Allogeneic hematopoietic stem cell transplantation(aHSCT)is a standard validated therapy for patients suffering from malignant and nonmalignant hematological diseases.However,aHSCT procedures are limited by potentiall...Allogeneic hematopoietic stem cell transplantation(aHSCT)is a standard validated therapy for patients suffering from malignant and nonmalignant hematological diseases.However,aHSCT procedures are limited by potentially life-threatening complications,and one of the most serious complications is acute graft-versus-host disease(GVHD).During the last decades,DNA sequencing technologies were used to investigate relationship between composition or function of the gut microbiome and disease states.Even if it remains unclear whether these microbiome alterations are causative or secondary to the presence of the disease,they may be useful for diagnosis,prevention and therapy in aHSCT recipients.Here,we summarized the most recent findings of the association between human gut microbiome changes and acute GVHD in patients receiving aHSCT.展开更多
BACKGROUND Multipotent mesenchymal stromal cells(MSCs)are widely used in the clinic due to their unique properties,namely,their ability to differentiate in all mesenchymal directions and their immunomodulatory activit...BACKGROUND Multipotent mesenchymal stromal cells(MSCs)are widely used in the clinic due to their unique properties,namely,their ability to differentiate in all mesenchymal directions and their immunomodulatory activity.Healthy donor MSCs were used to prevent the development of acute graft vs host disease(GVHD)after allogeneic bone marrow transplantation(allo-BMT).The administration of MSCs to patients was not always effective.The MSCs obtained from different donors have individual characteristics.The differences between MSC samples may affect their clinical efficacy.AIM To study the differences between effective and ineffective MSCs.METHODS MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution.Aliquots of 52 MSC samples that were administered to patients were examined,and the same cells were cultured in the presence of peripheral blood mononuclear cells(PBMCs)from a third-party donor or treated with the pro-inflammatory cytokines IL-1β,IFN and TNF.Flow cytometry revealed the immunophenotype of the nontreated MSCs,the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines.The proportions of CD25-,CD146-,CD69-,HLA-DR-and PD-1-positive CD4+and CD8+cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined.RESULTS Differences in the immunophenotypes of effective and ineffective MSCs were observed.In the effective samples,the mean fluorescence intensity(MFI)of HLAABC,HLA-DR,CD105,and CD146 was significantly higher.After MSCs were treated with IFN or cocultured with PBMCs,the HLA-ABC,HLA-DR,CD90 and CD54 MFI showed a stronger increase in the effective MSCs,which indicated an increase in the immunomodulatory activity of these cells.When PBMCs were cocultured with effective MSCs,the proportions of CD4+and CD8+central memory cells significantly decreased,and the proportion of CD8+CD146+lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD;in addition,the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples.The proportion of CD4+CD146+lymphocytes increased only when cocultured with the inefficient samples.CONCLUSION For the first time,differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective.Thus,it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.展开更多
Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT)....Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Methods: Forty-two patients undergoing allo-PBSCT were included in this study. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze gene expression of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ. Results: All patients achieved engraftment, 18 patients developed grade ⅠGVHD, 6 patients developed grade Ⅱ-Ⅳ GVHD. The gene expression of IL-2, IL-12, and IFN-γ increased, the gene expression of IL-4 and IL-10 decreased. Conclusion: Cytokines IL-2, IL-12, and IFN-γ lead to a positive regulation of the development in human aGVHD, and IL-4 and IL-10 play negative regulatory roles.展开更多
Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-C...Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.展开更多
