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Role of immune and nervous system interaction : pre-clinical and clinical studies

typ_thesis

English

<10670/1.it9ilf>

Abstract

While the immune system is well known for its protective role against infectious pathogens, its role in cancer progression is more complex with some immune mechanisms being protective while others are detrimental. The primary physiological role of the brain is to perceive external physical and social conditions, assess their implications for organismal well-being and modulate the activity of internal physiological processes to optimally adapt to those external conditions. Immune and the nervous systems have long been considered to operate independently from each other, many preclinical and clinical studies have clearly demonstrated that these two systems interact and regulate each other. Despite more and more studies aim at investigating the interactions between the nervous and the immune systems, important issues remain to be elucidated. For example, while human studies have demonstrated a positive impact of well-being on cancer progression, the underlying molecular mechanisms have not been elucidated. On another topic, and while many investigators have investigated whether cytokines could be used as diagnosis or prognosis biomarkers is psychiatric diseases, none of the cytokine studied to date have proven to possess the sensitivity and specificity expected for an accepted diagnostic test value. During my PhD, I have worked on two different projects both related to the interactions between the nervous and the immune system. The goal of my first project was to elucidate the mechanisms by which enriched environment conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in mice. We have found that mice housed in enriched environment were protected from lung metastasis. Protection was associated with lower serum corticosterone levels, increased lung inflammation following extravasation of circulating tumour cells, and rapid killing of early infiltrating tumour cells. Protection was abolished when inflammatory monocytes were deficient in glucocorticoid receptor signalling. Thus, while inflammatory monocytes have been shown to promote cancer progression, our results disclosed a novel anti-tumour mechanism whereby glucocorticoid receptor-dependent reprogramming of inflammatory monocytes can inhibit cancer metastasis. The goal of my second project was to identify immune-related biomarkers of remission in first-episode psychotic (FEP) patients. To this aim, we have taken advantage of our privileged access to clinical data and serum samples from 325 FEP patients who have all been treated with an atypical antipsychotic. We have first used a hierarchical unsupervised clustering approach to stratify 325 FEP patients into four subtypes based on their clinical symptoms. Compared to the rest of the cohort, one subtype (C1A) exhibited more severe positive and negative symptoms and were the most at risk of being non-remitters following treatment for 4 weeks. C1A patients also exhibited higher levels of several pro-inflammatory biomarkers therefore providing an external validation to our clustering approach. Most importantly, six biological variables (serum levels of IL-15, C reactive protein, CXCL-12, anti- cytomegalovirus and anti-Toxoplasma immunoglobulins) and two clinical variables (age, recreational drug use), predicted early remission following treatment with Amisulpride in C1A patients. Prediction accuracy assessed by cross-validation calculated by 10,000 iterations of 4-fold cross-validation was very good with a mean area under the curve (AUC) of 81.0% ± 0.05. Further validation of our results in future clinical trials would pave the way for the development of a blood-based assisted clinical decision support system for the choice of treatment in psychotic patients.

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