Advancing mouse models for transplantation research.

Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field.

Evaluation of physicomechanical properties of gluten-based film incorporated with Persian gum and Guar gum.

This study aimed to optimize the formulation of gluten-based composite film incorporated with Persian gum and Guar gum using the response surface method. The effects of three variables gluten (37%wt), Persian gum (1-2%wt), and guar gum (1-2%wt) on the physicochemical properties of the films (thickness, color parameters (L*, ΔE, WI, YI), swelling, solubility, water vapor permeability (WVP) and mechanical properties of the film were investigated. The results confirmed that gluten is compatible with Persian gum and Guar gum.

AL Lambda Amyloidosis Activates Acute Liver Failure in the Absence of Plasma Cell Dyscrasia.

A patient with systemic amyloidosis developed portal hypertension, acute liver failure and multiorgan dysfunction. Extensive testing was unrevealing for paraproteinemia, plasma cell dyscrasia, infectious, or inflammatory conditions. He was transferred to our institution for orthotopic liver transplant evaluation but was ultimately declined given clinical instability and dysautonomia.

The Effect of Adding Memantine to Clonidine in Reducing Withdrawal Symptoms in Opioid-Dependent Patients: A Double-Blind Randomized Controlled Trial.

Objective: Addiction is a complex condition and a brain disease manifested by compulsive substance use despite its harmful consequence. Addicted individuals have an intense focus on using substances. This study aimed to investigate the effect of adding memantine to clonidine and buprenorphine in reducing withdrawal symptoms, compared with placebo, in drug-dependent patients (opium and heroin).

A Drug-Drug Interaction Study Evaluating the Effect of Givosiran, a Small Interfering Ribonucleic Acid, on Cytochrome P450 Activity in the Liver.

Givosiran (trade name GIVLAARI) is a small interfering ribonucleic acid that targets hepatic delta-aminolevulinic acid synthase 1 (ALAS1) messenger RNA for degradation through RNA interference (RNAi) that has been approved for the treatment of acute hepatic porphyria (AHP). RNAi therapeutics, such as givosiran, have a low liability for drug-drug interactions (DDIs) because they are not metabolized by cytochrome 450 (CYP) enzymes, and do not directly inhibit or induce CYP enzymes in the liver. The pharmacodynamic effect of givosiran (lowering of hepatic ALAS1, the first and rate limiting enzyme in the heme biosynthesis pathway) presents a unique scenario where givosiran could potentially impact heme-dependent activities in the liver, such as CYP enzyme activity.

Pharmacokinetic and Pharmacodynamic Properties of Cemdisiran, an RNAi Therapeutic Targeting Complement Component 5, in Healthy Subjects and Patients with Paroxysmal Nocturnal Hemoglobinuria.

Background: Cemdisiran, an N-acetylgalactosamine (GalNAc) conjugated RNA interference (RNAi) therapeutic, is currently under development for the treatment of complement-mediated diseases by suppressing liver production of complement 5 (C5) protein. This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cemdisiran in healthy subjects and in patients with paroxysmal nocturnal hemoglobinuria (PNH) in order to support dose selection for late-stage clinical trials.

Methods: Healthy volunteers (HVs; n = 32, including 12 Japanese subjects) were randomized (3:1) to receive single doses of subcutaneous cemdisiran (50-900 mg) or placebo, or repeat doses of subcutaneous cemdisiran (100-600 mg) or placebo weekly, biweekly, weekly/biweekly, or weekly/monthly for 5, 8, or 13 weeks (n = 24).

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection.

Background: In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies.

Methods: We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant.

Notch-1 Inhibition Promotes Immune Regulation in Transplantation Via Regulatory T Cell-Dependent Mechanisms.

Background: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression.

Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection.

Commonly available clinical parameters fail to predict early acute cellular rejection (EAR, occurring within 6 months after transplant), a major risk factor for graft loss after kidney transplantation. We performed whole-blood RNA sequencing at the time of transplant in 235 kidney transplant recipients enrolled in a prospective cohort study (Genomics of Chronic Allograft Rejection [GoCAR]) and evaluated the relationship of pretransplant transcriptomic profiles with EAR. EAR was associated with downregulation of NK and CD8+ T cell gene signatures in pretransplant blood.

Being accompanied to liver discharge clinic: An easy measure to identify potential liver transplant candidates among those previously considered ineligible.

