Weiming Li

The Different Immunoregulatory Functions of Mesenchymal Stem Cells in Patients with Low-Risk or High-Risk Myelodysplastic Syndromes

Myelodysplastic syndrome (MDS) are a group of progressive, clonal, neoplastic bone marrow disorders characterized by hematopoietic stem cell dysregulation and abnormalities in the immune system. Mesenchymal stem cells (MSC) have gained further interests after the demonstration of an immunoregulatory role. Nevertheless, the immunoregulatory function of MDS bone marrow derived MSC (MDS-MSC) remains poorly defined. In addition, it is not clear whether there are differences in the regulatory functions between low-risk and high-risk MDS-MSC. In this study, we obtain and expand MSC from bone marrow of patients with MDS. Our results show that there are significant differences in the immunoregulatory functions between low-risk and high-risk MDS-MSC. Compare to low-risk MDS-MSC, high-risk MDS-MSC is associated with the presence of increased TGF-β1, higher apoptosis, higher immunosuppressive rate and a poor ability of hematopoietic support. In addition, our results find that there are great differences in the CD4+CD25+Foxp3+Tregs inducible rate between high-risk MDS-MSC and low-risk MDS-MSC. Compared to high-risk MDS-MSC, the inducible rate of CD4+CD25+Foxp3+Tregs of low-risk MDS-MSC is lower. At last, we find that MDS-MSC derived TGF-β1 is largely responsible for the increase in CD4+CD25+Foxp3+Tregs based on knockdown studies. These results elucidate the different immunoregulatory role of MSC in low-risk and high-risk MDS, which may be important for understand the pathogenesis of MDS and the development of novel immunomodulatory strategies for the treatment of MDS.

Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patients with chronic myeloid leukemia.

Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of differentiating into multiple mesenchymal lineages and supporting hematopoiesis. Recently, MSCs have gained further interests after the demonstration of an immunosuppressive role. However, it is still unclear whether the immunosuppressive capability of MSCs will be altered with disease state. In this study, we obtained and expanded MSCs from bone marrow of patients with chronic myeloid leukemia (CML). Our results showed that MSCs derived from CML do not express costimulatory molecules CD40, CD80, and CD86. When MSCs derived from CML were added back to T cells stimulated by mitogens, a significant inhibition of T-cell proliferation was evident. MSCs differentiated into various mesenchymal lineages did not alter their immunosuppressive effect on T-cell proliferation. A significant T-cell inhibition was found in a transwell system, in which cell-cell contact between MSCs and effector cells was prevented. Furthermore, we found that transforming growth factor β1 (TGF β1) and hepatocyte growth factor (HGF) were major mediators of T-cell suppression by MSCs derived from CML. These results demonstrated that autologous MSCs derived from CML could effectively suppress T-cell proliferation.

The Different Immunoregulatory Functions on Dendritic Cells between Mesenchymal Stem Cells Derived from Bone Marrow of Patients with Low-Risk or High-Risk Myelodysplastic Syndromes

Myelodysplastic syndrome (MDS) is a group of progressive,clonal, neoplastic bone marrow disorders characterized by hematopoietic stem cell dysregulation and abnormalities in the immune system. Mesenchymal stem cells (MSC) appear to modulate the immune system at the very first step of the immune response through the inhibition of dendritic cells (DCs) differentiation and maturation. However, it is still unclear whether the effects of MSC on the development of DCs will be altered with disease state. In addition, it is not clear whether there are differences in the effects between low-risk and high-risk MDS-MSC on DCs development. In this study, our data confirm that MDS-MSC mediate a potent inhibition of DCs differentiation. Additionaly, MDS-MSC greatly alter DCs functions, including endocytosis, IL-12 secretion, their ability to inhibit T cell proliferation. Moreover, our results show that there are major differences in DCs development and function between low-risk and high-risk MDS-MSC. Compared to high-risk MDS-MSC, low-risk MDS-MSC is characterized by a poor ability to inhibit DCs differentiation and maturation; and correspondingly, less dysfunctional DC endocytosis, mildly decreased IL-12 secretion, and a reduction in DC-mediated inhibition of T cell proliferation. Finally, our results demonstrate that MDS-MSC derived TGF-β1 is largely responsible for the inhitory effects. These results elucidate the different immunoregulatory role of MSC in low-risk and high-risk MDS on DCs development, which may be important for understanding the pathogenesis of MDS and the development of novel immune therapies for the treatment of MDS.