To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C57BL/...To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C57BL/6→BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor α (TNFα) and Interferon (IFNγ) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFα were lower on day +7 than on day +3. In group B, the levels of TNFα attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFα were highest on day +7 and there was a significant difference between those on days +7 and +14 (P=0.816). In group A, the levels of IFNγ on day +7 were higher than on day +3. In group B, the levels of IFNγ increased progressively, but the comparison of IFNγ levels in different times had no statistical significance (P=0.521, 0.118, 0.340). In group C, the levels of IFNγ attained a peak by day +7 and decreased on day +14. aGVHD is the main cause of early non-infectious lung injury. T lymphocytes and TNFα are possibly implicated in the pathogenesis of acute GVHD-induced lung injury. The decreased levels of IFNγ in lung tissues following transplantation might be associated with pulmonary fibrosis in late non-infectious pulmonary complications.展开更多
Six patients treated with human leukocyte antigen (HLA)-mismatched bone marrow transplantation (BMT) suffered from grade I to IV acute graft-versus-host disease (aGvHD) after engrafting. Up to date, 4 patients with gr...Six patients treated with human leukocyte antigen (HLA)-mismatched bone marrow transplantation (BMT) suffered from grade I to IV acute graft-versus-host disease (aGvHD) after engrafting. Up to date, 4 patients with grade I to II GvHD have lived for over 2920, 910, 740 and 680 days, respectively. Two other patients died of grade IV hyperacute GvHD. The results seem to indicate that patients in mismatched BMT have a high incidence of aGvHD within a month. The severity of aGvHD is positively correlated with the degree of HLA mismatching. The higher the degree of mismatch of HLA, the earlier and the more severe the aGvHD occurrs. The cutaneous lesion of the patient with GvHD is severe and of ten complicated by mucositis. Lethal hyperacute GvHD must be considered when a patient shows following signs at beginning: (1) The symptoms appear early (within 2weeks) ;(2) peripheral white blood cell count does not recover (<0. 5×109/L) to normal; and (3) high fever persists. In the epidermal ultrastructure of patients, besides acantholysis, autophagic degeneration of keratinocytes,and satellite cell dyskeratosis, there were scattered necrotic keratinocytes, breaking and thickening of basal membrane and presence of a lot of pigment in the intercellular space. These imply that the ultrastructural damages in the skin of patients with aGvHD after mismatched transplantation are more severe than after matched ones.展开更多
目的探讨以皮疹为主要表现的急性移植物抗宿主病(aGVHD)在免疫监控指导下的精准诊疗效果。方法回顾1例因高危急性髓系白血病接受非血缘脐血移植、其后出现顽固性皮疹的患儿的临床资料及诊治过程,以“造血干细胞移植”“免疫重建”和“...目的探讨以皮疹为主要表现的急性移植物抗宿主病(aGVHD)在免疫监控指导下的精准诊疗效果。方法回顾1例因高危急性髓系白血病接受非血缘脐血移植、其后出现顽固性皮疹的患儿的临床资料及诊治过程,以“造血干细胞移植”“免疫重建”和“急性移植物抗宿主病”的中英文为检索词,对以下数据库的相关论文进行检索:PubMed、Web of Science、CNKI、万方数据知识服务平台,收集检索到的病例资料并进行分析。结果该例1岁9月龄女性患儿成功获得造血重建,移植后22 d患儿头部、后颈部出现密集红色丘疹(面积约19%)、瘙痒明显,口服他克莫司、外用激素类药物后皮疹无好转(面积>90%),此时监测CD3^(+)细胞、CD8^(+)细胞、CD3^(+)CD69^(+)细胞、CD3^(+)HLADR^(+)细胞比例明显升高,调节性T细胞(Treg)比例下降。免疫指标支持T淋巴细胞活化,考虑Ⅱ度aGVHD(皮肤3级),遂予加强免疫抑制治疗方案。期间患儿皮疹有消退,但仍反复,并伴皮肤明显脱屑,复查CD3^(+)细胞、CD8^(+)细胞、CD3^(+)HLA-DR^(+)细胞比例仍偏高,遂再次调整治疗方案、加强抗排斥,患儿皮肤aGVHD好转。定期监测原发病完全缓解、植入比例100%、免疫重建稳定,随访至移植后32个月,患儿无病存活。检索到相关文献9篇,均论证了早期CD3^(+)细胞、CD8^(+)细胞、活化T淋巴细胞比例升高以及Treg下调与aGVHD发生相关。结论对异基因造血干细胞移植术后患者的免疫状态进行动态监测,有利于评估其免疫重建情况及疾病状态(如aGVHD),有助于制定合理的免疫抑制治疗方案,使患者获得良好预后。展开更多
文摘Allogeneic hematopoietic stem cell transplantation(aHSCT)is a standard validated therapy for patients suffering from malignant and nonmalignant hematological diseases.However,aHSCT procedures are limited by potentially life-threatening complications,and one of the most serious complications is acute graft-versus-host disease(GVHD).During the last decades,DNA sequencing technologies were used to investigate relationship between composition or function of the gut microbiome and disease states.Even if it remains unclear whether these microbiome alterations are causative or secondary to the presence of the disease,they may be useful for diagnosis,prevention and therapy in aHSCT recipients.Here,we summarized the most recent findings of the association between human gut microbiome changes and acute GVHD in patients receiving aHSCT.
