Although chronic lung allograft dysfunction (CLAD) remains the major life-limiting factor following lung transplantation, much of its pathophysiology remains unknown. The discovery that CLAD can manifest both clinically and morphologically in vastly different ways led to the definition of distinct subtypes of CLAD. In this review, recent advances in our understanding of the pathophysiological mechanisms of the different phenotypes of CLAD will be discussed with a particular focus on tissue-based and molecular studies. An overview of the current knowledge on the mechanisms of the airway-centered bronchiolitis obliterans syndrome (BOS), as well as the airway and alveolar injuries in the restrictive allograft syndrome (RAS) and also the vascular compartment in chronic antibody mediated rejection is provided. Specific attention is also given to morphological and molecular markers for early CLAD diagnosis or histological changes associated with subsequent CLAD development. Evidence for a possible overlap between different forms of CLAD is presented and discussed. In the end, “tissue remains the (main) issue”, as we are still limited in our knowledge about the actual triggers and specific mechanisms of all late forms of post-transplant graft failure, a shortcoming which needs to be addressed in order to further improve the outcome of lung transplant recipients. This article is protected by copyright. All rights reserved.In December of 2019, the Centers for Medicare and Medicaid Services (CMS) put out a notice of proposed rule-making (NPRM) for 42 CFR Part 486, specifically the section that covers the organ procurement organization (OPO) Conditions for Coverage (CfCs). Most crucially, the proposed rule included two new OPO performance metrics using objective, standardized data from the Centers for Disease Control and Prevention (CDC). These new metrics would employ a denominator that included inpatient deaths from certain causes that could lead to organ donation, rather than the current unverifiable eligible death metric. While there has been near-uniform support for replacing the eligible death denominator with CDC data, a source of contention is CMS’s proposal to not risk adjust for race in their OPO outcome. Nonetheless, there have been calls for race and ethnicity to be included as risk adjusted variables in the CMS donation metric. Herein, we lay out an argument as to why inclusion of race and ethnicity as risk adjustment variables in an OPO performance metric is not only statistically suspect but will hide the inequities that are detrimental to optimal system performance and assurance that all patients have timely access to donation. This article is protected by copyright. All rights reserved.In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete anti-tumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient’s CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically-immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of anti-tumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple anti-tumor and anti-allograft immunity. This article is protected by copyright. All rights reserved.We analyzed humoral immune responses to non-HLA antigens after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, p1R) with an area under the curve (AUC) of .87 (p less then 0.05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection. This article is protected by copyright. EGFR phosphorylation All rights reserved.Laboratory tests to assess CMV-specific cell-mediated immunity (CMV-CMI), such as the QuantiFERON®-CMV assay (QTF-CMV), can be utilized across different clinical scenaria (1) at the end of primary prophylaxis, especially among high-risk (CMV donor-positive/recipient-negative) patients, to determine if extended prophylaxis might be of benefit; at the end of treatment, to support the need for secondary prophylaxis; finally, in patients with asymptomatic DNAemia, to determine if pre-emptive antiviral treatment is indicated. This article is protected by copyright. All rights reserved.Ultrafiltration and diafiltration (UF/DF) unit operations are widely used for the manufacture of therapeutic antibodies to control drug substance protein concentration, pH and excipient properties. During UF/DF, molecular interactions and volume exclusion effects often lead to substantial differences in pH and excipient concentrations between the diafiltration buffer and final UF/DF pool. These differences complicate the design process beyond simply specifying a buffer with the desired drug substance pH and excipient conditions. This paper describes a UF/DF process model which dynamically and accurately simulates UF/DF retentate pool pH and excipient conditions throughout the UF/DF process. This multiscale model accounts for microscopic descriptions of ion-protein charge interactions using the Poisson-Boltzmann equation as well as macroscopic descriptions of volume exclusion and mass transfer. Model predictions of the final UF/DF pool properties were experimentally verified through comparisons to design of experiment (DoE) data from four monoclonal antibody (mAb) processes, each with differing formulations and UF/DF operating conditions.