The characteristics and immunoregulatory functions of regulatory dendritic cells induced by mesenchymal stem cells derived from bone marrow of patient with chronic myeloid leukaemia

Dendritic cells (DCs) are specialised antigen-presenting cells that play crucial roles in the initiation and regulation of immune responses. Recently, mesenchymal stem cells (MSCs) have gained further interest after demonstration of immunomodulatory effects on complicated interactions between T cells and even DCs. However, the mechanisms underlying these immunoregulatory effects of MSCs induced DCs are poorly understood. In addition, it is unclear whether the immunoregulatory functions of MSCs are altered in disease states. In this study, we showed that chronic myeloid leukaemia (CML) patients bone marrow derived MSCs (CML-MSC) could differentiate mature DCs (mDCs) into a distinct regulatory DC population, they had lower expression of CD40, CD80, CD83 and CD86. Similar to immature DCs (imDCs), CML-MSC induced DCs (CML-MSC-DCs) displayed powerful phagocytic capacity. Moreover, CML-MSC-DCs had the capacity to induce T cell anergy, another capacity of regulatory DCs. CML-MSC-DCs could inhibit the proliferation of T cells not only through TGF-β1, but also by inducing the production of Treg cells or T-cell anergy. At last, CML-MSC-DCs could efficiently induce more CD4+CD25+Foxp3+Tregs from naive CD4+CD25-Foxp3-T cells than that of normal-MSC-DCs in vitro. CML-MSC-DCs derived TGF-β1 was largely responsible for the increase in CD4+CD25+Foxp3+Tregs based on knockdown studies. The immunoregulatory effects of DCs induced by CML-MSCs enhance the potential use of autologous MSCs in cell therapy.

Prophylactic Effects of Interleukin-2 Receptor Antagonists against Graft-versus-Host Disease Following Unrelated Donor Peripheral Blood Stem Cell Transplantation

Basiliximab and daclizumab, two interleukin-2 receptor antagonists (IL-2RAs), prevent graft failure in renal transplantation, which also effectively treat steroid-refractory graft-versus-host disease (GVHD). However, only a few studies report that IL-2RAs prevent GVHD. Here we first retrospectively explored the prophylactic effects of basiliximab or daclizumab against GVHD in 82 patients with hematologic malignancies following unrelated donor-peripheral blood stem cell transplantation (URD-PBSCT). All recipients achieved engraftment. The rates of grade II-IV and III-IV acute GVHD (aGVHD) were 35.4% and 15.9%, respectively. Chronic GVHD (cGVHD) developed in 38.7% of evaluable patients. The transplantation-related mortality was 13.4%, while relapse rate was 8.5%. The 2-year overall survival (OS) reached 77.1% and disease-free survival (DFS) accumulated to 72.2%. The side effects of basiliximab and daclizumab were moderate and tolerable. There were no significant differences in aGVHD onset and survival between the daclizumab and basiliximab groups. However, basiliximab presented superior prophylactic effects on cGVHD than daclizumab. In conclusion, basiliximab or daclizumab prevents GVHD efficiently and feasibly following URD-PBSCT, and contributes to favorable outcome. Basiliximab has a similar effect on aGVHD but superior activity against cGVHD. Further prospective and randomized control studies are needed.

Analysis of hematogones in bone marrow from acute myeloid leukaemia cases posttherapy

Increased bone marrow (BM) hematogones (HGs) are often observed in patients with marrow regenerating status. Many studies have focused on the role of HGs in acute lymphoblastic leukaemia (ALL), but very little has been done to understand their effects on acute myeloid leukaemia (AML).

Analysis of seizure risk factors after allogeneic hematopoietic stem cell transplantation: A 8 case report and literature review

The clinical characteristics of patients with seizures after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were analyzed. A total of 8 cases of seizures after allo-HSCT were investigated. Clinical data of these cases were studied retrospectively. Of 159 cases subjected to allo-HSCT, seizure occurred in 8 cases during 29–760 days after transplantation, median survival time was 46 days, and there were 6 cases of tonic-clonic seizure. The incidence of seizure after matched unrelated HSCT was higher than that after related HSCT (P=0.017). Of 7 cases treated with cyclosporine A (CsA), 4 cases obtained high blood levels of CsA. In addition, hyponatremia was diagnosed in 5 cases. Abnormal electroencephalogram and brain MRI findings were found in some cases. During 20 days after seizure, 2 cases died due to infection and graft-versus-host disease (GVHD), respectively. It was suggested that multiple factors are associated with seizures after allo-HSCT. Rapid identification and correction of the causative factors are very important to prevent permanent central nervous system damage and reduce the mortality.SummaryThe clinical characteristics of patients with seizures after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were analyzed. A total of 8 cases of seizures after allo-HSCT were investigated. Clinical data of these cases were studied retrospectively. Of 159 cases subjected to allo-HSCT, seizure occurred in 8 cases during 29–760 days after transplantation, median survival time was 46 days, and there were 6 cases of tonic-clonic seizure. The incidence of seizure after matched unrelated HSCT was higher than that after related HSCT (P=0.017). Of 7 cases treated with cyclosporine A (CsA), 4 cases obtained high blood levels of CsA. In addition, hyponatremia was diagnosed in 5 cases. Abnormal electroencephalogram and brain MRI findings were found in some cases. During 20 days after seizure, 2 cases died due to infection and graft-versus-host disease (GVHD), respectively. It was suggested that multiple factors are associated with seizures after allo-HSCT. Rapid identification and correction of the causative factors are very important to prevent permanent central nervous system damage and reduce the mortality.

