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BACKGROUND@#Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted.@*METHODS@#We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored.@*RESULTS@#Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2-5] loci vs. 5 [3-5] loci, P = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P = 0.024). On the other hand, those with decreased CD4 + /CD8 + T-cell ratio developed more fever (0.8 [0.7-1.2] vs. 1.4 [1.1-2.2], P = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932-0.995, P = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859-0.975, P = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control.@*CONCLUSIONS@#Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.
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Humanos , Leucocitos Mononucleares , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Donante no Emparentado , Factor Estimulante de Colonias de Granulocitos , Enfermedad Injerto contra HuéspedRESUMEN
Objective To investigate the effects of recombinant human granulocyte colonystimulating factor(G-CSF) on murine thymic emigration and subsets reconstitution after a sublethal dose of irradiaton.Methods Female BALB/c mice were irradiated with a 6.0 Gy of γ-ray total-body irradiation and then randomly divided into GCSF group and control group.For mice in the GCSF group,recombinant human G-CSF 100 μg · kg-1 · d-1 was injected subcutaneously once daily for 14 continuous days and mice in the control group were given the same volume of phosphate buffered solution (PBS).At 7,14,21 and 28 days later,mice were killed and thymus mononuclear cell suspension were analyzed by flow cytometry for the percentage of the four stages of thymic CD4 -CD8 - double negative cells (DN1-4) and the CD4 + CD8 + double positive ( CD4 + CD8 + DP),CD4 + CD8 - single positive ( CD4 + SP),CD4 -CD8 + single positive cells (CD8 + SP).Real-time PCR was used for detection and quantitation of murine T cell receptor rearrangement excision circles(sjTRECs) of the thymic cells of 30 and 60 d after irradiation.Results The percentage of thymic DN1 cells in GCSF group was significantly higher than that of the control group 7 d after irradiation (t =9.59,P ＜ 0.05 ).21 d later,the proportion of thymic DN3 and DN4 cells were higher than those of the control group ( t =16.37,7.6,P ＜ 0.05 ).The percentage of thymic CD4 + CD8 + DP cells decreased 7 d after irradiation,increased at 14 d,decreased again at 21 days,and then got a permanent recover.The percentage of thymic CD4 + CD8 + DP cells in the GCSF group recovered to normal and was significantly higher than that of the control group 28 days after irradiation (t =12.22,P＜ 0.05).The percentage of thymic CD8 + SP cells of the GCSF group was significantly higher than that of the control group 21 d after irradiation ( t =3.77,P ＜ 0.05 ),while G-CSF had no obvious influence on the percentage of the thymic CD4 + SP cells.The sjTRECs copies in the GCSF group was significantly higher than that of the control group 30 d after irradiation ( t =5.95,P ＜ 0.01 ),which disappeared 60 d later.Conclusions G-CSF could promote the proliferation and differentiation of thymic DN and DP cells,enhance the recent thymic emigrants and accelerate central immunologic reconstitution after acute irradiation.
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Objective To investigate the effects of recombinant human granulocyte colonystimulating factor(G-CSF) on central and peripheral lymphocyte subset reconstitution after a sublethal dose of irradiation. Methods Sixty female BALB/c mice were given a 6.0 Gy γ-ray total body irradiation (TBI) and randomly divided into 2 equal groups. The mice in G-CSF + TBI group were injected subcutaneously with recombinant human G-CSF 100 μg·kg-1·d-1 for 14 d and the mice in TBI group were injected subcutaneously with the same volume of phosphate buffered solution (PBS) once daily for 14 d. 7,14,21, and 28 d later the mice were killed and their thymus were taken out to prepare of the mononuclear cell suspension to analysis the percentage of thymic CD4 + CD8 + double positive, CD4 +CD8 - single positive, CD4 - CD8 + single positive and CD4 - CD8 - double negtive cells by flow cytometry. Peripheral blood samples were collected from the caudal vein twice a week, and the white blood cell(WBC) counts and absolute number of lymphocytes were assessed by automatic hemocyte analyzer. 