文摘BACKGROUND Multipotent mesenchymal stromal cells(MSCs)are widely used in the clinic due to their unique properties,namely,their ability to differentiate in all mesenchymal directions and their immunomodulatory activity.Healthy donor MSCs were used to prevent the development of acute graft vs host disease(GVHD)after allogeneic bone marrow transplantation(allo-BMT).The administration of MSCs to patients was not always effective.The MSCs obtained from different donors have individual characteristics.The differences between MSC samples may affect their clinical efficacy.AIM To study the differences between effective and ineffective MSCs.METHODS MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution.Aliquots of 52 MSC samples that were administered to patients were examined,and the same cells were cultured in the presence of peripheral blood mononuclear cells(PBMCs)from a third-party donor or treated with the pro-inflammatory cytokines IL-1β,IFN and TNF.Flow cytometry revealed the immunophenotype of the nontreated MSCs,the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines.The proportions of CD25-,CD146-,CD69-,HLA-DR-and PD-1-positive CD4+and CD8+cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined.RESULTS Differences in the immunophenotypes of effective and ineffective MSCs were observed.In the effective samples,the mean fluorescence intensity(MFI)of HLAABC,HLA-DR,CD105,and CD146 was significantly higher.After MSCs were treated with IFN or cocultured with PBMCs,the HLA-ABC,HLA-DR,CD90 and CD54 MFI showed a stronger increase in the effective MSCs,which indicated an increase in the immunomodulatory activity of these cells.When PBMCs were cocultured with effective MSCs,the proportions of CD4+and CD8+central memory cells significantly decreased,and the proportion of CD8+CD146+lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD;in addition,the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples.The proportion of CD4+CD146+lymphocytes increased only when cocultured with the inefficient samples.CONCLUSION For the first time,differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective.Thus,it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.
文摘Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Methods: Forty-two patients undergoing allo-PBSCT were included in this study. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze gene expression of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ. Results: All patients achieved engraftment, 18 patients developed grade ⅠGVHD, 6 patients developed grade Ⅱ-Ⅳ GVHD. The gene expression of IL-2, IL-12, and IFN-γ increased, the gene expression of IL-4 and IL-10 decreased. Conclusion: Cytokines IL-2, IL-12, and IFN-γ lead to a positive regulation of the development in human aGVHD, and IL-4 and IL-10 play negative regulatory roles.
基金Supported by Grant from the National Center for Global Health and Medicine
文摘Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.
