AIM： To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal ...AIM： To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation. METHODS： A rat model of fractionated colorectal γ-irradiation （4-Gy fractions, 3 fractions per week） was designed to investigate the effects of cumulative dose on inflammatory mediators （cytokines and chemo- kines） and immune response （Th1/Th2 profile and immunosuppressive mediator IL-10） during acute （early） response and 6 mo after the end of fractionated irradiation （chronic response）. Analyses were performed 1 d after the cumulative doses of 16 Gy and 36 Gy and 1 d, 3 d, and 26 wk after the cumulative dose of 52 Gy. RESULTS： Without causing histological damage, fractionated radiation induced elevated expression of IL-1β, TNFα, MCP-1, and iNOS in distal colonic mucosa during the early post-irradiation phase. At that time, a Th2 profile was confirmed by expression of both the Th2- specific transcription factor GATA-3 and the chemokine receptor CCR4 and by suppression of the Thl cytokine IFNγ/IP-10 throughout the irradiation protocol. After 6 mo, despite the 2-fold reduction of iNOS and MCP-1 levels, the Th2 profile persisted, as shown by a 50% reduction in the expression of the Thl transcription factor T-bet, the chemokine receptor CCXCR3, and the IFNγ/ STAT1 pathway. At the same time-point, the immunosuppressive IL-10/STAT3 pathway, known to regulate the Th1/Th2 balance, was expressed, in irradiated rats, at approximately half its level as compared to controls.This suppression was associated with an overexpression of SOCS3, which inhibits the feedback of the Thl polarization and regulates IL-10 production. CONCLUSION： Colorectal irradiation induces Th2 polarization, defective IL-10/STAT3 pathway activation and SOCS3 overexpression. These changes, in turn, maintain a immunological imbalance that persists in the long term.展开更多
High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is there...High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animalmodels, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.展开更多
AIM： To pharmacologically modulate Th polarization in the ileum exposed to ionizing radiation by using the immuno-modulatory/apoptotic properties of Caffeic Acid Phenethyl Ester （CAPE）. METHODS： Rats received CAPE...AIM： To pharmacologically modulate Th polarization in the ileum exposed to ionizing radiation by using the immuno-modulatory/apoptotic properties of Caffeic Acid Phenethyl Ester （CAPE）. METHODS： Rats received CAPE （30 mg/kg） treatment ip 15 min prior to intestinal 10 Gy γ-irradiation and once a day for a 6 d period alter irradiation. Expression of genes implicated in Th differentiation in ileal mucosa （IL-23/IL-12Rβ2）, Th cytokine responses （IFN-γ, IL-2, IL-4, IL-13）, Th migratory behaviour （CXCR3, CCR5, CCR4）, Th signalling suppressors （SOCS1, SOCS3）, transcription factor （T-Bet, GATA-3） and apoptosis （FasL/Fas, TNF/TNFR, XIAP, Bax, caspase-3） was analyzed by RT-PCR 6 h and 7 d post-irradiation. CD4^＋ and TUNEL positive cells were visualized by immunostaining. RESULTS： The expression of Thl-related cytokine/ chemokine receptors （IFN-γ, IL-2, CXCR3, CCR5） was repressed at 7 d post-irradiation while Th2 cell cytokine/ chemokines （IL-4, IL-13, CCR4） were not repressed or even upregulated. The irradiation-induced Th2 profile was confirmed by the upregulation of both Th2-specific transcription factor GATA-3 and SOCS3. Although an apoptosis event occurred 6 h alter 10 Gy of intestinal γ-irradiation, apoptotic mediator analysis showed a tendency to apoptotic resistance 7 d post-irradiation. CAPE amplified apoptotic events at 6h and normalized Bax/FasL expressions at 7 d. CONCLUSION： CAPE prevented the ileal Th2 immune response by modulating the irradiation-influenced cytokine environment and apoptosis.展开更多
Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded...Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell(MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation.We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.展开更多
文摘AIM： To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation. METHODS： A rat model of fractionated colorectal γ-irradiation （4-Gy fractions, 3 fractions per week） was designed to investigate the effects of cumulative dose on inflammatory mediators （cytokines and chemo- kines） and immune response （Th1/Th2 profile and immunosuppressive mediator IL-10） during acute （early） response and 6 mo after the end of fractionated irradiation （chronic response）. Analyses were performed 1 d after the cumulative doses of 16 Gy and 36 Gy and 1 d, 3 d, and 26 wk after the cumulative dose of 52 Gy. RESULTS： Without causing histological damage, fractionated radiation induced elevated expression of IL-1β, TNFα, MCP-1, and iNOS in distal colonic mucosa during the early post-irradiation phase. At that time, a Th2 profile was confirmed by expression of both the Th2- specific transcription factor GATA-3 and the chemokine receptor CCR4 and by suppression of the Thl cytokine IFNγ/IP-10 throughout the irradiation protocol. After 6 mo, despite the 2-fold reduction of iNOS and MCP-1 levels, the Th2 profile persisted, as shown by a 50% reduction in the expression of the Thl transcription factor T-bet, the chemokine receptor CCXCR3, and the IFNγ/ STAT1 pathway. At the same time-point, the immunosuppressive IL-10/STAT3 pathway, known to regulate the Th1/Th2 balance, was expressed, in irradiated rats, at approximately half its level as compared to controls.This suppression was associated with an overexpression of SOCS3, which inhibits the feedback of the Thl polarization and regulates IL-10 production. CONCLUSION： Colorectal irradiation induces Th2 polarization, defective IL-10/STAT3 pathway activation and SOCS3 overexpression. These changes, in turn, maintain a immunological imbalance that persists in the long term.
文摘High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animalmodels, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.
文摘AIM： To pharmacologically modulate Th polarization in the ileum exposed to ionizing radiation by using the immuno-modulatory/apoptotic properties of Caffeic Acid Phenethyl Ester （CAPE）. METHODS： Rats received CAPE （30 mg/kg） treatment ip 15 min prior to intestinal 10 Gy γ-irradiation and once a day for a 6 d period alter irradiation. Expression of genes implicated in Th differentiation in ileal mucosa （IL-23/IL-12Rβ2）, Th cytokine responses （IFN-γ, IL-2, IL-4, IL-13）, Th migratory behaviour （CXCR3, CCR5, CCR4）, Th signalling suppressors （SOCS1, SOCS3）, transcription factor （T-Bet, GATA-3） and apoptosis （FasL/Fas, TNF/TNFR, XIAP, Bax, caspase-3） was analyzed by RT-PCR 6 h and 7 d post-irradiation. CD4^＋ and TUNEL positive cells were visualized by immunostaining. RESULTS： The expression of Thl-related cytokine/ chemokine receptors （IFN-γ, IL-2, CXCR3, CCR5） was repressed at 7 d post-irradiation while Th2 cell cytokine/ chemokines （IL-4, IL-13, CCR4） were not repressed or even upregulated. The irradiation-induced Th2 profile was confirmed by the upregulation of both Th2-specific transcription factor GATA-3 and SOCS3. Although an apoptosis event occurred 6 h alter 10 Gy of intestinal γ-irradiation, apoptotic mediator analysis showed a tendency to apoptotic resistance 7 d post-irradiation. CAPE amplified apoptotic events at 6h and normalized Bax/FasL expressions at 7 d. CONCLUSION： CAPE prevented the ileal Th2 immune response by modulating the irradiation-influenced cytokine environment and apoptosis.
文摘Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell(MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation.We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.
