Perivascular Macrophages in Neuroinflammation, the role of the Scavenger Receptor CD163

Afvalverwijdering door de poortwachters van de hersenen Babs Fabriek, promotie 23 februari 2007, faculteit geneeskunde VUmc Rond de bloedvaten in de hersenen bevinden zich cellen die in staat zijn om gevaar te herkennen en om alarm te slaan. Mogelijk spelen deze cellen ook een rol bij de ontstekingen in de hersenen bij de ziekte multiple sclerose (MS). Dit zijn de belangrijkste conclusies van het promotieonderzoek van Babs Fabriek. Op vrijdag 23 februari zal zij haar proefschrift bij de faculteit geneeskunde aan VU medisch centrum verdedigen. Babs Fabriek heeft zich tijdens haar promotieonderzoek gericht op de perivasculaire macrofagen. Deze cellen liggen in de hersenen bij de bloedvaten en leveren een bijdrage aan het beschermen van het hersenweefsel tegen bacteriën en ontstekingsverwekkers vanuit de bloedbaan. Dit doen de cellen doordat ze deeltjes, zoals bacteriën kunnen opnemen en verteren. Potentiële ziekteverwekkers worden door de macrofaag herkend door herkenningseiwitten (receptoren) op het celoppervlak. Belangrijk hiervoor zijn de scavenger-receptoren. Deze receptoren zijn zo genoemd omdat ze een rol spelen bij het opruimen van afvalstoffen in het lichaam. Babs Fabriek heeft zich in haar promotieonderzoek met name gericht op de scavenger receptor CD163. Het onderzoek laat zien dat CD163 functioneert als een receptor voor een scala aan bacteriën. De herkenning van bacteriën door CD163 leidt tot de productie van bepaalde signaalstoffen, cytokinen, door macrofagen, die op hun beurt ontstekingsreacties in gang kunnen zetten of versterken. Daarnaast bleek CD163 ook, in afwezigheid van bacteriën, een rol te kunnen spelen in de herkenning tussen cellen onderling. Bovendien heeft ze gevonden dat CD163 verhoogd aanwezig is in het brein van mensen met MS. Verder heeft ze een verband gevonden tussen de hoeveelheid CD163 aanwezig op de cellen en de effectiviteit van een steroïden kuur bij MS-patiënten tijdens een Schub. Bovenstaande bevindingen suggereren een belangrijke rol voor de scavenger receptor CD163 tijdens ontstekingsprocessen in de hersenen, en identificeren CD163 als een potentieel interessant target voor therapeutische interventie.Dijkstra, C.D. [Promotor]Berg, T.K. van den [Copromotor

High body mass index and pre-existing autoimmune disease are associated with an increased risk of immune-related adverse events in cancer patients treated with PD-(L)1 inhibitors across different solid tumors

BACKGROUND\nPATIENTS AND METHODS\nRESULTS\nCONCLUSION\nTreatment with anti-PD-(L)1 antibodies, approved for several oncology indications, can lead to immune-related adverse events (irAEs). We aimed to investigate risk factors associated with an increased reporting of irAEs in patients treated with PD-(L)1 inhibitors approved for solid tumor indications.\nA retrospective review was performed of individual data from patients in phase II/III registrational studies for PD-(L)1 inhibitors in solid tumors. Data on baseline characteristics and adverse events were extracted. Univariate and multivariable logistic regression models were used to identify risk factors.\nIn total, 5123 patients were included from 15 studies reporting on the use of four PD-(L)1 inhibitors for five solid tumor indications. Univariate analysis suggested that type of study drug (P 2 [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.2-1.8] in comparison to normal BMI, having an autoimmune disease at baseline (OR 1.8, 95% CI 1.1-2.7), and use of a PD-L1 inhibitor (OR 1.6, 95% CI 1.2-2.0). The latter finding is probably biased due to the selection of the studies in the dataset with complete information on baseline characteristics.\nThis study was conducted using a large dataset of individual patient data from clinical trials comprising multiple solid tumor indications. We demonstrated that patients with obesity and concurrent autoimmune disease were at increased risk of developing irAEs.FWN – Publicaties zonder aanstelling Universiteit Leide

Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively.Conclusions: We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.Background: Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons.Methods: In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry.Objective: The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children

Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus.

