RESUMEN
Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.
Asunto(s)
Apoptosis/efectos de la radiación , Células de la Médula Ósea/efectos de la radiación , Aberraciones Cromosómicas/efectos de la radiación , Células Madre Hematopoyéticas/efectos de la radiación , Células Madre Mesenquimatosas/efectos de la radiación , Traumatismos por Radiación/patología , Irradiación Corporal Total/efectos adversos , Adulto , Células Madre Adultas/efectos de la radiación , Células de la Médula Ósea/citología , Células de la Médula Ósea/patología , Diferenciación Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Células Cultivadas , China , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/patología , Femenino , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/patología , Hospitales Universitarios , Humanos , Leucemia/patología , Leucemia/terapia , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/patología , Necrosis , Traumatismos por Radiación/etiología , Acondicionamiento Pretrasplante/efectos adversos , Células Tumorales Cultivadas , Adulto JovenRESUMEN
BACKGROUND: CD4(+)interferon (IFN)-γ(+) T cell (Th1) and CD4(+)interleukin (IL)-4(+) T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real world situation remains unknown. METHODOLOGY: Peripheral blood was collected every week prospectively from Day 0 to Day 210 (patients without GVHD) or Day 300 (patients with chronic GVHD) after allogeneic peripheral blood stem cell transplantation in consecutive 27 patients. The frequencies of Th1 and Th2 within CD4(+) T cells were determined by flow cytometry and pplasma IFN-γ, IL-12, IL-4, and IL-10 were determined by ELISA. PRINCIPAL FINDINGS: Kinetics of Th1, Th2 frequency, and the plasma IL-10 and IFN-γ more commonly coincided with, rather than predicted, the activity of GVHD. These markers are significantly higher when acute or chronic GVHD developed. The kinetics of IL-10 is especially correlated well with the activity of GVHD during clinical course of immunosuppressive treatment. For patients with hepatic GVHD, there is a positive correlation between plasma IL-10 levels and the severity of hepatic injury. The frequency of Th2 is also significant higher in acute GVHD and tends to be higher in chronic GVHD. Interestingly, there is a very good positive correlation between the frequency of Th1 and Th2 (r = 0.951, p<0.001). The plasma level of IL-4 and IL-12 are not associated with the activity of GVHD. CONCLUSIONS: The frequency of Th1, Th2 within CD4(+) T cells and plasma IL-10 and IFN-γ are good biomarkers of GVHD. Plasma IL-10 can also be used to monitor the therapeutic responsiveness. Furthermore, both Th1 and Th2 likely contribute to the pathogenesis of GVHD.
Asunto(s)
Citocinas/metabolismo , Enfermedad Injerto contra Huésped/metabolismo , Interferones/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Animales , Biomarcadores/metabolismo , Citometría de Flujo/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-4/metabolismo , Cinética , Células TH1/citología , Células Th2/citología , Factores de TiempoRESUMEN
Both bone marrow hematopoietic cells (BM-HCs) and mesenchymal stem cells (BM-MSCs) may have cytogenetic aberrations in leukemic patients, and anti-leukemic therapy may induce cytogenetic remission of BM-HCs. The impact of anti-leukemic therapy on BM-MSCs remains unknown. Cytogenetic studies of BM-MSCs from 15 leukemic patients with documented cytogenetic abnormalities of BM-HCs were investigated. To see the influence of anti-leukemic therapy on BM-MSCs, cytogenetic studies were carried out in seven of them after the completion of anti-leukemic therapy, including anthracycline/Ara-C-based chemotherapy in two patients, high-dose busulfan/cyclophosphamide-based allogeneic transplantation in two patients, and total body irradiation (TBI)-based allogeneic transplantation in three patients. To simulate the effect of TBI in vitro, three BM-MSCs from one leukemic patient and two normal adults were irradiated using the same dosage and dosing schedule of TBI and cytogenetics were re-examined after irradiation. At the diagnosis of leukemia, two BM-MSCs had cytogenetic aberration, which were completely different to their BM-HCs counterpart. After the completion of anti-leukemic therapy, cytogenetic aberration was no longer detectable in one patient. Unexpectedly, BM-MSCs from three patients receiving TBI-based allogeneic transplantation acquired new, clonal cytogenetic abnormalities after transplantation. Similarly, complex cytogenetic abnormalities were found in all the three BM-MSCs exposed to in vitro irradiation. In conclusion, anti-leukemic treatments induce not only "cytogenetic remission" but also new cytogenetic abnormalities of BM-MSCs. TBI especially exerts detrimental effect on the chromosomal integrity of BM-MSCs and highlights the equal importance of investigating long-term adverse effect of anti-leukemic therapy on BM-MSCs as opposed to beneficial effect on BM-HCs.
Asunto(s)
Antineoplásicos/efectos adversos , Células de la Médula Ósea , Aberraciones Cromosómicas , Leucemia/terapia , Células Madre Mesenquimatosas , Trasplante Homólogo/efectos adversos , Irradiación Corporal Total/efectos adversos , Adolescente , Adulto , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/efectos de la radiación , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Aberraciones Cromosómicas/efectos de los fármacos , Aberraciones Cromosómicas/efectos de la radiación , Citogenética/métodos , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de la radiación , Humanos , Cariotipo , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de la radiación , Persona de Mediana Edad , Inducción de Remisión , Adulto JovenRESUMEN
BACKGROUND: The involvements of matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA) in the pathogenesis of various types of lung cancers have been established. The aim of the present study was to determine the concentrations of MMP-9 and uPA in the plasma of nonsmall cell lung cancer (NSCLC) patients. METHODS: Gelatin zymography and ELISA were used to measure MMP-9 and uPA concentrations, respectively, in 90 NSCLC patients and 50 control subjects. RESULTS: Compared with that of control subjects, MMP-9 and uPA levels were significantly higher in the plasma of NSCLC patients (P<0.001 and P<0.01, respectively). Further statistical analysis for clinic pathological parameters revealed that MMP-9 and uPA levels were significantly increased in patients with metastasis (P<0.01 and P<0.05, respectively). Furthermore, the MMP-9 level was significantly different between smokers and nonsmokers (P<0.05) while uPA levels varied between histological types (P<0.05). CONCLUSIONS: Plasma MMP-9 and uPA might play an important role in the metastasis of NSCLC by involvement in the processes of invasion and metastasis.