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Cytokines are crucial molecules for intercellular communication. Interleukin-9 (IL-9), IL-22 Binding protein (IL-22BP) were discovered in the Experimental Medicine Unit. Further research is currently focusing on their implication in human and murine inflammatory diseases. Indeed, cytokines are potential therapeutic targets.
In this context, the production of antibodies specifically targeting a cytokine ca be very useful. Monoclonal antibodies against several human cytokines were already produced. They provide an efficient tool for diagnosis by precisely detecting the presence of a cytokine. Furthermore, inhibitory antibodies are able to neutralize cytokines activities to treat inflammatory disease.
Besides passive antibody treatment, several studies succeeded in generating auto-antibodies in mouse and human, against an endogenous cytokine. Their principle is ti introduce a foreign epitope into the endogenous cytokine structure. T lymphocytes can recognize the heterologous element and activated autoreactive B lymphocytes for the production of antibodies.
The goal of this work was to evaluate the efficiency of an anti-cytokine vaccination with P1-HTR tumor cell, expressing the antigen to their surface, as a vaccinal vector. In the first part of this work, we have tried to vaccinate three strains of mice; Balb/c, C57BL/6 and DBA/2. These mice were injected with a clone of P1-HTR expressing human IL-22R and the result showed that an immunisation can be obtained when mice with the same haplotype as P1-HTR were vaccinated.
In the second part, we have tried to extend this type of immunization to non transmembrane antigens such as cytokines. In order to express such human antigens at the surface of P1-HTR we fused them to CD134L, a natural transmembrane human protein. This allows for surface expression of proteins that are normally secreted. After vaccination, we were able to produce specific antibodies and, among them, we isolated blocking antibodies.
In the last part of my work, we have attempted to autovaccinate mice against their own cytokines, such as IL-9 and IL-22, or soluble receptor, such as IL-22BP. This allowed us to induce the production of auto-antibodies. These antibodies include blocking antibodies able to block IL-9 in vivo biological activities, such as upregulation of mast cell protease production.
With our results, we demonstrate that P1-HTR cells could be used as a vaccinal vector in order to induce auto-antibodies, although this method is restricted to MHC haplotype. Several perspectives come with this work, including its extensions to other cytokines or its use to obtain knock down models Les cytokines sont des acteurs cruciaux de la communication entre les cellules d’un organisme vivant. L’interleukine-9 (IL-9), l’IL-22 Binding Protein (IL22BP) ont été découvertes à l’unité de Médecine Expérimentale et y font, depuis, lors, l’objet d’intenses recherches. En effet, ces protéines ont dévoilé leur implication dans de nombreuses pathologies inflammatoires humaines et murines, et constituent de ce fait des cibles thérapeutiques potentielles.
Dans ce contexte, la production d’anticorps spécifiques d’une cytokine s’avère particulièrement utile à plusieurs titres. Sur cette base, des anticorps monoclonaux contre diverses cytokines humaines ont déjà été produits et constituent des outils diagnostiques performants permettant de détecter avec précision la présence d’une cytokine. De plus l’obtention d’anticorps inhibiteurs permet de neutraliser l’effet néfaste de certaines cytokines dans le décours de maladies inflammatoires.
Au-delà de l’administration passive d’anticorps, plusieurs études ont montré qu’il était possible d’induire chez l’animal, et chez l’homme, des auto-anticorps contre une cytokine endogène. Le principe de ces auto-vaccinations est d’introduire un épitope étranger dans la structure de l’auto-antigène concerné. La reconnaissance de cet élément hétérologue permet l’activation des lymphocytes T, qui peuvent alors aider les lymphocytes B autoréactifs à produire des anticorps contre la cytokine du soi.
Le but de ce travail était d’évaluer l’efficacité d’une vaccination anti-cytokine utilisant comme vecteur la lignée tumorale P1-HTR transfectée de façon à exprimer l’antigène à sa surface. Dans la première partie du travail, nous avons cherché à déterminer l’applicabilité de cette méthode vaccinale à plusieurs races murines. Trois races de souris syngéniques ont reçu des injections de cellules P1-HTR suresprimant le récepteur de l’IL22 humaine. Les résultats ont montré qu’une immunisation satisfaite n’était obtenue que dans les races murines exprimant le même haplotype H-2 que les cellules P1-HTR.
Dans la deuxième partie, nous avons tenté d’établir s’il était possible d’étendre cette stratégie à des ant !gènes comme les cytokines, qui ne sont pas des protéines transmembranaires. Les cellules P1-HTR injectées surexprimaient à leur surface une cytokine humaine ou un récepteur soluble grâce à la fusion avec une protéine humaine naturellement transmembranaire (CD134 ligand). Les résultats ont montré que les souris immunisées produisaient des anticorps spécifiques, et parmi eux, des anticorps inhibiteurs.
Pendant la dernière partie de ce travail, nous avons tenté d’effectuer une auto-vaccination. Les protéines surexprimées par les cellules P1-HTR contenaient une cytokine (IL-9 ou IL-22) ou un récepteur soluble (IL22Bp) murins en fusion avec le CD134 ligand humain. Les résultats obtenus dans le cas de l’IL-9 murine permettent d’affirmer que la méthode de vaccination induit la production d’auto-anticorps. Ceux-ci contenaient une proportion non négligeable d’anticorps inhibiteurs, en outre capables de bloquer un effet biologique de l’IL-9 in vivo.
Nos résultats démontrent donc que l’utilisation de la lignée tumorale P1-HTR comme vecteur vaccinal peut être appliquée avec succès à l’induction d’auto-anticorps inhibiteurs contre des cytokines, quoique cette stratégie soit restreinte à l’haplotype MHC. Plusieurs perspectives se dégagent de ce travail, comme l’extension de cette méthode de vaccination à d’autres cytokines ou son utilisation pour l’obtention de modèles de souris knock down