14,28, and 60 d later blood samples were collected from angular vein to examine the peripheral lymphocyte subsets by flow cytometry. Cell counting kit-8 was used to detect lipopolysaccharide (LPS) or concanavalin A (ConA) stimulated splenic lymphocyte proliferation. Results The percentage of thymic CD4 + CD8 +double positive cells decreased 7 d after irradiation, rebounded at 14 d, decreased again at 21 d, and then got a permanent recovery. 28 d after irradiation the percentage of thymic CD4 + CD8 + double positive cells in the G-CSF + TBI group recovered to normal and was significantly higher than that of the TBI group (t =12. 22, P < 0. 05). 21d after irradiation the percentage of thymic CD4-CD8 + single positive cells of the G-CSF + TBI group was significantly higher than that of the TBI group (t = 3.77, P < 0. 05). The peripheral WBCs and lymphocytes decreased to the lowest levels 7 d after irradiation and then gradually increased, however, WBCs and lymphoeytes of the G-CSF + TBI group began to recover earlier and faster than the TBI group. The proportion of CD3 + CD8 + T cells of the G-CSF + TBI group was significantly higher than that of the TBI group 14 and 60 d after irradiation (t =4. 31,5.78, P <0.05). But there was no significant difference in the proportion of CD3 + CD4 + T cells between the two groups. The proportion of B lymphoeytes of the G-CSF + TBI group was significantly lower than that of the TBI group 14 d after irradiation(t =7.30, P <0.05), but it recovered quickly, and there were no significant differences in the proportion of B lymphoeytes between the two groups 28 and 60 d after irradiation. The proliferation indexes of splenic lymphocytes in response to LPS and ConA in the G-CSF + TBI group were 4. 37 and 2.98 times higher than those in the TBI group 14 d after irradiation. Conclusions G-CSF could accelerate the recovery of central and peripheral lymphocyte subsets, raise the absolute number of lymphocytes, and enhance their proliferative function, which contributes to the central and peripheral immune reconstitution after acute irradiation.
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Objective To investigate the value of cytokinesis-block micronuclei(CBMN)assay in estimation of the biological doses of the victims of radiation accident.Methods Samples of peripheral blood were collected from the 5 victims(Subjects 1-5)at 16 h after the radiation accident of Taiyuan,Shanxi Province.And the peripheral blood samples and bone marrow sample were collected from the victim No.1 at 23 and 24 h after the radiation.Eight days after the accident Subject 1 underwent allogeneic peripheral blood hematopoietic stem cell transplantation.At difierent time points in the period of 1 year after the accident.peripheral blood samples were collected from these 5 victims.CBMN assay was conducted on the peripheral blood lymphocytes on the samples,and the biological doses were estimated based on the micronuclei(MN)frequencies.The nuclear division index(NDI)obtained from in vitro irradiation experiment using high dose of 60Coγ-rays was used to estimate the exposed doses for Subject 1. Dynamic arialysis of the MN frequency for the 5 victims was performed in the period of 1 year after the accident.Results The MN frequency of Subject 1 surpassed the value corresponding to the upper limit of the MN dose.effective curve.The dose range estimated bv the combination of the CBMN and NDI (CBMN+NDl)assay was 10-20 Gy for Subject 1.The doses estimated by MN frequency for Subjects 2,3,4,and 5 were 3.6,2.9,2.3,and 2.9 Gy,respectively.The estimated doses were in accordance with those estimated by physicat method.chromosome aberration analysis.and clinical symptoms.Prominent decrease of the MN frequency was observed at 26 d after the accident(18 d after the transplantation)for Subject 1(u=3.295,P<0.05).Gradual decrease of MN frequency was observed after the accident for Subjects 2,3,4,and 5.The MN frequencies 1 month after the accident of Subjects 3,4,and 5 were all significantly lower than those 16 h later(u=6.874,4.526,and 7.811,P<0.05).Conclusions Quick and accurate.CBMN assay reinforces and verifies the result of chromosome aberration analysis.The new index CBMN+NDI assay is of reference valne for estimating higher dose of irradiation.
