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Soutenance d'HDR

Biothérapie des irradiations

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Alain Chapel a soutenu son HDR lundi 12 juin 2017



La thérapie cellulaire est en train de révolutionner la médecine. Les progrès très rapides des biothérapies associées à une imagerie de plus en plus performante permettent de concevoir de manière différente les stratégies thérapeutiques. Les missions auxquelles j’ai été associé au sein de l’Institut de radioprotection et de sureté nucléaire ont contribué à proposer des stratégies thérapeutiques innovantes, fondées sur l’utilisation de la thérapie cellulaire pour le traitement des tissus sains lésés lors d’une irradiation. L’ensemble de nos travaux a été le fondement d’une nouvelle doctrine qui a révolutionné le traitement des séquelles des irradiations là où la pharmacologie et la chirurgie avaient atteint leurs limites ; la thérapie cellulaire par les Cellules souches mésenchymateuses (CSM) est l’alternative thérapeutique.



​Abstract


Biotherapies offered new hope for the treatment of radiation-induced severe tissue damage, including acute radiation syndrome (ARS) and severe, chronic radiation-induced abdomino-pelvic complications—i.e. pelvic radiation disease (PRD)—refractory to standard therapy. This work was initially applied to ARS. One approach uses ex vivo expansion to amplify non-irradiated bone marrow hematopoietic stem cells (HSCs) from patients with bone marrow aplasia. The expanded HSCs are reinjected into the patients to treat hematopoietic syndrome. Another approach taken stimulates residual hematopoiesis by targeting in vivo nonirradiated HSCs with an antibody coupled to a growth factor gene. The transfected HSCs then produce growth factors necessary for their proliferation, restoring hematopoiesis. The last approach uses growth factors to enhance proliferation of residual HSCs. In the most severe cases, none of these strategies completely reverses aplasia. The solution is to generate autologous HSCs from differentiated cells. We have produced HSCs from autologous inductive pluripotent stem cells (iPSCs) to treat bone marrow aplasia. They will be following up with an exploration of ARS-associated acute gastrointestinal subsyndrome.


One avenue of cell therapy research investigates the role of mesenchymal stem cells (MSC) in the treatment of multiple organ dysfunction syndrome (MODS), also known as multiple organ failure (MOF). We have demonstrated that MSCs migrate to irradiated tissues; restore the bone marrow microenvironment, enhancing hematopoiesis; promote intestinal and hepatic regeneration; and limit muscle and skin tissue radionecrosis.


We have demonstrated that MSCs migrate to damaged tissues and restore gut functions after irradiation, making them a promising tool for the medical management of radiation-induced gastrointestinal disorders. MSCs can be incorporated into the enteric mucosa and are able to repair radiation-induced intestinal damage by inhibiting ulceration. They release cytokines and growth factors such as IL-11, human hepatocyte growth factor, fibroblast growth factor 2, and insulin-like growth factors. These factors have previously been reported to facilitate intestinal mucosa repair, either through enhancement of cell proliferation or inhibition of epithelial cell apoptosis. By lowering levels of pro-inflammatory cytokines, while inducing anti-inflammatory cytokines, MSCs may also dampen systemic inflammatory response syndrome associated with radiation-induced gastrointestinal syndrome. Furthermore, MSC treatment of a target organ may affect distant tissues. MSCs regenerate the small intestine epithelium, which in turn restores the enterohepatic recirculation pathway initially damaged by irradiation. Another mechanism that should be considered is the role of cytokines and growth factors produced by MSCs homing to other organs, as in distant hepatic protection without introduction of MSCs into the liver. To consider further applications in patients, we carefully studied the side effects of MSC injection. None were observed in healthy tissue or residual tumors after radiotherapy. MSCs limited the progression of colorectal fibrosis. MSC therapy could reduce acute or chronic side effects of ionizing radiation and may be of therapeutic interest. These studies helped to provide irradiated patients with compassionate treatment for hematopoietic damage and radionecrosis of muscle and skin tissue, and also permitted treatment of four victims of accidental radiation overdose at Jean Monnet Hospital in Épinal, France. Clinical transfer of stem cell therapy for treating late side effects of pelvic radiation is currently under way. Initial participants in Phase II clinical research will be recruited in 2017.