Hyperacute Rejection Research Articles

Indoleamine 2,3-Dioxygenase 1 (IDO1) in Kidney Transplantation: A Guardian against Rejection.

Kidney transplantation is a crucial treatment for end-stage kidney disease, with immunosuppressive drugs helping to reduce acute rejection rates. However, kidney graft longevity remains a concern. This study explores the role of indoleamine 2,3-dioxygenase 1 (IDO1) in kidney transplant immunology. IDO1 breaks down tryptophan, affecting immune cell behavior, primarily T-cells. The research focuses on both cellular and antibody-mediated immune responses, often causing graft damage. The study assessed IDO1 expression in renal transplant biopsies from patients with graft function decline, examining its connection to clinical parameters. A total of 121 biopsy samples were evaluated for IDO1 expression using immunohistochemistry. Patients were categorized as IDO1(+) positive or IDO1(-) negative based on immunoreactivity in tubular epithelium. Results showed a significant link between IDO1 expression and rejection incidence. IDO1(+) positive patients had lower rejection rates (32.9%) compared to IDO1(-) negative ones (62.2%) [p = 0.0017], with substantial differences in antibody-mediated rejection (AMR) (5.2% vs. 20%) [p = 0.0085] and T-cell mediated rejection (TCMR) (31.6% vs. 57.8%). These associations suggest that IDO1 may play a protective role in kidney transplant rejection. IDO1 modulation could offer novel therapeutic avenues to enhance graft survival. The study underscores IDO1 as a potential marker for rejection risk assessment, with its potential applications in personalized interventions and improved patient outcomes. Further research is needed to fully comprehend the mechanisms behind IDO1's immunomodulatory functions and its potential clinical translation.

Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) Tcells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of isletallo-transplantation. We find that treatment of allo-sensitized hosts with CAR Tcells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent isletallografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.

The potential of cardiac xenotransplantation for management of infants with complex congenital heart disease.

Gene editing of the porcine genome has enabled the production of pigs that do not express the three known carbohydrate antigens that are associated with hyperacute rejection of a pig organ xenotransplant. In addition, it is now possible to insert a variety of human transgenes to protect against the human immune response, e.g., to protect from complement and coagulation activation. As a result, cardiac xenotransplantation of the gene-edited porcine heart is progressing towards clinical application. Many hope that it will definitively address the disparity between organ supply and demand. The role of cardiac xenotransplantation in pediatric care remains controversial but we believe there is an infant patient population with complex congenital heart disease (CHD) (not optimally managed by conventional surgical approaches) that is ideally suited to initial clinical application of this new technology. The most efficacious start would be to initiate clinical use as a short-term bridge to allotransplantation, particularly in infants with single ventricle pathology and significant risk factors for first stage Norwood palliation. Infants with end-stage heart failure after first stage palliation would represent a second target population. Infants experience unacceptably high mortality and morbidity when placed on mechanical circulatory support as a bridge to allotransplant. Effectively bridging these vulnerable populations could promote acceptance of cardiac xenotransplantation, allowing indications and use to expand, e.g., by (I) bridging patients with failed second and third stage single ventricle disease, or (II) with complex biventricular CHD, or (III) those with a restrictive or dilated cardiomyopathy. Finally, there is a reasonable expectation that the immunologic privilege of infants will allow porcine heart xenotransplantation to be destination therapy for some patients. In summary, heart allotransplantation in infants offers superior outcomes when compared to three-stage single ventricle palliation, but there is a continual shortage of deceased human donor organs. We should pursue research towards the application of xenotransplantation in patients with single ventricle pathology, in whom the results of staged palliation are likely to be suboptimal. There are many remaining issues to be resolved before cardiac xenotransplantation enters regular pediatric clinical use, but experience in this field is progressing rapidly.