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BACKGROUND:The immunomodulatory ability of bone marrow mesenchymal stem cells(BMSCs)gives it a promising future in treating graft-versus-host disease(GVHD),especially with previous success in treating patients with acute GVHD.However,there are fewer reports concerning BMSCs in treating chronic GVHD,particularly for sclerodermatous chronic graft-versus-host disease(ScGVHD).OBJECTIVE:To evaluate the efficacy and safety of treatment of BMSCs for ScGVHD,and to primarily explore the immunological mechanism of clinical efficacy.METHODS:Four ScGVHD patients at the Affiliated Hospital of Academy of Military Medicine Science,between September 2006 and August 2008,were enrolled for this trial.The median patient age was 41 years,1 female and 3 male.The patients received BMSCs infusion at a dose of(1.0～2.0)×10~7 cells every time by intrabone marrow injection from the anterosuperior iliac spine and BMSCs from the same donor for the same patient were infused more than once.Concomitant medications for ScGVHD were individualized for each patient,but all were current standard medicines and the doses were significantly tapered.RESULTS AND CONCLUTION:After BMSCs infusion,the ratio of Th1 to Th2 was dramatically overturned,with an increase of Th1 and a decrease of Th2 reaching at a new balance.Correspondingly,symptoms of all the four patients gradually improved.During the course of BMSCs treatment,the life signs and laboratory results from the recipients remained normal.By the time of this report,there has been no recurrence of leukemia in the four patients.Although this study alone cannot guarantee the application of BMSCs in ScGVHD,the results are strongly in favor of the idea that the BMSCs treatment for ScGVHD patients is therapeutically practical without any detectable side effects,which may provide a new insight into the matter of treating ScGVHD clinically,thus will greatly increase the survival rate of leukemia after allogeneic bone marrow transplantation.
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Objective To establish a dose-effect curve of premature condensation chromosome ring (PCC-R)in lymphocytes of human peripheral blood after exposed to high doses of Y-rays. Methods Peripheral blood samples was drawn from three healthy individuals, and exposed to 60Co γ-rays with doses between 0 and 30 Gy. The frequencies of PCC-R in premature condensation chromosome (PCC) cells obtained by Okadaic acid (OA) induction were calculated, and a dose-effect curve was fitted. Results PCC index tapered with dose. Frequencies of PCC-R per cell increased until 20 Gy, and then saturation was observed. The results were fitted to a lineal model up to 20 Gy: y = - 0.020 + 0.052D ,where y was the frequencies of PCC-R per cell, D was the radiation dose (Gy). Conclusins The highest dose could be estimated is 20 Gy by the dose-effect curve established with PCC-R method. Its utility and validity will be verified in the future application of radiation accident.
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Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.
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Objective To investigate the mechanism of mesenchymal stem cells in enhancing the effects of haploid matched bone marrow cells transplantation in mice with acute radiation syndrome(ARS).Methods The survival of mice infused with difierent levels of MSCs and bone marrow cells after 8 Gy TBl were examined.BALB/c female mice irradiated with 8 Gy of 60Co γ-rays were randomly divided into two groups,MSCs group,infused with MSCs of female CB6F1 mice labeled with cm-DiI and bone marrow monocytes of male CB6F1,Control group,only infused with bone marrow monocytes.Peripheral blood counts,T-lymphocyte subpopulation of peripheral blood cells,the sry-gene chimerism of bone marrow of the receiptors,the distribution of MSCs in the receiptors,the occurrence time of cGVHD,pathologic variety of medulla were observed.Resuits MSCs improved the survival of mice after 8 TBI,but 1.5×108/kg of MSCs increased the mortality of irradiated mice.In comparison with the control group,leukocytes and plastocytes recovered rapidly in MSCs group.Megacaryocytes in sternum marrows grew fastly in MSC group.The percent of CD3 and CD4 positive cells in the MSCs group were hisher than those in control post-transplantation.The sry-gene chimerism of bone marrow of the receiptors was higher in the MSCs group than that in the control at 30 d.The MSCs were distributed in intestine,thymus,bone marrow,liver,heart of the receiptors at 30 d.The cGVHD occurrence was 30 d later in MSCs group than that of the control.Conclusions MSCs could improve stem cell engraftment,enhance T-lymphocyte and plastocytes recevery,delay occurrence of cGVHD,repair injured organs and increase survivals.It is indicated that MSCs can enhance the treatment effects of haploid hematopoietic stem cells transplant for ARS.
