Inducible Costimulator Gene Transduced Bone Marrow Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in a Mouse Haploidentical Model.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2996-2996
Author(s):  
Dan Yang ◽  
Jian-Min Wang ◽  
Li-ping Wang ◽  
Hong Zhou
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
Early Stage ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Acute Graft

Abstract Abstract 2996 It is reported that both block of costimulator (ICOS) or its ligand signal pathway and transfusion of mesenchymal stem cells (MSCs) can reduce the severity of acute graft-versus-host disease (GvHD). Using a MHC-haploidentical murine model of acute GvHD, we investigated the effects of MSC-ICOS-EGFP, bone marrow derived MSCs transduced with ICOS-gene using an adenoviral vector, on acute GvHD. Lethally irradiated CB6F1 mice were transplanted with bone marrow cells and spleen cells from C57BL/6 mice, and injected with MSC-ICOS-EGFP, MSCs, ICOS-Ig fusion protein or the diluent (control), respectively. Survival in recipients of MSC-ICOS-EGFP was significantly higher than that in GVHD group (74.29±7.39% vs 0, P=0.000, n=35), and also higher than in MSCs, ICOS-Ig, or MSCs+ICOS-Ig groups (74.29±7.39% vs 42.86±8.36% or 48.57±8.45% or 50.43±8.45%, P=0.0039 or 0.0323 or 0.0418, n=35). The lower mortality in recipients of MSC-ICOS-EGFP was related to lower incidence of acute GvHD. MSC-ICOS-EGFP can reduce the number of CD4+T cells in the early stage of GvHD due to the increased apoptosis, and it can produce CD4+CD25+Treg cells meanwhile. The effect on GvHD in recipient of MSC-ICOS-EGFP was also associated with higher serum levels of IL-4, IL-10 and lower levels of IFN-γ, IL-2, IL-12, IL-17A, as well as inducing expression of GATA-3, STAT6 transcription factors while inhibiting expression of T-bet, STAT4, ROR-rt in spleen. In vitro, the CD4+T cells of donor were sharply inhibited by MSC-ICOS-EGFP and the B7h blockade. In MLRs we can also detect lower levels of IFN-γ, IL-2and higher levels of IL-4, IL-10. These data indicate that MSC-ICOS-EGFP is a more prospective strategy for acute GvHD prevention, which had a synergism effect between MSCs and ICOS-Ig. The mechanisms of MSC-ICOS-EGFP on acute GvHD were closely associated with modulation of CD4+T cells, CD4+CD25+Tregs, and regulation of the Th1/Th2/Th17 balance in the early stage of GvHD. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2342-2350 ◽  
Author(s):  
Ho-Jin Shin ◽  
Jeanette Baker ◽  
Dennis B. Leveson-Gower ◽  
Aaron T. Smith ◽  
Emanuela I. Sega ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Acute Gvhd ◽  
Graft Versus Host ◽  
Donor Type ◽  
Ifn Γ ◽  
And Function ◽  
Acute Graft ◽  
Stimulation Of

Abstract Previous work has demonstrated that both rapamycin (RAPA) and IL-2 enhance CD4+CD25+Foxp3+ regulatory T-cell (Treg) proliferation and function in vitro. We investigated whether the combination of RAPA plus IL-2 could impact acute GVHD induction after bone marrow transplantation (BMT). RAPA plus IL-2 resulted in improved survival and a reduction in acute GVHD lethality associated with an increased expansion of donor type CD4+Foxp3+ Tregs and reduced CD4+CD25− conventional T cells (Tcons). RAPA plus IL-2, but not either drug alone, increased both expansion of donor natural Tregs and conversion of induced Tregs from donor CD25− Tcons while IL-2 alone increased conversion of Tregs from CD25− Tcon. RAPA plus IL-2 treatment resulted in less production of IFN-γ and TNF, cytokines known to be important in the initiation of acute GVHD. These studies indicate that the pharmacologic stimulation of T cells with IL-2 and the suppression of Tcon proliferation with RAPA result in a selective expansion of functional Tregs and suppression of acute GVHD.

Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5304-5304 ◽  
Author(s):  
Katarina Le Blanc ◽  
Francesco Frassoni ◽  
Lynne Ball ◽  
Edoardo Lanino ◽  
Berit Sundberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate into several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. Within the EBMT MSC expansion consortium we have used MSC to treat grades III–IV acute graft-versus-host disease (GvHD) in 40 patients. The MSC dose was median 1.0 (range 0.4–9) 10^6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nineteen patients received one dose, 19 patients received two doses, two patients received three and five doses respectively. MSC donors were in five cases HLA-identical sibling donors, 19 haploidentical donors and 41 third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GvHD, 19 had complete responses, nine showed improvement, seven patients did not respond, four had stable disease and one patient was not evaluated due to short follow-up. Twenty-one patients are alive between six weeks up to 3.5 years after transplantation. Nine of these patients have extensive chronic GvHD. One patient with ALL has recurrent leukaemia and one patient has denovo AML of recipient origin. We conclude that MSC have immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GvHD in prospective randomized trials.

Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2918-2918 ◽  
Author(s):  
Katarina Le Blanc ◽  
Francesco Frassoni ◽  
Lynne Ball ◽  
Edoardo Lanino ◽  
Berit Sundberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate into several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. Within the EBMT MSC expansion consortium we have used MSC to treat grades III-IV acute graft-versus-host disease (GvHD) in 40 patients. The MSC dose was median 1.0 (range 0.4–9) 10^6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nineteen patients received one dose, 19 patients received two doses, two patients received three and five doses respectively. MSC donors were in five cases HLA-identical sibling donors, 19 haploidentical donors and 41 third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GvHD, 21 had complete responses, eight showed improvement, eight patients did not respond, two had stable disease and one patient was not evaluated due to short follow-up. Twenty patients are alive between six weeks up to 3.5 years after transplantation. Nine of these patients have extensive chronic GvHD. One patient with ALL has recurrent leukaemia and one patient has denovo AML of recipient origin. We conclude that MSC have immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GvHD in prospective randomized trials.

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 Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis

2001 ◽  
Vol 194 (10) ◽  
pp. 1433-1440 ◽  
Author(s):  
Pavan Reddy ◽  
Takanori Teshima ◽  
Mark Kukuruga ◽  
Rainer Ordemann ◽  
Chen Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Acute Graft

Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 → B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P &lt; 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-γ knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-γ is critical for this protective effect.

scholarly journals IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5772
Author(s):  
Hyun-Joo Lee ◽  
Harry Jung ◽  
Dong-Kyu Kim
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Suppressive Effect ◽  
Tnf Α ◽  
Immunomodulatory Capacity ◽  
Ifn Γ

Background: Tonsil-derived mesenchymal stem cells (T-MSCs) were reported to have suppressive effect on T cells, yet much remains unknown about the underlying mechanisms supporting this effect. We investigated the underlying mechanism of the immunomodulatory effect of T-MSCs on immune cell proliferation and cytokine production. Methods: We isolated T-MSCs from human palatine tonsil and evaluated the immunomodulatory capacity using RT-PCR, ELISA, and flow cytometry. Additionally, we assessed the expression of various soluble factors and several costimulatory molecules to detect the priming effect on T-MSCs. Results: T-MSCs significantly inhibited the immune cell proliferation and cytokine expression (TNF-α and IFN-γ) in the direct co-culture, but there was no suppressive effect in indirect co-culture. Additionally, we detected a remarkably higher expression of indoleamine 2,3-dioxygenase (IDO) in the primed T-MSCs having co-expression CD40. Moreover, immune cells or CD4+ T cells showed lower TNF-α, IFN-γ, and IL-4 expression when the primed T-MSC were added; whereas those findings were reversed when the inhibitor for IDO (not IL-4) or CD40 were added. Furthermore, T-bet and GATA3 levels were significantly decreased in the co-cultures of the primed T-MSCs and CD4+ T cells; whereas those findings were reversed when we added the neutralizing anti-CD40 antibody. Conclusions: Primed T-MSCs expressing IDO and CD40 may have immunomodulatory capacity via Th1-mediated and Th2-mediated immune response.

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