I-JAMM-(I): A survey providing an insight into the practices of isoagglutinin titration in ABO incompatible kidney and liver transplantation

Background and objectivesABO-incompatible transplantations allow patients to receive timely transplants. Isoagglutinin titration to ascertain levels of incompatible antibodies in the recipient is important in determining patient selection and transplant survivability. To find out the prevalent trends in India, the largest, first of its kind survey was carried out among the transplant centers regarding their practices in isoagglutinin titration. MethodsThe survey was drafted by a working group of Transfusion and Transplant Immunology specialists from six different centers. Data was obtained via the use of an online questionnaire. ResultsResults were categorized into four categories, Hospital information, Titration methodology, Role of transfusion specialists and cut-off titers. Most centers had a well-established solid-organ transplant program with considerable number of ABO-incompatible transplantations. Most centers performed isoagglutinin titration in Transfusion Medicine department. Column Agglutination Technique (CAT) was the most common method, using EDTA blood samples and freshly-prepared in-house pooled cells. Most centers had a turn-around time of less than 12 h. While the policy for ascertaining baseline and threshold titers is well-defined in ABO-incompatible renal transplants, variations from center to center still exist for ABO-incompatible liver transplants. Most centers required a Transfusion Medicine consultation for the patients before such transplants. ConclusionWith increasing ABO-incompatible kidney and liver transplants across the country, the role of Transfusion medicine specialists has become vital in pre-conditioning regimes enabling the viability and success of such transplants. This was a unique survey that provided a snapshot of current trends and practices of isoagglutinin titration for ABO-incompatible transplants in India.

Reproductive Immunology and Embryo Acceptance

Pregnancy is a test of the fundamental laws of transplantation immunology - the coexistence of genetically disparate tissues without host immune rejection. Advances over recent decades show that implantation and placental development depend on an active state of maternal immune tolerance, and breakdown of tolerance is a key contributor to infertility and recurrent pregnancy loss. Tolerance in pregnancy depends on regulatory T (Treg) cells, which are critical to inhibit effector immunity, constrain inflammation, and support maternal vascular adaptations that allow placental access to maternal nutrient supply. Treg cell defects are implicated in disorders of embryo implantation and placental development, but the origins of Treg cell dysfunction are unknown. In recent studies, we have comprehensively analysed the phenotypes and transcriptional profile of peripheral blood Treg cells in individuals with early pregnancy failure (recurrent miscarriage and recurrent implantation failure). Compared to fertile women, women with early pregnancy failure have fewer total Treg cells and altered Treg cell phenotypes, accompanied by lower Treg:Th1 and Treg:Th17 ratios. RNAseq demonstrates an aberrant Treg cell gene expression profile in early pregnancy failure, with upregulation of pro-inflammatory genes including CSF2, IL4, IL17A, IL21, and IFNG. Our data indicate that Treg cell defects in women with early pregnancy failure can arise due to loss of lineage fidelity associated with impaired FOXP3 regulation. Factors including metabolic function, luteal phase progesterone, and male partner seminal fluid components are all implicated in causing Treg cell deficit. Treg cells may be a useful target for therapeutic interventions to improve uterine receptivity, but this will depend on developing diagnostic tests that are informative. Moreover, safe, and effective interventions to modulate these cells are in their infancy, and personalized approaches matched to specific diagnostic criteria will be needed.

Evaluation of the Venous System of Wistar Rat Liver by Injection with Epoxy Resin

The rat is the most widely used experimental model in surgical research due to several factors, including that it is easy to handle and inexpensive. It can be used in investigations related to liver regeneration, liver metastases, or transplant immunology. This study highlights the venous components of the hepatic circulation in the Wistar rat by intravascular injection of a polymer that allows the assessment of the distribution of vessels, regardless of their caliber. Five cadavers of 11-month-old male Wistar rats from the USAMV Cluj-Napoca biobase destined for incineration, were used to highlight the liver venous system. A dye mixture, consisting of epoxy resin-catalyst-blue acrylic dye in a 2:1:1 ratio, was injected. After 24 hours, biological tissues were macerated by immersion in 10% KOH solution for five days. The intrahepatic venous system is represented by the venous branches that continue into the liver lobes. Those vessels follow a parallel trajectory with the hepatic artery branches represented by the right and left ramifications. The right portal vein presents branches to the lateral and medial parts of the right lobe of the liver and the caudate lobe. The left branch of the portal vein has ramificationsfor the lateral and medial parts of the left lobe and the quadrate lobe. The technique of injecting the venous circulation of the liver, followed by tissue maceration, allowed the removal by anatomical dissection of all liver components that permits the identification of all components of the venous system, including the finest venous branches of the hepatic circulation.

