients (pKTR) in the UK.MethodsQuestionnaires specifying kidney transplant type, desensitisation requirement and kidney allograft function were sent to 13 paediatric nephrology centres that performed kidney transplantation in children and young people under 18 years of age who received an ABOi and/or HLAi transplant between 1 January 2006 and 31 December 2016. Patient and kidney allograft survival were compared between ABOi, HLAi and ABO/HLA compatible (ABOc/HLAc) groups.ResultsAmong 711 living donor kidney transplants performed in the UK, 23 were ABOi and 6 were HLAi. Patient survival was 87%, 100% and 96% in ABOi, HLAi and ABOc/HLAc groups, respectively, at median follow-up of 6.8 (3.6-14.0) years post-transplant. Death-censored kidney allograft survival was 100% in all 3 groups at last follow-up. There were no cases of primary non-function in ABOi or HLAi groups, but 2% in the ABOc/HLAc group. There was one reported case of Epstein-Barr viral-induced post-transplant lymphoproliferative disorder.ConclusionLonger term follow-up has shown that ABOi and HLAi kidney transplantation are feasible for pKTR where no compatible donors are available, and that minimising desensitisation should be achieved where possible. A higher resolution version of the Graphical abstract is available as Supplementary information.
| S-EPMC9763153 | biostudies-literature
Project description:BackgroundC4d is a specific biomarker for the diagnosis of antibody-mediated rejection (AMR) after cardiac transplantation. Although strongly recommended, routine C4d surveillance is hindered by the invasive nature of endomyocardial biopsy. Targeted ultrasound (US) has high sensitivity, and C4d is abundantly expressed within the graft of patients experiencing AMR, which makes it possible to visualize C4d deposition in vivo using targeted US.MethodsWe designed a serial dilution of C4d-targeted microbubbles (MBC4d) using a streptavidin-biotin conjugation system. A rat model of AMR with C4d deposition was established by pre-sensitization with skin transplantation before cardiac transplantation. MBC4d were injected into recipients and then qualitatively and quantitatively analyzed using the destruction-replenishment method with a clinical US imaging system and analyzed by software.FindingsWe successfully obtained qualitative images of C4d deposition in a wide cardiac allograft section, which, for the first time, reflected real-time C4d distribution. Moreover, normal intensity difference was used for quantitative analysis and exhibited an almost nearly linear correlation with the grade of C4d deposition according to the pathologic evidence. In addition, MBC4d injection did not affect the survival and aggravate injury, which demonstrates its safety.InterpretationThis study demonstrates a noninvasive, quantitative and safe evaluation method for C4d. As contrast-enhanced US has been widely used in clinical settings, this technology is expected to be applied quickly to clinical practice. FUND: National Natural Science Foundation of China and Guangdong Province, Leading Scientific Talents of Guangdong special support program, the Science and Technology Project of Guangdong Province and Guangzhou City.
| S-EPMC6286270 | biostudies-literature