Comparison of outcomes of idarubicin intensified TBI–CY and traditional TBI–CY conditioning regimen for high-risk acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A single center experience

High-risk acute lymphoblastic leukemia (ALL) carries a very poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Exploring novel conditioning regimen to more effectively eliminate leukemic clone while not alter transplant-related mortality (TRM) has become focus of attention. We retrospectively evaluated outcomes of 87 high-risk ALL patients undergoing allo-HSCT: 47 patients received idarubicin (IDA) intensified TBI-CY and 40 patients received traditional TBI-CY regimen. In IDA intensified group, patients received TBI (8Gy) on day-8, IDA of 15mg/m2/d from day-6 to -5, followed by CY (60mg/kg/d) on day-3 to -2. The cumulative incidence of relapse was significantly lower in IDA intensified group compared with TBI-CY group (P=0.018). Oropharyngeal mucositis was observed more frequent in IDA intensified group (P=0.013), while not followed by increased TRM. Very high-risk ALL patients benefit from IDA intensified regimen with only two of eight patients in no remission (NR) pre-transplantation and two of twelve ph+ALL patients relapsed after transplantation. After a median follow-up for all survivors of 21 months (range, 12-53 months), 2-year estimated OS and DFS was 66.2% vs 45.3% (P=0.031) and 62.5% vs 43.5% (P=0.044), respectively. In conclusion, IDA intensified TBI-CY regimen may reduce relapse while not increasing TRM, providing better survival for high-risk ALL patients undergoing allo-HSCT.

Idarubicin-intensified BUCY2 conditioning regimen improved survival in high-risk acute myeloid, but not lymphocytic leukemia patients undergoing allogeneic hematopoietic stem cell transplantation: A retrospective comparative study

The intensity of conditioning regimen is highly correlated with outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported that idarubicin (IDA) intensified BUCY2 regimen could reduce relapse and improve survival for high-risk hematological malignancies undergoing allo-HSCT. However, there is no published study comparing the efficacy of IDA-BUCY2 regimen for high-risk acute myeloid leukemia (AML) versus acute lymphocytic leukemia (ALL). We further retrospectively compared therapeutic outcomes of intensified conditioning regimen on 140 high-risk AML and ALL patients in the data analyses. IDA 15mg/m(2)/d was administered by continuous infusion from day -11 to -9, followed by intravenous injection of busulfan (BU) (3.2mg/kg/d) from day -6 to -4, and intravenous injection of cyclophosphamide (CY) (1.8g/m(2)/d) from day -3 to -2 in IDA-BUCY2 regimen. For high-risk AML, cumulative probabilities of 3-year relapse rates in IDA-BUCY2 and traditional BUCY2 regimens were 16.9%, 43.3% (P=0.016). Cumulative probabilities of 3-year overall survival (OS) and disease-free survival (DFS) were 69.2% vs 44.0% (P=0.024), and 66.9% vs 38.2% (P=0.01). However, two regimens showed no significant differences for high-risk ALL. Multivariate analysis also indicated that IDA intensified BUCY2 conditioning was the favorable variable to reduce relapse and elevate survival for high-risk AML patients. In conclusion, IDA-BUCY2 regimen reduces relapse and improves survival for high-risk AML undergoing allo-HSCT, but not presenting uniform therapeutic effects for high-risk ALL.

A novel e8a2 BCR-ABL1 intronic fusion through insertion of a chromosome 22 BCR gene fragment into chromosome 9 in an atypical Philadelphia (Ph) chromosome chronic myeloid leukemia patient

Lifeng Chen, Yaohui Wu, Yong You, Min Xiao, Ye Yao and Weiming Li Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P.R. China; Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P.R. China; Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, P.R. China; Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, P.R. China