CONTEXT: Recent findings point to an increasing number of hypothalamic proteins involved in the central regulation of thyroid hormone feedback. The functional neuroanatomy of these proteins in the human hypothalamus is largely unknown at present. OBJECTIVE: The aim of this study was to report the distribution of type II and type III deiodinase (D2 and D3) as well as the recently identified T(3) transporter, monocarboxylate transporter 8 (MCT8), in the human hypothalamus. DESIGN: The study included enzyme activity assays, immunocytochemical studies, and mRNA in situ hybridizations in postmortem human hypothalamus (n = 9). RESULTS: D2 immunoreactivity is prominent in glial cells of the infundibular nucleus/median eminence, blood vessels, and cells lining the third ventricle. By contrast, both D3 and MCT8 are expressed by neurons of the paraventricular (PVN), supraoptic, and infundibular nucleus (IFN). In support of these immunocytochemical data, D2 and D3 enzyme activities are detectable in the mediobasal human hypothalamus. Combined D2, D3, MCT8, and thyroid hormone receptor immunohistochemistry and TRH mRNA in situ hybridization clearly showed that D3, MCT8, and thyroid hormone receptor isoforms are all expressed in TRH neurons of the PVN, whereas D2 is not. CONCLUSIONS AND IMPLICATIONS: Based on these findings, we propose three possible routes for thyroid hormone feedback on TRH neurons in the human PVN: 1) local thyroid hormone uptake from the vascular compartment within the PVN, 2) thyroid hormone uptake from the cerebrospinal fluid in the third ventricle followed by transport to TRH neurons in the PVN or IFN neurons projecting to TRH neurons in the PVN, and 3) thyroid hormone sensing in the IFN of the mediobasal hypothalamus by neurons projecting to TRH neurons in the PVN.

The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria

The plasma membrane glycoprotein receptor CD163 is a member of the scavenger receptor cystein-rich (SRCR) superfamily class B that is highly expressed on resident tissue macrophages in vivo. Previously, the molecule has been shown to act as a receptor for hemoglobin-haptoglobin complexes and to mediate cell-cell interactions between macrophages and developing erythroblasts in erythroblastic islands. Here, we provide evidence for a potential role for CD163 in host defense. In particular, we demonstrate that CD163 can function as a macrophage receptor for bacteria. CD163 was shown to bind both Gram-positive and -negative bacteria, and a previously identified cell-binding motif in the second scavenger domain of CD163 was sufficient to mediate this binding. Expression of CD163 in monocytic cells promoted bacteria-induced proinflammatory cytokine production. Finally, newly generated antagonistic antibodies against CD163 were able to potently inhibit cytokine production elicited by bacteria in freshly isolated human monocytes. These findings identify CD163 as a macrophage receptor for bacteria and suggest that, during bacterial infection, CD163 on resident tissue macrophages acts as an innate immune sensor and inducer of local inflammation

Pediatric Microdose Study of [C-14] Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Background Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons. Objective The objective of this study was to present pilot data of an oral [C-14] paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children. Methods In an open-label microdose pharmacokinetic pilot study, infants (0-6 years of age) received a single oral [C-14] AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and [C-14] AAP and metabolites ([C-14] AAP-Glu and [C-14] AAP-4Sul) were measured by accelerator mass spectrometry. Results Ten infants (aged 0.1-83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [C-14] AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (C-max) [C-14] AAP 1.68 (0.75-4.76) ng/L, [C-14] AAP-Glu 0.88 (0.34-1.55) ng/L, and [C-14] AAP-4Sul 0.81 (0.29-2.10) ng/L. Dose-normalized oral [C-14] AAP C-max approached median intravenous average concentrations (C-av): 8.41 mg/L (3.75-23.78 mg/L) and 8.87 mg/L (3.45-12.9 mg/L), respectively. Conclusions We demonstrate the feasibility of using a [C-14] labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children