Yan Hm

Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells.

BACKGROUND AIMS The purpose of this study was to observe the clinical effect and safety of umbilical cord mesenchymal stem cells (UC-MSCs) in treating spinal cord injury (SCI) by intrathecal injection. METHODS From January 2008 to October 2010, we treated 22 patients with SCI with UC-MSCs by intrathecal injection; dosage was 1 × 10(6) cells/kg body weight once a week given four times as a course. Four patients received two courses, one patient received three courses and all other patients received one course. American Spinal Injury Association scoring system and International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale were used to evaluate neural function and ability to perform activities of daily living. RESULTS Treatment was effective in 13 of 22 patients; nine patients had no response. Among patients with incomplete SCI, the response to treatment was 81.25%; there was no response to treatment among six patients with complete SCI. Five patients with a response to treatment received two to three courses of therapy, and effects in these patients were further enhanced. In most patients in whom treatment was effective, motor or sensory functions, or both, were improved, and bowel and bladder control ability was improved. In 22 patients 1 month after therapy, algesia, tactile sensation, motion and activity of daily living scale were significantly improved (P < 0.01). During therapy, common adverse effects were headache (one case) and low back pain (one cases); these disappeared within 1-3 days. No treatment-related adverse events occurred during a follow-up period ranging from 3 months to 3 years. CONCLUSIONS UC-MSC therapy by intrathecal injection is safe and can improve neurologic function and quality of life in most patients with incomplete SCI.

HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILD HEMATOLOGIC MALIGNANCIES WITH G-CSF-MOBILIZED MARROW GRAFTS WITHOUT T-CELL DEPLETION: A Single-Center Report of 45 Cases

In this report, the authors describe a protocol for haploidentical bone marrow transplantation in children who received G-CSF-mobilized bone marrow grafts without T-cell depletion from HLA-mismatched parents. Forty-two of 45 patients achieved complete donor hematopoietic engraftment; the medium time for neutrophil and platelet recovery was 17 and 19 days, respectively. Three died of early transplantation-associated complications; other causes of death included relapse (11 cases), fungal pneumonia (5), and acute graft-versus-host disease (2). The total disease-free survival rate longer than 2 years was 53.3%. These data suggest that haploidentical hematopoietic transplantation is an alterative strategy for children who lack immediate access to HLA-matched sources.

Cotransplantation of Allogeneic Mesenchymal and Hematopoietic Stem Cells in Children With Aplastic Anemia

We report here the preliminary results of allogeneic hematopoietic stem cell transplantation with mesenchymal stem cells (MSCs) for 6 cases of severe aplastic anemia. The patients ranged in age from 3 to 16 years, and the median time from diagnosis to transplantation was 32 months (range: 3–156 months). The conditioning regimens consisted of fludarabine, cyclophosphamide, and antithymocyte globulin with or without busulfan. Graft-versus-host disease (GvHD) was prevented by the administration of cyclosporine A, methotrexate, and mycophenolate mofetil, with or without anti-CD25 monoclonal antibody. The grafts were granulocyte colony–stimulating factor–mobilized bone marrow and peripheral blood from HLA antigen-haploidentical donors (3 cases) or peripheral blood only from unrelated HLA antigen-identical donors (3 cases). MSCs were intravenously injected at a median dose of 1.43 × 106/kg (range: 0.85–2.5 × 106/kg). The mean time for neutrophil and platelet recovery was 12.3 and 13.8 days, respectively. Acute GvHD grade I and II developed in 2 cases, and no chronic GvHD was documented. All patients were alive and transfusion independent at a median follow-up of 15 months (range: 6–29 months). Our report suggests that cotransplantation of allogeneic hematopoietic stem cells and MSCs might provide an opportunity for therapy for children with severe aplastic anemia.

