A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.

Effect of temperature control upon a mouse model of partial hepatic ischaemia/reperfusion injury.

In vivo models of hepatic ischaemia/reperfusion injury (IRI) are widely used to study both the mechanisms of hepatic ischaemic injury and to seek means of hepatic protection. Achieving high-quality reproducible data are essential if the results of multiple studies are to be compared and reconciled. This paper presents our findings concerning the effect of intraoperative thermoregulation upon signal to noise ratios of hepatic IRI experiments in mice. Four experiments were conducted, using three different strategies for core temperature maintenance. Animals underwent hepatic IRI and euthanized 24 h postoperatively for measurement of plasma alanine aminotransferase (ALT). Duration of ischaemia was used to adjust the severity of injury. Experiment 1 utilized a constant output heating system and resulted in rising postoperative ALTs following increasing durations of hepatic ischaemia. Experiment 2, using the same constant output heating system confirmed a difference between ischaemic and sham-operated animals. Experiment 3 used a thermostatically controlled heating system and resulted in highly variable results with a small, but statistically significant correlation between ALT levels and rectal temperature readings. Experiment 4 used a homeothermic warming system and demonstrated highly reproducible data from increasing durations of ischaemia. High-quality data from hepatic ischaemia/reperfusion models are dependent upon careful control of intraoperative temperature. The use of homeothermic warming systems is recommended and conversely, the use of thermostatically controlled warming mats is to be avoided in these models.

The chronology of oligodendrocyte differentiation in the rat optic nerve: evidence for a signaling step initiating myelination in the CNS.

In order to determine the signals that initiate axon myelination in the CNS, we have chronicled the differentiation of oligodendrocytes in the rat optic nerve and related this to the time course and spatial gradient seen for optic axon myelination. By using markers specific to the varying stages of oligodendrocyte differentiation we found that oligodendrocyte progenitor cells, present throughout the length of the nerve at postnatal day 2, mature into GC+ oligodendrocytes in a chiasm to eye progression. This gradient along the nerve of oligodendrocyte differentiation continues with oligodendrocytes near the chiasm expressing the genes and encoded proteins to MBP and PLP 3 d before oligodendrocytes near the eye. Although oligodendrocyte differentiation and maturation occurs in a chiasm to eye gradient along the nerve, optic axon segments near the eye are ensheathed with myelin before segments near the chiasm. This suggests that the myelination of optic axons is initiated by a signaling step that is independent of oligodendrocyte differentiation and is stronger near the eye than the chiasm region of the nerve. By examining proposed axonal signals, we found that the onset of myelination is independent of the electrical activity of an axon but can be correlated to the size of an axon.