Personne : Poubelle, Patrice
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Centre de recherche en Rhumatologie et Immunologie, Université Laval
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- PublicationAccès libreThe evaluation of cytokines to help establish diagnosis and guide treatment of autoinflammatory and autoimmune diseases(Md. Society for Leukocyte Biology, 2020-02-10) Chetaille, Anne-Laure; Poubelle, Patrice; Pelletier, MartinOur knowledge of the role of cytokines in pathologic conditions has increased considerably with the emergence of molecular and genetic studies, particularly in the case of autoinflammatory monogenic diseases. Many rare disorders, considered orphan until recently, are directly related to abnormal gene regulation, and the treatment with biologic agents (biologics) targeting cytokine receptors, intracellular signaling or specific cytokines improve the symptoms of an increasing number of chronic inflammatory diseases. As it is currently impossible to systematically conduct genetic studies for all patients with autoinflammatory and autoimmune diseases, the evaluation of cytokines can be seen as a simple, less time consuming, and less expensive alternative. This approach could be especially useful when the diagnosis of syndromes of diseases of unknown etiology remains problematic. The evaluation of cytokines could also help avoid the current trial-and-error approach, which has the disadvantages of exposing patients to ineffective drugs with possible unnecessary side effects and permanent organ damages. In this review, we discuss the various possibilities, as well as the limitations of evaluating the cytokine profiles of patients suffering from autoinflammatory and autoimmune diseases, with methods such as direct detection of cytokines in the plasma/serum or following ex vivo stimulation of PBMCs leading to the production of their cytokine secretome. The patients' secretome, combined with biomarkers ranging from genetic and epigenetic analyses to immunologic biomarkers, may help not only the diagnosis but also guide the choice of biologics for more efficient and rapid treatments.
- PublicationAccès libreThe use of leukocytes’ secretome to individually target biological therapy in autoimmune arthritis : a case report(Springer, 2019-06-05) Longchamps, Marie-Pier; Poubelle, Patrice; Pagé, Nathalie; Sampaio Moura, Natalia; Tessier, Philippe; Beck, David B.; Pelletier, Martin; Aksentijevich, IvonaBackground Biological agents have allowed remarkable improvement in controlling autoimmune arthropathies, although none of the numerous biologics readily available represent a universal treatment standard. Moreover, classical and genetic predictors are currently unsatisfactory to predict individual response to a biologic, and the best treatment selection is still based on a trial-and-error approach. Here, we report a clinical case demonstrating the usefulness of examining the leukocytes’ secretome of patients. We set up and standardized a protocol that examines a patient's immune responses to establish the secretome of the blood mononuclear leukocytes and personalize the biotherapy. Case presentation A 24-year-old woman was diagnosed with active early rheumatoid arthritis. The initial treatment regimen (prednisone, methotrexate, hydroxychloroquine, naproxen) was inefficient, as well as the anti-TNF adalimumab. The diagnosis was revised as possible rheumatoid arthritis-like psoriatic arthritis and adalimumab was replaced by abatacept (IgG1 Fc-CTLA-4) to no avail. Five years later, abatacept was replaced by the anti-IL-12/IL-23 ustekinumab with no objective control over the symptoms. The patient was thus enrolled in a prospective study based on the quantification of cytokines secreted by peripheral blood leukocytes stimulated with well-known immune activators of pattern recognition receptors and cytokine signalling. The results of this study revealed that plasma concentrations of cytokines were similar between the patient and healthy donors. In comparison to leukocytes from healthy donors, the patient's secretome showed a unique overproduction of IL-6. The anti-IL-6 receptor tocilizumab was, therefore, administered with a rapid improvement of her active psoriatic arthritis that remained dependent on low prednisone dosage. Clinical parameters progressively returned to normal levels and her quality of life was greatly improved, despite the major delay to begin the present personalized treatment. Conclusions An efficient way to effectively treat patients with complex autoimmune arthropathies, and avoid irreversible disability, is to know their leukocytes’ secretome to identify abnormally secreted cytokines and personalize their biotherapy, as exemplified by this case report.
- PublicationAccès libreA tagged parathyroid hormone derivative as a carrier of antibody cargoes transported by the G protein coupled PTH1 receptor(ScienceDirect, 2014-08-12) Fortin, Jean-Philippe.; Allaeys, Isabelle; Poubelle, Patrice; Marceau, François; Lodge, Robert; Charest-Morin, XavierBased on the known fact that the parathyroid hormone (PTH) might be extended at its C-terminus with biotechnological protein cargoes, a vector directing the secretion of PTH1–84 C-terminally fused with the antigenic epitope myc (PTH-myc) was exploited. The functional properties and potential of this analog for imaging PTH1R-expressing cells were examined. The PTH-myc construct was recombinantly produced as a conditioned medium (CM) of transfected HEK 293a cells (typical concentrations of 187 nM estimated with ELISAs for PTH). PTH-myc CM induced cyclic AMP formations (10 min), with a minor loss of potency relative to authentic PTH1–84, and c-Fos expression (1–3 h). Treatment of recipient HEK 293a cells transiently expressing PTH1R with PTH-myc CM (supplemented with a fluorescent monoclonal anti-myc tag antibody, either 4A6 or 9E10) allowed the labeling of endosomal structures positive for Rab5 and/or for β-arrestin1 (microscopy, cytofluorometry). Authentic PTH was inactive in this respect, ruling out a non-specific form of endocytosis like pinocytosis. Using a horseradish peroxidase-conjugated secondary antibody, the endocytosis of the PTH-myc-based antibody complex by endogenous PTH1R was evidenced in MG-63 osteoblastoid cells. The secreted construct PTH-myc represents a bona fide agonist that supports the feasibility of transporting cargoes of considerable molecular weight inside cells using arrestin and Rab5-mediated PTH1R endocytosis. PTH-myc is also transported into cells that express PTH1R at a physiological level. Such tagged peptide hormones may be part of a cancer chemotherapy scheme exploiting a modular cytotoxic secondary antibody and the receptor repertoire expressed in a given tumor.