Necropsy findings in heart transplant recipients with and without primary graft dysfunction: a retrospective study

Abstract Background Primary graft dysfunction (PGD) is the leading cause of death in the first year after heart transplant (HT). Physiopathology of PGD is not clear, and histological findings are not defined in literature. Purpose The objective of this study is to describe the morphological findings in the hearts of patients who died within the first 14 days after HT and to compare findings between 2 groups: a group with the diagnosis of PGD and a group without PGD. Methods We included all adult patients submitted to HT in one center who died within the first 14 days after the procedure and were submitted to necropsy between January 1st, 2013 and March 31st, 2020. Demographic, perioperative, histological and immunohistochemical data on heart slides obtained on necropsy were recorded retrospectively. We retrospectively analyzed if the patients met the ISHLT criteria for PGD, and then we categorized them in two groups: PGD group or non-PGD group. All heart slides were reviewed by an experienced pathologist considering the presence of histological features of acute cellular rejection, antibody-mediated rejection, necrosis and its morphological characteristics if present. Pathologist was blind for each patient group. We considered the necrosis significant if it took more than 10% of the examined area. All findings were compared between groups. Results Among 322 HTs performed, 31 patients died within 14 days after the procedure. Five patients were not subjected to autopsy, and the remaining 26 patients were included. Twelve patients presented PGD, while 14 patients did not. Comparison between groups shows longer ischemia time, higher incidence of pre-transplant mechanical circulatory support, lower post-transplant left ventricular ejection fraction and higher incidence of post-transplant right ventricular dysfunction in PGD group (Table 1). Necropsy findings were similar between groups and four patterns of necrosis were found, namely microcalcified, contraction-band, coagulative and liquefactive necrosis (Table 2). Necrosis was detected in the 80.7% of all cases, taking more than 10% of the myocardial area in 46.1% of them. Seven patients (26.9%) presented signs of mild cellular rejection (1R). One of them had also antibody-mediated rejection. One patient presented hyperacute graft rejection. The cause of death was defined by necropsy in 21 cases. The most common cause of death in PDG group was cardiogenic shock (66.7%), while in non-PGD group septic shock (28.5%) and bleeding (21.4%) were the most common causes. Conclusion While left ventricular ejection fraction was significantly lower in PGD group, necrosis was a frequent finding both groups, raising the hypothesis maybe necrosis is not directly the cause of cardiac dysfunction in PGD. More studies are needed to fully understand PGD pathology.Table 1Table 2

A Phase 1 Study of RJMty19: Anti-CD19 Humanized CAR-Engineered Allogeneic Double Negative T Cells in Adults with B-Cell Non-Hodgkin's Lymphoma

Introduction: Autologous CAR-T cell therapies has been shown to benefit patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). However, the intrinsic characteristics of autologous CAR-T cell products such as preparation failure, high cost, long production cycle, and bridging therapy required for some patients make it less accessible for a wide range of patients. RJMty19 is a first-in-class humanized anti-CD19 CAR-engineered allogeneic double negative T cells (DNTs). RJMty19 exhibits the advantages of both adaptive and natural immunity and has a high proportion of stem cell-like memory T cells (Tscm). Furthermore, RJMty19 fulfills the requirements of an off-the-shelf cellular immunotherapy, including not causing graft-versus-host disease (GvHD), resistance to host-versus-graft (HvG) rejection, scalability, and storability (WYZE 2022). Preclinical studies had shown that CD19-CAR-DNT has a better safety profile compared to conventional CD19-CAR-T (Zhang 2022). Hence, the first-in-human clinical evaluation of RJMty19 is being undertaken in this Phase 1 study in patients with B-NHL. Methods: This is a first-in-class, open-label, single-dose, phase 1 study of CD19-CAR-DNT cells. The study is designed to evaluate five dose levels (DL) of RJMty19 in a 3+3 dose-escalation scheme: 1×10 6, 3×10 6, 9×10 6, 2×10 7 and 3×10 7 viable CAR + DNT cells per kilogram of body weight. Eligibility criteria included the presence of measurable lesions, at least 2 lines of prior therapy, ECOG score of 0 to 1. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The primary endpoint is dose-limiting toxicities, incidence of adverse events and clinically significant laboratory abnormalities. Secondary endpoints include evaluation of standard cellular PK parameters, PD, immunogenicity, objective response rates (ORR) and disease control rate (DCR) per Lugano 2014 Criteria. This phase 1 study is registered on clinicaltrials.gov (NCT05453669). Results ： As of July 31 2023, 15 patients with B-NHL were enrolled and 12 patients were evaluable (including one subject finished infusion for just 10 days). Of the 11 patients who had completed DLT evaluations at Day 28, five (45.5%) were male, and the average age was 59.7 years (range 45-74). At baseline, 73% of patients with IPI score ≥ 3 (range 0-4); the median volume of target lesion was 169,000 (4520-513,688) mm 3. The median number of prior therapies was three (range2-9). Furthermore, five patients had prior BTKi therapy and four patients had prior lenalidomide/venetoclax therapy before recruiting into the trial. No patients had been treated with autologous CD19-CART products. Following single RJMty19 infusion, there was no cases of GvHD, ICANS and SAEs. Only one patient developed a grade 2 CRS which was resolved within 24 hours. Except for fever, all of ≥grade 3 adverse events were hematologic disorders including leukopenia, lymphocytopenia, neutropenia, reduced platelet count and anemia (Table 1). Among patients who received ≥ 9×10 6 CAR-DNT cells/kg (DL ≥3; N=5), best DCR and ORR were 100% (5/5) and 40% (2/5) respectively at Day 28 with B-ultrasound imaging. One of patients in DL4 achieved 87% reduction of tumor lesions (SPD) at Day 31 and Day 61. CD19-CAR-DNT cell kinetics improved in a dose-dependent manner with peak cell expansion occurring between Day 5 and 7 at DL4 based on flow cytometry. Additionally, the mean of C max in DL4 is 384 CAR + DNT cells per microliter (μl) blood (N=3), and the highest peak value of 936 CAR + DNT cells/μl was detected in the recent enrolled patient.

