Effects of Early IL-17A Neutralization on Disease Induction in a Primate Model of Experimental Autoimmune Encephalomyelitis

We report on the effect of antibody-mediated neutralization of interleukin (IL)-17A in a non-human primate experimental autoimmune encephalomyelitis (EAE) model induced with recombinant human myelin oligodendrocyte glycoprotein (rhMOG). We tested a human-anti-human IL-17A-antibody in two doses (3 and 30 mg/kg) against placebo (PBS). The treatment was started 1 day before EAE induction and continued throughout the experiment. Although all monkeys developed clinically evident EAE, the onset of neurological signs was delayed in some monkeys from both treatment groups. Total CNS lesion volumes, demyelination, or inflammation did not differ between the different groups. Immune profiling revealed an altered distribution of IL-17A producing cells in the lymphoid organs of antibody-treated monkeys. Comparable numbers of IL-17A producing cells were observed in the brain. RhMOG-induced T cell proliferation in the lymph nodes was slightly reduced after anti-IL-17A antibody treatment. To summarize, we found that anti-IL-17A antibody as a single treatment from disease induction effects a trend towards delayed neurological disease progression in the marmoset EAE model, although the effect did not reach statistical significance. This suggests a role of IL-17A in late stage disease in the marmoset EAE model, but IL-17A may not be the dominant pathogenic cytokine

Memantine treatment does not affect compulsive behavior or frontostriatal connectivity in an adolescent rat model for quinpirole-induced compulsive checking behavior

RATIONALE: Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment. OBJECTIVE: Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity. METHODS: Juvenile Sprague-Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8). RESULTS: Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections. CONCLUSIONS: The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI

Antibodies Against Human BLyS and APRIL Attenuate EAE Development in Marmoset Monkeys

B lymphocyte stimulator (BLyS, also indicated as BAFF (B-cell activating factor) and CD257), and A Proliferation Inducing Ligand (APRIL, CD256) are two members of the TNF superfamily with a central role in B cell survival. Antibodies against these factors have potential therapeutic relevance in autoimmune inflammatory disorders with a proven pathogenic contribution of B cells, such as multiple sclerosis (MS). In the current study we performed a multi-parameter efficacy comparison of monoclonal antibodies against human anti-BLyS and anti-APRIL in a common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE). A MS-like disease was induced by immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) in complete Freund's adjuvant. The results show that the anti-BLyS and anti-APRIL antibody cause significant depletion of circulating CD20+ B cells, but a small subset of CD20 + CD40highB cells was not depleted. Induction of CD20+ B cell depletion from lymph nodes was only observed in the anti-BLyS treated monkeys. Both antibodies had a significant inhibitory effect on disease development, but all monkeys developed clinically evident EAE. Anti-BLyS treated monkeys were sacrificed with the same clinical signs as saline-treated monkeys, but nevertheless displayed significantly reduced spinal cord demyelination. This effect was not observed in the anti-APRIL treated monkeys. The two antibodies had a different effect on T cell subset activation and the profiles of ex vivo released cytokines. In conclusion, treatment with anti-BLyS and anti-APRIL delays the development of neurological disease in a relevant preclinical model of MS. The two mAbs achieve this effect via different mechanisms

Bragatston study protocol: a multicentre cohort study on automated quantification of cardiovascular calcifications on radiotherapy planning CT scans for cardiovascular risk prediction in patients with breast cancer

Introduction Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECGtriggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called ‘cardiovascular calcifications’) measured automatically on planning CT scans of patients with breast cancer and CVD risk. Methods and analysis In a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n≈16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n≈200) and a random sample of the baseline cohort (n≈600). Ethics and dissemination The Institutional Review Boards of the participating hospitals decided that the Medical R

An Open Resource for Non-human Primate Imaging.

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets

MRI-guided immunotherapy development for multiple sclerosis in a primate

Multiple sclerosis is a serious neurological disease that affects 1 in 1000 young adults in Europe and the USA. The development of an effective therapy for this enigmatic disease is plagued by the failure of many treatments to reproduce in patients the promising effects observed in animal models. This review describes a new preclinical model in a non-human primate that might help to bridge the gap between currently used animal models and the patient