Immunotherapy --- Cytokines --- Mice, Inbred DBA --- Mice, Inbred BALB C

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The transcription factor NF-kB has long been known to play a central role in the immune system by regulating the expression of key genes. Moreover, activation of this transcription factor helps a wide variety of cell types survive damage induced by pro-apoptotic stimuli. Owing to its critical role in the regulation of pro-inflammatory genes, NF-kB has long been regarded as a promising target for the discovery of anti-inflammatory drugs. More recently, NF-kB has emerged as a major culprit in a variety of human cancers mainly due to its ability to protect transformed cells from apoptosis. This finding should not have come as a surprise since there exists a link between inflammation and many types of cancer which was already suggested by Galen and later demonstrated by Virchow. This link, of crucial importance for the design of novel strategies for cancer treatment, is the topic of this book. Series Editor Cover Comments: "Inflammation is a known risk factor for a number of cancers. In this text, experts discuss the pathophysiology and molecular alterations that link these two processes. Potential therapeutics and preventive strategies are discussed." Steven T. Rosen, M.D. Series Editor

Cancer --- Carcinogenesis. --- Inflammation. --- Cytokines. --- Inflammation --- Neoplasms --- Neoplasms. --- Immunological aspects. --- Therapy. --- Etiology.

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animal embryos --- animal embryos --- irradiation. --- irradiation --- Radiation damage --- Radiation damage --- genetic code --- genetic code --- Embryonic development --- Embryonic development --- Morphogenesis --- Morphogenesis --- Induced mutation --- Induced mutation --- Mortality --- Mortality --- apoptosis --- apoptosis --- Cytokines --- Cytokines --- cytogenetics --- cytogenetics --- Laboratory animals --- Laboratory animals

