Adeno-associated virus-mediated transduction of PD-L1 in a rodent lung transplant model.

Acute cellular rejection is a key contributor to chronic lung allograft dysfunction following transplantation; while treatable, traditional immunosuppressive therapies are associated with significant side effects. Gene therapy offers an approach to modulate recipient immune responses while minimizing the toxicity of conventional immunosuppressive therapy. In this study, we evaluated adenoassociated virus (AAV)-mediated programmed death-ligand (PD-L)1 overexpression, an inhibitory ligand of T cells, in a rat single-lung transplant model.

Donor-specific mesenchymal stem cell infusion in human and nonhuman primate kidney transplantation.

We report the results of 2 independent, concurrently performed studies evaluating the safety and efficacy of donor-derived mesenchymal stromal cell (MSC) infusions in inducing immune-tolerance in nonhuman primate (NHP) and human kidney transplant recipients treated with depletional induction and belatacept/sirolimus maintenance. Fifteen NHPs received rhesus ATG induction and were divided into 3 groups: control (n = 6), pretransplant thymic irradiation (n = 4), and thymic irradiation with monthly donor-MSC infusion (n = 5). Sirolimus was discontinued at day-180, and belatacept at day-365 posttransplant.

Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries.

The difficulty of delivering genes to the kidney has limited the translation of genetic medicines, particularly for the more than 10% of the global population with chronic kidney disease. Here we show that new variants of adeno-associated viruses (AAVs) displaying robust and widespread transduction in the kidneys of mice, pigs and non-human-primates can be obtained by evolving capsid libraries via cross-species cycling in different kidney models. Specifically, the new variants, AAV.

Transforming the logistics of liver transplantation with normothermic machine perfusion: Clinical impact versus cost.

Normothermic machine perfusion (NMP) facilitates the utilization of marginal liver allografts. It remains unknown whether clinical benefits offset additional costs in the real-world setting. We performed a comparison of outcomes and hospitalization costs for donor livers preserved by NMP versus static cold storage at a high-volume center.

Immunomodulation of T cell-mediated alloimmunity by proximity to endothelial cells under the mammalian target of rapamycin blockade.

Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mammalian target of rapamycin inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection. It also has numerous effects on ECs.

Rapamycin Prevents Expansion of Costimulation Blockade-resistant CD8+ Alloreactive Memory Cells following Depletional Induction in Renal Transplant Recipients.

Alemtuzumab induction with belatacept/rapamycin-based maintenance immunotherapy (ABR) prevents kidney allograft rejection and specifically limits early costimulation blockade-resistant rejection (CoBRR). To evaluate the mechanisms by which this regimen alters CoBRR, we characterized the phenotype and functional response of preexisting memory cells to allogeneic endothelial cells using intracellular cytokine staining and flow cytometry. IL-7-induced lymphocyte proliferation in the presence or absence of rapamycin was assessed to characterize the phenotype of proliferating cells.

Optimizing DCD Liver Grafts With Prolonged Warm Ischemic Time Using Stabilized Plasmin in a Static Cold Storage Orthotopic Rat Liver Transplant Model.

Background: The clinical success of liver transplantation has led to increased demand, requiring further expansion of the donor pool. Therapeutic interventions to optimize organs from donation after circulatory death (DCD) have significant potential to mitigate the organ shortage. Dysfunction in DCD liver grafts is mediated by microvascular thrombosis during the warm ischemic period, and strategies that reduce this thrombotic burden may improve graft function.

Subnormothermic Oxygenated Machine Perfusion (24 h) in DCD Kidney Transplantation.

Background: Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate.

Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma.

Background: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA.

Methods: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT.

Adeno-associated virus mediates gene transduction after static cold storage treatment in rodent lung transplantation.

Objective: Adeno-associated virus is a clinically used gene therapy vector but has not been studied in lung transplantation. We sought to determine the efficacy of adeno-associated virus delivery during static cold storage via the airway versus the pulmonary artery before lung transplantation in a rodent model.

Methods: Lewis rat lung grafts were treated with a dose of 8e8 or 4e9 viral genome/μL recombinant adeno-associated virus subtype-9 vectors containing firefly luciferase genomes administered via the pulmonary artery or airway during cold storage.

Longitudinal Integrated Clerkships and Undergraduate Surgical Education: A Scoping Review and Gap Analysis.

Objective: Longitudinal integrated clerkships (LICs) are an increasingly popular approach to medical student clinical education, and the literature describing them is expanding. Despite this, there is a lack of understanding for how surgery didactics and skills are currently taught as a part of the LIC curriculum.

Design: We conducted a scoping literature review in July 2022 using terms related to LIC and surgical education.

Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model.

Objective: Ex vivo lung perfusion has emerged as a platform for organ preservation, evaluation, and restoration. Gene delivery using a clinically relevant adeno-associated vector during ex vivo lung perfusion may be useful in optimizing donor allografts while the graft is maintained physiologically active. We evaluated the feasibility of adeno-associated vector-mediated gene delivery during ex vivo lung perfusion in a rat transplant model.

Impact of simultaneous heart procurement on outcomes of donation after circulatory death lung transplantation.

Donation after circulatory death (DCD) heart procurement is done using either direct procurement (DP) or thoracoabdominal normothermic machine perfusion (TA-NRP). Both approaches could impact lung transplant outcomes with combined heart and lung procurements from the same donor. The impact of such practice on DCD lung transplant remains unstudied.

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates.

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation.

Sterile inflammation in liver transplantation.

Sterile inflammation is the immune response to damage-associated molecular patterns (DAMPs) released during cell death in the absence of foreign pathogens. In the setting of solid organ transplantation, ischemia-reperfusion injury results in mitochondria-mediated production of reactive oxygen and nitrogen species that are a major cause of uncontrolled cell death and release of various DAMPs from the graft tissue. When properly regulated, the immune response initiated by DAMP-sensing serves as means of damage control and is necessary for initiation of recovery pathways and re-establishment of homeostasis.

AAV9-mediated gene delivery to liver grafts during static cold storage in a rat liver transplant model.

Introduction: Recombinant adeno-associated virus (rAAV) is a novel strategy used clinically for gene delivery, but has not been characterized in the context of organ transplantation. We sought to determine the efficacy of rAAV-mediated gene delivery during static cold storage (SCS) prior to liver transplantation.

Methods: A triple-plasmid transfection protocol was used to produce rAAV subtype-9 vectors containing firefly luciferase genomes in HEK293 cells.

Microstructural changes of cartilage and subchondral bone in a guinea pig model of early- and middle-stage patellofemoral arthritis.

Objective: Patellofemoral arthritis is a common type of knee osteoarthritis and a prime cause of anterior knee pain and disability. Most of the existing research on knee osteoarthritis focuses on tibial-femoral arthritis, while studies on patellofemoral arthritis are relatively rare. This study aims to observe changes in osteochondral and subchondral bone structure over time in the patella and femoral trochlea in an animal model of spontaneous patellofemoral arthritis.

Incidence of Postreperfusion Hyperfibrinolysis in Liver Transplantation by Donor Type and Observed Treatment Strategies.

Background: Hyperfibrinolysis is a possible complication during liver transplantation, particularly immediately after reperfusion.

Methods: We performed a retrospective study to examine the incidence, treatment, and resolution of postreperfusion hyperfibrinolysis in patients undergoing liver transplantation at Duke University Hospital from 2015 to 2020.

Results: Out of 535 patients undergoing liver transplantation, 21 or 3.