Immunologic Effects Of Mesenchymal Stem Cells In The Treatment Of Refractory Acute Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2056-2056
Author(s):  
Qifa Liu ◽  
Ke Zhao ◽  
Can Liu ◽  
Meiqing Wu ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Research Funding ◽  
Graft Versus Host ◽  
Cellular Immune ◽  
Acute Graft

Abstract Background Mesenchymal stem cells (MSCs) have been considered as a promising strategy for the prevention and treatment of acute graft-versus-host disease (aGVHD), but the mechanism of MSCs ameliorating GVHD is still not fully understood. A few studies suggested that MSCs ameliorated GVHD via protecting and repairing the function of thymus. Methods Twenty refractory aGVHD patients receiving MSCs treatment were enrolled in this study, and twenty grade II to IV aGVHD patients treated without MSCs were matched as non-MSCs group. MSCs were given at a median dose of 1×106 cells/kg once weekly until aGVHD got complete response (CR) or MSCs were infused for a total of 8 doses. Lymphocyte subsets of T-cell, B-cell, and NK-cell in peripheral blood were analyzed by flow cytometry before and 30, 60, 90, 180 and 360 days after the MSC infusion in MSC group and the corresponding period in the control group. Results A total of the 33 patients who survived more than 30 days after the study treatments were evaluated for the alterations in cellular immune compartment and cGVHD, including 15 cases in MSCs group and 18 in non-MSCs group. In MSCs group, patients had a significantly higher CD4+/CD8+ T-cell ratio at 60, 90 and 180 day after MSCs treatments, which subsequently equalized at 360 day compared with non-MSCs group. The MSC group presented higher percentages of CD4+CD25+ regulatory T cells (Treg) comparing with non-MSCs group, especially at 90 and 180 day, and approached at 360 day. The proportion of CD4+CD45RO+ and CD4+CD45RA+ naïve T-cells in MSC group were also higher than those in non-MSCs group at 60, 90 and 180 day, but not different at 360 day. The proportion of CD19+ and CD16+CD56+ was not detected striking difference between the two groups. Four patients (26.7%) experienced cGVHD in MSCs group, compared with twelve (66.7%) in non-MSCs group (p=0.02). Conclusions In conclusion, our data indicate that MSCs might ameliorate aGVHD and induce longer-lasting immune tolerance by altering cellular immune compartments in peripheral blood. The alteration of the cellular immune compartments is associated with the protecting and repairing role of MSCs to thymus. Disclosures: Liu: 863 Program (No. 2011AA020105): Research Funding; National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647): Research Funding; Science and Technology Program of Guangzhou of China (11A72121174) : Research Funding.

scholarly journals MiR-223 Derived from Mesenchymal Stem Cell Exosomes Alleviates Acute Graft-Versus-Host Disease

2020 ◽  
Author(s):  
Weijiang Liu ◽  
Na Zhou ◽  
Peng Wang ◽  
Yuanlin Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
High Throughput Sequencing ◽  
Human Umbilical Cord ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Acute Graft

Abstract Background Mesenchymal stem cells (MSCs) have been utilized in treating acute graft-versus-host disease (aGvHD) as they show strong immunosuppressive capacity, but the mechanisms are not well defined.Methods In this study, we demonstrated that microRNA-223 (miR-223) derived from exosomes secreted by human umbilical cord mesenchymal stem cells (huc-MSCs) and murine compact bone mesenchymal stem cells (mb-MSCs) could inhibit aGvHD progression by reducing the migration and homing of donor T cells in aGvHD mice.Results MiR-223 was one of the conserved microRNAs highly expressed in huc-MSCs exosomes and mMSCs exosomes, which was identified by high-throughput sequencing. MiR-223 derived from MSC exosomes showed enhanced immunosuppressive capacity, as it could inhibit expression of the target gene ICAM-1 and restrain adhesion and migration of T cells in vitro. Moreover, miR-223Agomir was effective in reducing the inflammatory reaction, and declining the donor T cells infiltration into the spleen, liver and intestine in aGvHD mice. Subsequently, it could alleviate aGvHD symptoms. Taken together, the MSC exosome derived miR-223 could attenuate aGvHD in mice through regulating ICAM-1 expression.Conclusions Our results unveil a new role for MSC exosomes derived miR-223 in the treatment of aGvHD.