Haploidentical hematopoietic stem cell transplantation in hematologic malignancies with G-CSF mobilized bone marrow plus peripheral blood stem cells grafts without T cell depletion: a single center report of 29 cases

Abstract Haploidentical Hematopoietic stem cell transplantation (Haplo-HSCT) has provided an alternative option since virtually all patients have an immediately available donor. Here, we report the results of Haplo-HSCT with granulocyte-colony-stimulating factor (G-CSF) mobilized bone marrow grafts plus peripheral blood stem cells as the grafts without T-cell depletion. Twenty-nine patients with the mean age of 27.27 years (ranging from 15 to 51 years) were enrolled in this study, and 10 cases were in high risk status. The patients received myeloablative preconditioning with or without total body irradiation and acute graft-versus-host disease (GVHD) prophylaxis consisting of basiliximab, cyclosporine A, methotrexate, mycophenolate mofetil and a rabbit anti-thymocyte globulin. All the patients attained successful neutrophil and platelet recovery. The mean times for neutrophil and platelet recovery were 17.1 and 20.9 days, respectively. During the follow-up at a median time of 30.69 months (ranging from 3 to 76 months), nine patients developed aGVHD grade II–IV, including two developed grade III–IV GVHD after donor lymphocyte infusion. The incidence of cGVHD was 48.3%. 13 patients died within the first two years after transplantation, and the total disease-free survival rate longer than 2 years was 55.2%. These results suggest that G-CSF-primed bone marrow plus peripheral blood stem cell grafts are an appropriate stem cell source for Haplo-HSCT and large scale investigations are needed to confirm this protocol.

Co-transfusion of haplo-identical hematopoietic and mesenchymal stromal cells to treat a patient with severe aplastic.

A 3-year-old girl with severe aplastic anemia (SAA) that was unresponsive to steroid, cyclosporine and filgrastim treatments received bone marrow (BM) mesenchymal stromal cells (MSC; 1.25 x 10(6)/kg), granulocyte colony-stimulating factor (G-CSF)-mobilized BM and peripheral blood stem cell grafts from her father. Prior to stem cell transplantation, she had experienced repeated bacterial infections and received 44 blood transfusions during 8 months after diagnosis. The conditioning regimen consisted of fludarabine, cyclophosphamide and busulfan, and prophylaxis of acute graft-versus-host disease (GvHD) was performed by administration of anti-CD25 monoclonal antibody, cyclosporine A, methotrexate, mycophenolate mofetil and anti-thymocyte globulin. The patient achieved rapid hematopoietic engraftment of donor origin and no acute or chronic GvHD was observed. She is now alive with a good performance status, and the dose of cyclosporine A is being tapered. The novel regimen described here might be a suitable option for children with SAA who lack immediate access to HLA-matched sources.

Haploidentical hematopoietic stem-cell transplantation for non-Hodgkin lymphoma with bone marrow involvement

Here, we report the preliminary results of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with granulocyte-colony-stimulating factor (G-CSF) mobilized bone marrow grafts without T-cell depletion for 10 patients with refractory non-Hodgkin lymphoma accompanied by bone marrow involvement. Eight patients received a conditioning regimen consisting of high-doses of cytarabine and cyclophosphamide with total body irradiation, whereas two cases were preconditioned with busulfan, thiotepa, and cyclophosphamide. All patients had rapid hematopoietic engraftment with the mean time for neutrophil and platelet recovery being 16.6 days and 19.2 days, respectively. Three cases died within 6 months after transplantation from severe acute graft-versus-host disease, fungal infection, or relapse. The others are currently alive in complete remission at a median follow-up of 60.71 months (range: 44–81months). The results here suggest that haplo-HSCT might provide an opportunity of myeloablative therapy for refractory lymphoma with marrow infiltration.