Background: Patients with cirrhosis deemed ineligible for liver transplantation are usually followed in general hepatology or gastroenterology clinics, with the hope of re-evaluation once they meet the appropriate criteria. Specific strategies to achieve liver transplant eligibility for these patients have not been studied.

Aim: To assess clinical and sociodemographic factors associated with future liver transplant eligibility among patients initially considered ineligible.

Advance Care Planning for Patients with Cirrhosis in a Structured Inpatient/Outpatient Hepatology Program.

Patients with end-stage liver disease (ESLD) have high mortality, but low utilization of palliative care. A transitional care liver clinic (TCLC), bridging inpatient hepatology care to outpatient clinics, should offer the ideal setting for advance care planning (ACP). To examine ACP and related outcomes for TCLC patients who died within one year of the initial TCLC visit.

Bariatric Surgery and Hepatocellular Carcinoma: a Propensity Score-Matched Analysis.

Background: The association between obesity and rising incidence of hepatocellular carcinoma (HCC) in the USA has been documented; however, the role of bariatric surgery remains less clear.

Aim: To evaluate the cross-sectional association of prior-bariatric surgery and HCC.

Methods: The United States Nationwide Inpatient Sample (NIS) database was queried from 2004 to 2014 for discharges with a diagnosis of morbid obesity.

IL-6 production by monocytes is associated with graft function decline in patients with borderline changes suspicious for acute T-cell-mediated rejection: a pilot study.

Although borderline changes (BL) suspicious for acute T-cell-mediated rejection represent a diagnostic category, its clinical relevance is questioned leading to heterogeneous therapeutic management. We hypothesized that measuring IL-6 secretion by peripheral blood mononuclear cells identifies patients with ongoing graft damage. We examined the association between secreted IL-6 and the change in estimated glomerular filtration rate at 6 months after the biopsy (ΔeGFR).

Ganciclovir Dosing Strategies and Development of Cytomegalovirus Resistance in a Kidney Transplant Recipient: A Case Report.

In renal transplant recipients, delayed graft function and accompanying renal impairment may lead to therapeutic underexposure of valganciclovir. We describe a case of a cytomegalovirus (CMV)-seronegative kidney transplant recipient from a CMV-seropositive donor, whose course was complicated during valganciclovir prophylaxis by CMV disease, ultimately progressing to ganciclovir, foscarnet, and cidofovir resistance. Assessments and adjustments for renal dysfunction, according to both Cockgroft-Gault and Modification of Diet in Renal Disease study equations, are described.

Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans.

Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue.

Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study.

Background: Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis.

Methods: This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study.

Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.

Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility.

Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27(KIP1) as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells.

Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival.

Progress in long-term renal allograft survival continues to lag behind the progress in short-term transplant outcomes. Dendritic cells are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to their presence in transplanted kidneys. We used dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as a marker of dendritic cells in 105 allograft biopsy samples from 105 kidney transplant recipients.

TIM-1 signaling is required for maintenance and induction of regulatory B cells.

Apart from their role in humoral immunity, B cells can exhibit IL-10-dependent regulatory activity (Bregs). These regulatory subpopulations have been shown to inhibit inflammation and allograft rejection. However, our understanding of Bregs has been hampered by their rarity, lack of a specific marker, and poor insight into their induction and maintenance.

Tregitope: Immunomodulation powerhouse.

IVIG is frequently used in the 'pre-conditioning' regimens for higher risk transplants; its effects are attributed in part to induction of Tregs. We have identified regulatory T cell (Treg) epitopes, now known as Tregitopes, in IgG, the main component of intravenous immunoglobulin therapy (IVIg). Tregitopes provide one explanation for the expansion and activation of Treg cells following IVIg treatment.

Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.

Tacrolimus and sirolimus are commonly used maintenance immunosuppressants in kidney transplantation. As their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of tacrolimus to sirolimus conversion on the frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late sirolimus conversion and 12 on tacrolimus maintenance were utilized.

T Helper Cells Fate Mapping by Co-stimulatory Molecules and its Functions in Allograft Rejection and Tolerance.

T cell differentiation is dictated by a combination of T cell receptor (TCR) interaction with an antigen-bound major histocompatibility complex (MHC), and co-stimulatory molecules signal. The co-stimulatory signal can be positive or negative, and amplifying or diminishing the initial signal. However, the secondary co-stimulatory signal is not obligatory and its necessity is dictated, in part, by the stage of T cell development.