RORγt inverse agonist TF-S14 inhibits Th17 cytokines and prolongs skin allograft survival in sensitized mice.

Chronic antibody mediated rejection (AMR) is the major cause of solid organ graft rejection. Th17 contributes to AMR through the secretion of IL17A, IL21 and IL22. These cytokines promote neutrophilic infiltration, B cell proliferation and donor specific antibodies (DSAs) production. In the current study we investigated the role of Th17 in transplant sensitization. Additionally, we investigated the therapeutic potential of novel inverse agonists of the retinoic acid receptor-related orphan receptor gamma t (RORγt) in the treatment of skin allograft rejection in sensitized mice. Our results show that RORγt inverse agonists reduce cytokine production in human Th17 cells in vitro. In mice, we demonstrate that the RORγt inverse agonist TF-S14 reduces Th17 signature cytokines in vitro and in vivo and leads to blocking neutrophilic infiltration to skin allografts, inhibition of the B-cell differentiation, and the reduction of de novo IgG3 DSAs production. Finally, we show that TF-S14 prolongs the survival of a total mismatch grafts in sensitized mice. In conclusion, RORγt inverse agonists offer a therapeutic intervention through a novel mechanism to treat rejection in highly sensitized patients.

Non-contrast CT markers of intracerebral hematoma expansion: a reliability study.

OBJECTIVES: We evaluated whether clinicians agree in the detection of non-contrast CT markers of intracerebral hemorrhage (ICH) expansion. METHODS: From our local dataset, we randomly sampled 60 patients diagnosed with spontaneous ICH. Fifteen physicians and trainees (Stroke Neurology, Interventional and Diagnostic Neuroradiology) were trained to identify six density (Barras density, black hole, blend, hypodensity, fluid level, swirl) and three shape (Barras shape, island, satellite) expansion markers, using standardized definitions. Thirteen raters performed a second assessment. Inter- and intra-rater agreement were measured using Gwet's AC1, with a coefficient > 0.60 indicating substantial to almost perfect agreement. RESULTS: Almost perfect inter-rater agreement was observed for the swirl (0.85, 95% CI: 0.78-0.90) and fluid level (0.84, 95% CI: 0.76-0.90) markers, while the hypodensity (0.67, 95% CI: 0.56-0.76) and blend (0.62, 95% CI: 0.51-0.71) markers showed substantial agreement. Inter-rater agreement was otherwise moderate, and comparable between density and shape markers. Inter-rater agreement was lower for the three markers that require the rater to identify one specific axial slice (Barras density, Barras shape, island: 0.46, 95% CI: 0.40-0.52 versus others: 0.60, 95% CI: 0.56-0.63). Inter-observer agreement did not differ when stratified for raters' experience, hematoma location, volume, or anticoagulation status. Intra-rater agreement was substantial to almost perfect for all but the black hole marker. CONCLUSION: In a large sample of raters with different backgrounds and expertise levels, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement. KEY POINTS: • In a sample of 15 raters and 60 patients, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement (Gwet's AC1> 0.60). • Intra-rater agreement was substantial to almost perfect for eight of nine hematoma expansion markers. • Only the blend, fluid level, and swirl markers achieved substantial to almost perfect agreement across all three measures of reliability (inter-rater agreement, intra-rater agreement, agreement with the results of a reference reading).