Successful unmanipulated stem cell transplantation from HLA-haploidentical 3-loci-mismatched parents in two children with severe aplastic anemia not responding to immunosuppressive therapy

Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) are two therapeutic modalities for severe aplastic anemia (SAA). Several reports indicate that 2- to 5-year overall survival for young patients following IST who lack HLA-matched sibling donors is between 60 and 90% [1,2]. The optimal treatment for the patients who have no response to 1ST has not been established. Haploidentical stem cell transplantation (haplo-HSCT) might be a feasible option as it has been successfully used in the management of malignant hematological diseases, and the transplantation protocols have been greatly improved since it was first introduced into clinical use by Aversa et al. [3]. Here, we report successful haplo-HSCT in two children with SAA who were refractory to IST and lacked HLA-identical donors.

Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation.

During human cytomegalovirus (CMV) infection after umbilical cord blood or HLA-matched hematopoietic stem cell transplantation (HSCT), a population of NKG2C-expressing natural killer (NK) cells expand and persist. The expanded NK cells express high levels of inhibitory killer immunoglobulin-like receptors (KIR) specific for self-HLA and potently produce IFNγ. However, it remains unknown whether similar events would occur after haploidentical HSCT (haplo-HSCT). Here, we demonstrated that IFNγ-producing NK cells were expanded in haplo-HSCT patients with CMV reactivation. We then identified these expanded cells as a subset of CD56dim NK cells that expressed higher levels of both NKG2C and KIR, but lower level of NKG2A. Functionally, the subset of NK cells expressing NKG2C and self-KIR in patients with CMV reactivation accounted for IFNγ production in response to K562 cells. However, these phenomena were not observed in patients without CMV reactivation. We therefore characterized a subset of NK cells with the CD56dim, NKG2C+, and self-KIR+ phenotype that expanded and were responsible for IFNγ production during CMV infection after haplo-HSCT. Together, these findings support a notion that CMV reactivation induces expansion of more mature NK cells with memory-like features, which contributes to long-term control of both CMV infection and leukemia relapse after haplo-HSCT.

Haploidentical hematopoietic stem cell transplant with umbilical cord-derived multipotent mesenchymal cell infusion for the treatment of high-risk acute leukemia in children

Abstract In this study, 25 children with high-risk acute leukemia received haploidentical hematopoietic stem cell transplant (haplo-HSCT) with co-transfusion of umbilical cord multipotent mesenchymal cells (UC-MSCs). Adverse effects, hematopoietic recovery, complications and outcome were observed during a median follow-up of 12.8 months (range: 3–25 months). Myeloid engraftment was rapid, and the median time to neutrophil and platelet recovery was 15.12 days and 20.08 days, respectively. Eight patients developed grade I skin acute graft-versus-host disease (aGVHD) that responded well to standard steroid therapy. Of note, cytomegalovirus viremia was observed in most patients (23/25 cases). Patients died mainly of leukemia relapse and pulmonary complication. Fourteen patients are currently alive and remain with full donor chimerism at the time of reporting. The present results suggest further clinical trials to testify the effectiveness of UC-MSCs to prevent aGVHD in haplo-HSCT for treating children with high-risk leukemia.

Functional mesenchymal stem cells remain present in bone marrow microenvironment of patients with leukemia post-allogeneic hematopoietic stem cell transplant

Abstract Mesenchymal stem cells (MSCs) and their progenies are important supporting cells in the bone marrow (BM) microenvironment. However, the function and kinetics of MSCs post-hematopoietic stem cell transplant (HSCT) remain unknown. In the present study, MSCs were cultured from a total of 76 BM samples from 15 patients receiving HSCT. Colony-forming unit fibroblasts in BM before pre-conditioning and 1, 3, 6 and 9 months post-HSCT were cultured and counted to quantify MSCs. Hematopoiesis-supporting activity of MSCs was observed with long-term culture of hematopoietic progenitors. An inhibitory effect of MSCs on in vitro lymphocyte proliferation was also observed. Results showed that post-HSCT MSCs supported in vitro hematopoiesis and inhibited lymphocyte growth. Moreover, the quantity of MSCs was reduced at an early stage and restored to baseline level 9 months post-transplant. The results indicate that functional MSCs remain present in the BM microenvironment, and these findings shed light on the understanding of BM microenvironment reconstitution post-HSCT.