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Objective To summarize the experimence of nonmyeloablative allogeneic peripheral blood cell transplantation in the treatment of chronic leukemia. Methods Seven patients, including 6 cases of chronic myeloid leukemia (in chronic phase), one of chronic lymphoid leukemia (in third stage), with HLA-identical siblings donor received allogeneic peripheral blood stem cell transplantation after a nonmyeloablative conditioning. Results All of them were engrafted with donor cells (4 with full of donor cells grafted, 3 with mixed chimerism) and recovered hematopoiesis (WBC recovered to more than 0.5 ?10 9/L during postoperative 9 day to 21 day and platelet recovered to more than 30?10 9/L during postoperative 11 day to 28 day). One of them developed a GVHD of degree IV. One of them developed aGVHD of degree I. Conclusion This procedure is much safe, effective and of less complications than the myeloablative condioning regimens and may represent another new approach in the management of patients with chronic leukemia.
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The author briefs the main research progress and way of the new developed nonmyeloablative allogeneic stem cell transplantation(NAST).The definition,conditioning regimen ,graft versus host disease(GVHD),graft versus leukemia(GVL) effects and clinical research are disussed.NAST is developed from theories and ideas of tranditional allogeneic stem cell transplantation,is a new way for hematological diseases ,malignant tumors and congenital immunodeficiencies.The author proposes cooperative researches on problems related with NAST.
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This paper investigate the methods to detect engraftment rate of the four patients with hematological disorders who accepted nonmyeloablative allogeneic peripheral blood stem cell transplantation(NAPBSCT). To find out the best method, their engraftment rates were detected serially at different time after NAPBSCT by means of either FISH, or conventional chromosome analysis combined with R-banding analysis concurrently.The results were carefully compared with one another. All these four sex-mismatched cases were engrafted partially,and two of them changed to full engrafment. The results show no statistically significant difference in 3 groups (conventional method, FISH for hypermetaphase, FISH for interphase nuclei). But the results strongly indicate that FISH is a rapid, precise, objective,and reliable menthod for detection of the engraftment rate,and it is suitable for sex-mismatched NAPBSCT.
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Objective To explore the clinical effects of second non-myeloablative stem cell transplantation (NAST). Methods Six cases of malignant hematological diseases receiving second NAST were retrospectively analyzed. Of them, 3 were suffered from transplant rejection after 1st NAST and the remaining 3 were stable mixed chimerism. Results Five of the patients achieved complete donor's chimerism and have been in disease-free-survival for 6～27 months. 1 GVHD occurred in only one of the 6 patients, and no transplant-related death happened. Conclusion Second NAST is effective for the treatment of patients with transplant rejection,and is also rational choice for those patients with refractory or relapse malignant hematological diseases.
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Objective To practice the prevention and treatment of severe bone marrow form and intestine form of acute radiation sickness complicated by bacteria infection for providing an effective method on the treatment of acute radiation sickness. Methods Two patients with severe acute radiation sickness suffered from different infection during treatment. Based on their clinical symptoms, image analysis and the findings of microbiological culture, the patients underwent different anti-bacteria and anti-fungi treatment, and the results were evaluated. Result Repeated multiple bacterial infection companied with fungi infection occurred in the two patients with severe acute radiation sickness during the period of treatment. The bacterial infection was controlled temporarily by an intensively antibacterial and antimycotic treatment, but the fungi infection was uncontrolled. In patient A, acute peritonitis occurred 14 days after exposure, and pulmonary infection occurred 19 days after exposure. The pulmonary infection in patient A was controlled by using antibacterial drugs Tienam and Vancocin, while the patient died of multiple organ failure and fungi infection 33 days after exposure. In patient B, pulmonary infection occurred 17 days after exposure, and the septicemia occurred twice with Gram-negative bacteria at 55th day and 71st day after exposure. The pulmonary infection was controlled provisionally by using antibacterial drugs Tienam and Vancocin, while the patient died of multiple organ failure 75 days after exposure. Conclusion The bacterial infection companied with severe acute radiation sickness is phased occurrence. The generalized and phased application of intensive antibiotics might be an effective treatment.