Risk Factors and Causality of Early Graft Loss in Kidney Transplanted Patients in Northwestern Iran: A 10-Year Retrospective Study

Background: Early graft loss (EGL) is one of the rare complications of kidney transplantation. Several factors play a role in the occurrence of EGL in kidney transplant recipients, which must be identified and limited. Objectives: This ten-year retrospective study was conducted in a single center on 32 kidney transplant recipients with EGL to determine the reasons for and risk factors of kidney transplant rejection in Iran. Methods: This descriptive-analytical study’s population included 605 kidney transplant recipients receiving kidneys during the last ten years in our center. The diagnosis of EGL was based on renal allograft biopsy examination and primary clinical complications, including a rapid increase in serum creatinine. The age, gender, blood group, and rhesus (Rh) of both donors and recipients, as well as the kinship between the donor and recipient (relative and non-relative), right/left-sided living donor/recipient kidneys, primary kidney disease, the presence of underlying disease in the recipient, dialysis duration, the year of kidney transplantation, transplant survival time, patient survival time, and complications (surgery and others) were gathered. The data were analyzed using SPSS version 18. Results: In this study, 32 out of 605 kidney transplant recipients (5.28%) experienced EGL (53.1% male and 46.9% female, average age of 41.12 years). The duration of kidney function after transplantation was 5.56 ± 0.13 days. The transplanted kidneys were functional between 72 hours and one week after transplantation in 34.4% of the patients. The causes of EGL were found to be tissue rejection in 31.3% of the patients and vascular thrombosis and hyperacute rejection in 21.8%. Nephrectomy occurred in 41% of the patients, and 43.75% died because of a heart attack. Conclusions: Our findings supported previous studies' results, suggesting that EGL is associated with receiving an incompatible kidney transplant and surgery-related complications, including bleeding and thrombosis.

Immune rejection: current understanding and new solutions

While organ transplantation has emerged as a successful treatment option for certain human diseases, failure to induce life-long graft tolerance remains the most significant obstacle to achieving optimal post-op outcomes. To better cope with this challenge, it is particularly important to understand and distinguish between the different mechanisms that induce graft rejection. After transplantation, host immune responses can be triggered by both stranger and danger signals. Genetic differences between individuals contribute to the identification of foreign entities by recipient immune cells. The recovery and preservation of organs lead to the cell stress or death, inducing inflammation and further aggravating graft damage. Herein, I aim to summarize the modern understanding of transplant immunology and compare the current medical scheme with innovative strategies. This review focuses on recent progresses in stem cell transplant and compiles technological breakthroughs to improve autologous iPSC therapeutics.

