The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and yearlong survival in clinically relevant pig to primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this commentary, we examine recent progress in islet xenotransplantation, with a critical eye towards the gaps between the current state of the art and the state required for appropriate clinical investigation.

Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. MethodsWe did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. FindingsWe included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58•0%) were male. Median gestational age at birth was 38 weeks (IQR 36-39) and median bodyweight at presentation was 2•8 kg (2•3-3•3). Mortality among all patients was 37 (39•8%) of 93 in low-income countries, 583 (20•4%) of 2860 in middle-income countries, and 50 (5•6%) of 896 in high-income countries (p<0•0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90•0%] of ten in lowincome countries, 97 [31•9%] of 304 in middle-income countries, and two [1•4%] of 139 in high-income countries; p≤0•0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2•78 [95% CI 1•88-4•11], p<0•0001; middle-income vs high-income countries, 2•11 [1•59-2•79], p<0•0001), sepsis at presentation (1•20 [1•04-1•40], p=0•016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4-5 vs ASA 1-2, 1•82 [1•40-2•35], p<0•0001; ASA 3 vs ASA 1-2, 1•58, [1•30-1•92], p<0•0001]), surgical safety checklist not used (1•39 [1•02-1•90], p=0•035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1•96, [1•4...

Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. Wild-type (WT) and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets (NPIs) were studied in non-immunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at one and 24 hours after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages, and platelets. Insulin, complement, antibody, neutrophils, macrophages, and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 hours in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.

Elevated POD2 phosphorus levels >2.4 mg/dl and a delayed nadir in phosphorus beyond POD3 are associated with increased post-operative hepatic insufficiency, major complications and early mortality. Failure to develop hypophosphataemia within 72 h after a major hepatectomy may reflect insufficient liver remnant regeneration.