Biotherapy of irradiation
Biothérapie des irradiations
Résumé
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
Mots clés
Domaines
Sciences du Vivant [q-bio]
Origine : Fichiers produits par l'(les) auteur(s)