Association between blood transfusion after kidney transplantation and risk for the development of de novo HLA donor-specific antibodies and poor clinical outcomes: A single-center retrospective study

BackgroundBlood transfusion after kidney transplantation may increase the risk of sensitization and development of de novo human leukocyte antigen (HLA) donor-specific antibodies (DSAs). This study aimed to evaluate whether blood transfusion during the first year after kidney transplantation influences the development of de novo DSAs and clinical outcomes of kidney transplantation recipients. MethodsThis retrospective cohort study included nonsensitized first-time kidney transplantation recipients at Tianjin First Central Hospital from 2010 to 2022. The incidence of de novo DSA development and clinical outcomes between the groups were compared. Luminex single antigen beads were used to monitor DSAs. ResultsOf the 538 non-HLA-sensitized kidney transplantation recipients included in the study, 164 patients who received at least one unit of leukoreduced red blood cell transfusion within the first year (the transfused group), whereas the remaining 374 patients received no blood transfusion (the non-transfused group). Our analysis showed that there was a significant difference in the development of de novo DSAs and de novo anti-class I HLA-Ab between the two groups. Indeed, the transfused recipients had a higher serum creatinine and lower estimated glomerular filtration rate (eGFR) at 1-, 6-, and 12-month (all p > 0.05) after transplantation. Futhermore, a higher incidence of CMV infection, antibody-mediated rejection (AMR), hyper acute rejection (HAR), and delayed graft function (DGF) was identified in the transfused group (all p < 0.05). The graft survival was lower in the transfused group compared with patients in the non-transfused group (P = 0.002). Blood transfusion post-transplantation was a risk factor for de novo DSAs development but not an independent predictive factor for AMR and graft loss (odds ratio = 2.064 [1.243–3.429], p = 0.005). ConclusionsOur study showed that blood transfusion after transplantation is associated with the occurrence of de novo DSAs increasing an immunological risk for poor clinical outcomes for kidney transplantation recipients.

Mode of action, indications and recommendations on extracorporeal photopheresis (ECP).

Extracorporeal photopheresis (ECP) has gained importance in the treatment of several diseases. Initially introduced as a new therapeutic modality for the treatment of patients with cutaneous T-cell lymphoma, the indications for the use of ECP have expanded to include hematology and transplantation immunology. Extracorporeal photopheresis has found its place in the treatment plan of cutaneous T-cell lymphoma, systemic sclerosis, graft-versus-host disease, organ transplantation such as heart and lung, sometimes as first-line therapy and very often in combination with various systemic immunosuppressive therapies. The procedure basically consists of three steps: leukapheresis, photoactivation and reinfusion. The following article presents possible theories about the mechanism of action, which is not yet fully understood, and discusses the five most common indications for ECP treatment with corresponding therapy recommendations.

The immunology of organ transplantation

The immunology of organ transplantation

The impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney: A retrospective cohort study

IntroductionThe preoperative examination of kidney transplantation includes HLA antibody screening to initially determine the presence of preexisting donor-specific antibody (DSA) that mediates hyperacute rejection. Recipients with positive HLA antibodies require further HLA specificity analysis to type the antigen and determine the antigen mismatches between the donor and recipient. However, recipients with suspected antibodies would have no further HLA specificity analysis. It is unclear whether suspected HLA antibodies would affect renal graft function. This study aimed to explore the impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney and thus determine the necessity of routinely performing the HLA specificity analysis in recipients with suspected HLA antibodies preoperatively. MethodsThis is a single-center retrospective cohort study. 179 kidney transplant recipients (KTRs) were included and further divided into HLA antibody-negative group (Group 1) and HLA antibody-suspected groups (Group 2) based on the result of the pretransplant HLA antibody screen test. And the antibody-suspected group was further divided into a low-mismatched group (Group A) and a high-mismatched group (Group B) according to the HLA specificity analysis. We tracked the renal function indexes, biochemical indexes, and posttransplant adverse events within 5 years after transplantation and explored the necessity of further HLA specificity analysis in recipients with pretransplant suspected HLA antibodies. ResultsThere was no statistically significant difference in demographics between HLA antibody-negative group and HLA antibody-suspected groups. At 5 years of follow-up, the KTRs in HLA antibody-negative group had significantly higher eGFR levels, lower serum creatinine levels, and less urinary protein compared to those in antibody-suspected group. Meanwhile, the KTRs in low-mismatched group also had significantly higher eGFR levels, lower serum creatinine levels, and less proteinuria compared to those in high-mismatched group. Correlation analysis showed that the age of KTRs, urinary protein levels and the load capacity of HLA mismatches were associated with eGFR levels of KTRs at 5 year posttransplant. ConclusionKTRs with suspected HLA antibodies before kidney transplantation have worse graft function than the preoperative HLA antibody-negative recipients in the long-term posttransplant follow-up. The specific load capacity of HLA mismatches, the age of the recipient and the urinary protein was found to be negatively correlated with long-term posttransplant renal outcomes. It is necessary to undergo further HLA specificity analysis for recipients with suspected HLA antibodies in HLA antibody screen test to explicit HLA mismatches and improve long-term posttransplant outcomes.