Predictive Markers for Acute Graft-Versus-Host Disease in the Peripheral Blood - Surface Receptor Profile Defines Alloreactive T Cells In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 622-622
Author(s):  
Andreas Beilhack ◽  
Robert Zeiser ◽  
Stephan Schulz ◽  
Janelle A. Olson ◽  
Ryosei Nishimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Target Organ ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Effector Phase ◽  
Selectin Ligand ◽  
Acute Graft

Abstract Acute graft-versus-host disease (aGVHD) still results in high morbidity and mortality in patients undergoing allogeneic hematopoietic cell transplantation (aHCT). Early diagnosis of aGVHD remains difficult and is made based on clinical symptoms and histological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestations. Therefore, it is important to develop predictive assays to identify patients at risk of developing aGVHD for improved disease prevention. Using bioluminescence imaging (BLI) we have recently demonstrated that aGVHD pathogenesis is tightly spatially and temporally regulated in a murine model across major histocompatibility barriers. Therefore, we asked whether insights in the timing of aGVHD initiation and effector phase could allow for the development of a diagnostic test whereby specific cell surface profiles can predict the onset of aGVHD. FVB/N (H-2q, Thy1.1+, 4x106) or C57Bl/6 (H-2b, Thy1.1+, 4x106) splenocytes plus bone marrow (BM) cells (5x106) were transplanted into conditioned (2x400rad) allogeneic Balb/c (H-2d, Thy1.2+) or syngeneic (2x450rad) C57Bl/6 (H-2b, Thy1.2+) recipients. Allogeneic recipients developed the first clinical signs of aGVHD starting at day+6 which progressed rapidly to animal death typically by day+14. However, BLI revealed that aGVHD target organ infiltration had already occurred days earlier. On day+3 after aHCT, dividing (BrdU+) donor derived allogeneic T cells (Thy1.1+) were still confined to the T cell areas in secondary lymphoid organs. Between day+3 and day+4 T cells appeared in the red pulp of the spleen, indicating likely entry into the blood circulation. Thereafter, increasing aGVHD target organ infiltration became apparent. These findings prompted us to analyze peripheral blood (PB) samples from allogeneic vs. syngeneic recipients (day+1 to +6). Until day+3 after aHCT, no significant PB T cell numbers were detectable. However, by day+4 we found a dramatic increase of PB T cells (mostly CD4+, by day+5 mostly CD8+) that were CD44hi and expressed the homing receptors α4β7 integrin, αEβ7 integrin, CCR9, E-selectin ligand, P-selectin ligand, CCR5, and CXCR3 in allogeneic recipients, but not in syngeneic or BM controls. These T cell populations could be verified as clonally expanded (CFSElo) donor-derived alloreactive T cell subsets (Thy1.1+). In summary, alloreactive T cells could be identified by the timed up-regulation of a panel of distinct homing receptors. Furthermore, the transition between aGVHD initiation and effector phase emerged as an early diagnostic window for the detection of alloreactive T cells in the peripheral blood days before aGVHD onset. Taken together, this approach could predict aGVHD in order to tailor immunosuppressive therapy for individual patients.

scholarly journals The Therapeutic Effect of ICAM-1-Overexpressing Mesenchymal Stem Cells on Acute Graft-Versus-Host Disease

2018 ◽  
Vol 46 (6) ◽  
pp. 2624-2635 ◽  
Author(s):  
Bo Tang ◽  
Xue Li ◽  
Yuanlin Liu ◽  
Xiuhui Chen ◽  
Ximei Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Culture Methods ◽  
Graft Versus Host

Background/Aims: Mesenchymal stem cells (MSCs) do not readily migrate to appropriate sites, and this creates a major obstacle for their use in the treatment of graft-versus-host disease (GVHD). Intercellular adhesion molecule-1 (ICAM-1) can guide the homing of various immune cells to the proper anatomical location within secondary lymphoid organs (SLOs), which are the major niches for generating immune responses or tolerance. MSCs rarely migrate to SLOs after intravenous infusion, and are constitutively low expression of ICAM-1. So in our previous work, ICAM-1 was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (ICAM-1MSCs). Here, we hypothesized that ICAM-1highMSCs may significantly improve their immunomodulatory effect. Methods: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate ICAM-1highMSCs immunomodulatory effect on dendritic cells (DCs) and T cells in vitro and in vivo. MSCs were labeled with carboxyfluorescein diacetate succinimidylester (CFSE) to detect its distribution in mouse model. Results: Our in vitro analyses revealed ICAM-1 MSCs could suppress DCs maturation according to co-culture methods and suppress the T cell immune response according to the mixed lymphocyte response (MLR) and lymphoblast transformation test (LTT) tests. We found that infusion of ICAM-1highMSCs potently prolonged the survival of GVHD mouse model. The infused ICAM-1highMSCs migrate to SLOs in vivo, and suppressed DCs maturation, suppressed CD4+ T cell differentiation to Th1 cells, and increased the ratios of Treg cells. Conclusions: Taken together, these data demonstrate that ICAM-1highMSCs had an enhanced immunosuppressive effect on DCs and T cells, which may help explain the protective effect in a GVHD model. This exciting therapeutic strategy may improve the clinical efficacy of MSC-based therapy for GVHD.