基金Supported by the National Natural Science Foundation of China (Grant No. 30971300)
文摘To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C57BL/6→BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor α (TNFα) and Interferon (IFNγ) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFα were lower on day +7 than on day +3. In group B, the levels of TNFα attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFα were highest on day +7 and there was a significant difference between those on days +7 and +14 (P=0.816). In group A, the levels of IFNγ on day +7 were higher than on day +3. In group B, the levels of IFNγ increased progressively, but the comparison of IFNγ levels in different times had no statistical significance (P=0.521, 0.118, 0.340). In group C, the levels of IFNγ attained a peak by day +7 and decreased on day +14. aGVHD is the main cause of early non-infectious lung injury. T lymphocytes and TNFα are possibly implicated in the pathogenesis of acute GVHD-induced lung injury. The decreased levels of IFNγ in lung tissues following transplantation might be associated with pulmonary fibrosis in late non-infectious pulmonary complications.
文摘Six patients treated with human leukocyte antigen (HLA)-mismatched bone marrow transplantation (BMT) suffered from grade I to IV acute graft-versus-host disease (aGvHD) after engrafting. Up to date, 4 patients with grade I to II GvHD have lived for over 2920, 910, 740 and 680 days, respectively. Two other patients died of grade IV hyperacute GvHD. The results seem to indicate that patients in mismatched BMT have a high incidence of aGvHD within a month. The severity of aGvHD is positively correlated with the degree of HLA mismatching. The higher the degree of mismatch of HLA, the earlier and the more severe the aGvHD occurrs. The cutaneous lesion of the patient with GvHD is severe and of ten complicated by mucositis. Lethal hyperacute GvHD must be considered when a patient shows following signs at beginning: (1) The symptoms appear early (within 2weeks) ;(2) peripheral white blood cell count does not recover (<0. 5×109/L) to normal; and (3) high fever persists. In the epidermal ultrastructure of patients, besides acantholysis, autophagic degeneration of keratinocytes,and satellite cell dyskeratosis, there were scattered necrotic keratinocytes, breaking and thickening of basal membrane and presence of a lot of pigment in the intercellular space. These imply that the ultrastructural damages in the skin of patients with aGvHD after mismatched transplantation are more severe than after matched ones.
文摘目的探讨以皮疹为主要表现的急性移植物抗宿主病(aGVHD)在免疫监控指导下的精准诊疗效果。方法回顾1例因高危急性髓系白血病接受非血缘脐血移植、其后出现顽固性皮疹的患儿的临床资料及诊治过程,以“造血干细胞移植”“免疫重建”和“急性移植物抗宿主病”的中英文为检索词,对以下数据库的相关论文进行检索:PubMed、Web of Science、CNKI、万方数据知识服务平台,收集检索到的病例资料并进行分析。结果该例1岁9月龄女性患儿成功获得造血重建,移植后22 d患儿头部、后颈部出现密集红色丘疹(面积约19%)、瘙痒明显,口服他克莫司、外用激素类药物后皮疹无好转(面积>90%),此时监测CD3^(+)细胞、CD8^(+)细胞、CD3^(+)CD69^(+)细胞、CD3^(+)HLADR^(+)细胞比例明显升高,调节性T细胞(Treg)比例下降。免疫指标支持T淋巴细胞活化,考虑Ⅱ度aGVHD(皮肤3级),遂予加强免疫抑制治疗方案。期间患儿皮疹有消退,但仍反复,并伴皮肤明显脱屑,复查CD3^(+)细胞、CD8^(+)细胞、CD3^(+)HLA-DR^(+)细胞比例仍偏高,遂再次调整治疗方案、加强抗排斥,患儿皮肤aGVHD好转。定期监测原发病完全缓解、植入比例100%、免疫重建稳定,随访至移植后32个月,患儿无病存活。检索到相关文献9篇,均论证了早期CD3^(+)细胞、CD8^(+)细胞、活化T淋巴细胞比例升高以及Treg下调与aGVHD发生相关。结论对异基因造血干细胞移植术后患者的免疫状态进行动态监测,有利于评估其免疫重建情况及疾病状态(如aGVHD),有助于制定合理的免疫抑制治疗方案,使患者获得良好预后。