Feasibility of an implantable bioreactor for renal cell therapy using silicon nanopore membranes

The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain >90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage, and recipient cytokine levels are not suggestive of hyperacute rejection. These initial data confirm the potential feasibility of an implantable bioreactor for renal cell therapy utilizing silicon nanopore membranes.

Sir Peter Brian Medawar and the Genesis of Transplantation Immunology

Sir Peter Brian Medawar and the Genesis of Transplantation Immunology

Graft rejection in paediatric congenital heart disease.

Congenital heart disease (CHD) affects around 1.35 million neonates worldwide per annum, and surgical repair is necessary in approximately 25% of cases. Xenografts, usually of bovine or porcine origin, are often used for the surgical reconstruction. These xenografts elicit an immune response due to significant immunological incompatibilities between host and donor. Current techniques to dampen the initial hyperacute rejection response involve aldehyde fixation to crosslink xenoantigens, such as galactose-α1,3-galactose and N-glycolylneuraminic acid. While this temporarily masks the epitopes, aldehyde fixation is a suboptimal solution, degrading over time, resulting in cytotoxicity and rejection. The immune response to foreign tissue eventually leads to chronic inflammation and subsequent graft failure, necessitating reintervention to replace the defective bioprosthetic. Decellularisation to remove immunoincompatible material has been suggested as an alternative to fixation and may prove a superior solution. However, incomplete decellularisation poses a significant challenge, causing a substantial immune rejection response and subsequent graft rejection. This review discusses commercially available grafts used in surgical paediatric CHD intervention, looking specifically at bovine jugular vein conduits as a substitute to cryopreserved homografts, as well as decellularised alternatives to the aldehyde-fixed graft. Mechanisms of biological prosthesis rejection are explored, including the signalling cascades of the innate and adaptive immune response. Lastly, emerging strategies of intervention are examined, including the use of tissue from genetically modified pigs, enhanced crosslinking and decellularisation techniques, and augmentation of grafts through in vitro recellularisation or functionalisation with human surface proteins.

The Clinical Utility of Post-Transplant Monitoring of Donor-Specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report With Guideline Statements for Clinical Practice.

Solid phase immunoassays improved the detection and determination of the antigen-specificity of donor-specific antibodies (DSA) to human leukocyte antigens (HLA). The widespread use of SPI in kidney transplantation also introduced new clinical dilemmas, such as whether patients should be monitored for DSA pre- or post-transplantation. Pretransplant screening through SPI has become standard practice and DSA are readily determined in case of suspected rejection. However, DSA monitoring in recipients with stable graft function has not been universally established as standard of care. This may be related to uncertainty regarding the clinical utility of DSA monitoring as a screening tool. This consensus report aims to appraise the clinical utility of DSA monitoring in recipients without overt signs of graft dysfunction, using the Wilson & Junger criteria for assessing the validity of a screening practice. To assess the evidence on DSA monitoring, the European Society for Organ Transplantation (ESOT) convened a dedicated workgroup, comprised of experts in transplantation nephrology and immunology, to review relevant literature. Guidelines and statements were developed during a consensus conference by Delphi methodology that took place in person in November 2022 in Prague. The findings and recommendations of the workgroup on subclinical DSA monitoring are presented in this article.

Pig-to-human heart xenotransplantation in two recently deceased human recipients.

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

Updates and Expert Opinions on Liver Transplantation for Gastrointestinal Malignancies.

Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) of the liver. Although there are established criteria for LT in HCC, evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.