HO-1 Activation In Bone-Mesenchymal Stem Cells For Treatment and Prevention Of Acute Graft-Versus-Host Disease In Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5427-5427
Author(s):  
Dan Ma ◽  
Jishi Wang ◽  
Yan Li ◽  
Qin Fang ◽  
Jia Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
T Cell Subsets ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Acute Graft

Abstract Objective Bone marrow mesenchymal stem cells (BMSCs) were confirmed that have great potential in decreasing acute graft-versus-host disease(aGVHD) after allogeneic hematopoietic stem cells transplantation(allo-HSCT) in various clinical trails. However, the immuno-modulatory effects of BMSCs are not always successfully achieved in vivo. In this study, we aimed to proved that activation of heme oxygenase-1(HO-1) in BMSCs could significantly enhance the capacity on decreasing aGVHD in vivo and explored the relative mechanism. Methods We cloned mice’s HO-1 cDNA from mice bone marrow and constructed recombinant lenti-virus vectors (Lentivirus-V5-D-TOPO-HO-1-EGFP/Lentivirus-V5-D-TOPO-EGFP), which titer was 1×1011pfu/mL. These mouse BMSCs were separated, cultured, purified, and detected by morphology, flow cytometry, osteogenic, adipogenic and chondrogenic induction. Then recombinant lenti-virus vectors were transferred into mouse BMSCs, and the expression of EGFP and HO-1 were detected by fluorescence microscope, RT-PCR and Western blot respectively. We established mice’s aGVHD model after allo-HSCT. Four groups were separated in vivo test (Group A: aGVHD control; Group B: aGVHD model injected into mouse BMSCs; Group C: aGVHD model injected into mouse BMSCs transfected with EGFP; Group D: aGVHD model injected into mBMSCs transfected with HO-1 gene). The survival time, body weight and clinical score of aGVHD in mice model were monitored. Liver, intestine and lung in each group were obtained for histological examination. Plasma concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ and TNF-„p were also determined using a Cytometric Bead Array. Results In vitro, over-expression of HO-1 promoted the proliferation of BMSCs, the cell proliferation rate of BMSC transfected with lenti-virus-HO-1 was 1.25 folder higher over natural BMSCs(p<0.05). In vivo, the immuno-suppressive capacity of BMSCs expressing HO-1 in a major histo-compatibility complex (MHC)-mismatched mouse model of bone marrow (BM) transplantation from C57BL/6 donors to BALB/c recipients. Treatment with HO-1 over-expressing BMSCs obviously decreased the animal mortality rate,60% mice in group BMSCs suffered from aGVHD and died, while 70% mice in group BMSCs-HO-1 were still alive, and expressed less clinical and pathological aGVHD scores. In addition, compared with other groups, the level of negative regulative cytokines, IL-2, IL-6, IFN-γ and TNF-„p in recipients injected with BMSCs-HO-1, were significantly decreased (FCBMSC-HO-1/BMSC=cytokines concentration detected in group infused BMSCs-HO-1/group infused BMSCs, if FCBMSC-HO-1/BMSC<1, means the cytokines concentration detected in group infused BMSCs-HO-1 decreased. Our study indicated that: FCBMSC-HO-1/BMSC of IL-2: 0.4±0.1; IL-6: 0.7±0.1; IFN-γ: 0.7±0.05; TNF-„p: 0.8±0.02. p<0.05), while those positively regulative cytokines, IL-4 and IL-10 were increased(FCBMSC-HO-1/BMSC>1, means the cytokines concentration detected in group infused BMSCs-HO-1 increased. Our study indicated that: FCBMSC-HO-1/BMSC of IL-4: 1.3±0.15; IL-10: 1.5±0.1; p<0.05). In field of Th1/Th2 cells proliferation, the value of CD8+ and CD4+ T cells and the ratio of Th1/Th2 T cell subsets decreased(CTBMSC-HO-1/BMSC= cells counts of group infused BMSCs-HO-1/group infused BMSCs, CTBMSC-HO-1/BMSC<1, means cells counts of group infused BMSCs-HO-1 decreased. Our data showed that, CTBMSC-HO-1/BMSC of CD8+ T cells: 0.25±0.09; CD4+ T cells:0.47±0.06; Th1/Th2 T cell subsets: 0.32±0.05; p<0.05) , at the same time the proportion of CD4+CD25+ T cells increased both in spleen lymphocytes in vivo after allo-HSCT with BMSCs expressing HO-1 compared with conventional allo-HSCT(CTBMSC-HO-1/BMSC of CD4+ CD25+ Foxp3+ cells:13.4±2.1; p<0.01. CTBMSC-HO-1/BMSC>1,means cells counts of group infused BMSCs-HO-1 increased). Conclusion our report strongly reveals that activation of HO-1 could enhance the ability of BMSCs to effectively alleviate aGVHD. The mechanism involved that the enhanced homing ability of BMSCs, immuno-suppressive ability to decrease negatively regulative cytokines, while to increase positive part. At last, BMSCs transfected lenti-virus-HO-1 expressed the potential ability to induce Treg cells proliferation. Disclosures: No relevant conflicts of interest to declare.

Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells

The Lancet ◽  
2004 ◽  
Vol 363 (9419) ◽  
pp. 1439-1441 ◽  
Author(s):  
Katarina Le Blanc ◽  
Ida Rasmusson ◽  
Berit Sundberg ◽  
Cecilia Götherström ◽  
Moustapha Hassan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft
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