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Objective To sum up the therapeutic experiences and to analyze the causes of multiple organ dysfunction syndrome (MODS) occurred in a patient who subjected to an accidental 60 Co exposure. Methods The patient was diagnosed as MODS by clinical manifestation, the auxiliary examinations and pathologic autopsy. In therapeutic aspects, intensive care, ventilator-assisted breathing, anti-infection, nutritional support treatment and protection management of important organs were given. Results After a successful transplantation of HLA-identical allogeneic peripheral blood stem cell, the complaints of MODS emerged repeatedly as fever, lung infection, respiratory failure, cardiac arrhythmia, circulatory failure, hepatic injury, decreased urine output and paralytic ileus. At last, the patient died of multi-organ failure 75 days after exposure to radiation. The results of auxiliary examinations showed enlargement of heart and cardiac arrhythmia. Biochemical examination also indicated the increased hyper-sensitive C-reactive protein. The results of pathologic autopsy indicated the existence of fungous infections in whole body, pulmonary fibrosis, myocardium degeneration and necrosis and radiation enteritis. In addition, congestive hepatopathy, renal hemorrhage and intracerebral hemorrhage were also found in the examination. Conclusion Some special clinical features were found in this case, and the cause of MODS is mainly related to radiation injury of important organs, low level of immunity and infection. So the measures of anti-infection and protective treatment of multiple organs should be taken. The key and difficulty for preventing such a kind of MODS might be to improve the patient's immunity and to help the tissue reparation after radiation injury.
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To evaluate the effects of donor stem cell infusion (DSI) in patients after nonmyeloablative allogeneic peripheral blood stem cell transplantation( NAPBSCT),6 patients were infused donor stem cell in+7d～+90d consisting of MNC (0.6～7.6)?10 8 /kg, CD34 + cells (0.3～3.4)?10 6 /kg,CD3 + cells (0.3～5.1)?10 8 /kg.The results showed that 5/6 patients had definite effects in promoting donor chimeras after DSI,of these 3 achieved full donor chimeras following mixed chimeras ;4/6 have graft versus leukemia(GVL)effects.No hematopoiesis aplasia was found, and only one Ⅳdegree aGVHD developed related with DSI. It was concluded that DSI have definite GVL effects and can convert mixed chimeras to full chimeras without causing GVHD and severe hematopoietic aplasia.
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This paper investigate the methods to detect engraftment rate of the four patients with hematological disorders who accepted nonmyeloablative allogeneic peripheral blood stem cell transplantation(NAPBSCT). To find out the best method, their engraftment rates were detected serially at different time after NAPBSCT by means of either FISH, or conventional chromosome analysis combined with R banding analysis concurrently.The results were carefully compared with one another. All these four sex mismatched cases were engrafted partially,and two of them changed to full engrafment. The results show no statistically significant difference in 3 groups (conventional method, FISH for hypermetaphase, FISH for interphase nuclei). But the results strongly indicate that FISH is a rapid, precise, objective,and reliable menthod for detection of the engraftment rate,and it is suitable for sex mismatched NAPBSCT.
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Objective To explore the clinical significance of allogeneic peripheral stem cell transplantation in the treatment of acute radiation sickness.Methods Two victims were accidentally irradiated by a 60Co source in a nuclear accident in Jining,Shandong province,China in 2004.They were exposed to more than 20-25 Gy(patient A)and 9-15Gy(patient B)of 60Co-ray,and were diagnosed as having developed intestinal form of acute radiation sickness(ARS)and extremely severe bone marrow form of ARS,respectively.After the treatment with the preparative regimens based on low-doses of fludarabine,antilymphocyte globulin and cyclophosphamide,the two patients successfully received HLA-haploidentical(patient A)and HLA-identical(patient B)peripheral blood stem cell transplantation(PBSCT),respectively,7 days after the exposure.Cyclosporin A combined with mycophenolate mofetil was used for the prevention of graft-versus-host disease(GVHD).In addition,bone marrow mesenchymal stem cells from a donor were administered into patient A by intra-bone marrow injection.Results Both peripheral blood and bone marrow examinations showed the recovery of hemopoiesis after PBSCT,and neither patients displayed obvious clinical signs of GVHD.However,patient A died of septicemia and multi-organ failure on day 33 after the exposure,while patient B died of heart failure dominant multi-organ failure on day 75 after the exposure.Conclusions Allogeneic PBSCT is a feasible and effective treatment for ARS,while infection and multi-organ failure are major causes of death of the patients.