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The transcription factor NF-kB has long been known to play a central role in the immune system by regulating the expression of key genes. Moreover, activation of this transcription factor helps a wide variety of cell types survive damage induced by pro-apoptotic stimuli. Owing to its critical role in the regulation of pro-inflammatory genes, NF-kB has long been regarded as a promising target for the discovery of anti-inflammatory drugs. More recently, NF-kB has emerged as a major culprit in a variety of human cancers mainly due to its ability to protect transformed cells from apoptosis. This finding should not have come as a surprise since there exists a link between inflammation and many types of cancer which was already suggested by Galen and later demonstrated by Virchow. This link, of crucial importance for the design of novel strategies for cancer treatment, is the topic of this book. Series Editor Cover Comments: "Inflammation is a known risk factor for a number of cancers. In this text, experts discuss the pathophysiology and molecular alterations that link these two processes. Potential therapeutics and preventive strategies are discussed." Steven T. Rosen, M.D. Series Editor.

Cancer --- Chemokines. --- Inflammation. --- Research. --- Inflammatory process --- Pathology --- Anti-inflammatory agents --- Chemotactic cytokines --- Inflammatory peptides --- Intercrines --- Cytokines --- Inflammation --- Peptides --- Cancer research --- Mediators --- Oncology  . --- Oncology. --- Medical laboratories. --- Cancer Research. --- Laboratory Medicine. --- Diagnosis, Laboratory --- Health facilities --- Laboratories --- Tumors --- Cancer research. --- Laboratory medicine. --- Clinical medicine --- Clinical pathology --- Diagnostic laboratory tests --- Laboratory diagnosis --- Laboratory medicine --- Medical laboratory diagnosis --- Diagnosis --- Cancer. --- Medicine --- Biology --- Cancer Biology. --- Biomedical Research. --- Health Workforce --- Cancers --- Carcinoma --- Malignancy (Cancer) --- Malignant tumors --- Biological research --- Biomedical research

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Over the last decade, the advent of biologic agents has greatly revolutionized therapeutic medicine in the management of chronic inflammatory diseases, such as rheumatoid arthritis, Crohn’s disease, and psoriasis. Elucidation of the complex web of cytokine network and the roles of these cytokines in the pathogenesis of inflammatory disorders provided one of the key catalysts for the advancement of targeted biologic therapy in autoimmune and inflammatory diseases. TNF-alpha is known to play a crucial role in the pathogenesis of many chronic inflammatory diseases. Elevated levels of TNF-alpha have been demonstrated in Crohn’s disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, suggesting a role for TNF-alpha in their pathogenesis. Although TNF-alpha plays a critical role in the activation of innate and acquired immune responses, the persistence of the immune response and inappropriate production of TNF-alpha can produce pathological changes resulting from chronic inflammation and tissue damage. This volume provides a comprehensive overview of the development, pharmacology, efficacy, and safety of the currently available TNF-alpha inhibitors – etanercept, infliximab, and adalimumab. The most recent preclinical and clinical data is presented on this topic, which should be of interest to the preclinical researcher, the clinician, and the patient who wants to learn more about these therapies.

Tumor necrosis factor --- Anti-inflammatory agents. --- Inhibitors. --- Anti-inflammatories --- Antiinflammatory agents --- Antiphlogistics --- Antipyretics --- Inflammation --- Cachectin --- Lymphotoxin --- TNF (Immunology) --- Cytokines --- Glycoproteins --- Growth factors --- Macrophages --- Immunology. --- Rheumatology. --- Dermatology. --- Toxicology. --- Gastroenterology. --- Pharmacology/Toxicology. --- Internal medicine --- Digestive organs --- Chemicals --- Medicine --- Pharmacology --- Poisoning --- Poisons --- Skin --- Connective tissues --- Joints --- Immunobiology --- Life sciences --- Serology --- Diseases --- Toxicology --- Pharmacology. --- Gastroenterology . --- Drug effects --- Medical pharmacology --- Medical sciences --- Chemotherapy --- Drugs --- Pharmacy --- Physiological effect