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

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 143-143 ◽  
Author(s):  
Katarina Le Blanc ◽  
Francesco Frassoni ◽  
Lynne Ball ◽  
Mehmet Uzunel ◽  
Edoardo Lanini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Early Death ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate to several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. We have used MSC to treat grades III-IV acute graft-versus-host disease (GVHD) in 14 patients and extensive chronic GVHD in two patients. The MSC dose was median 1.0 (range 0.4–9) x 10E6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nine patients received one dose, six patients received two doses and one patient received three doses. MSC donors were in two cases HLA-identical sibling donors, twelve haploidentical donors and ten third-party HLA-mismatched donors. Among the 14 patients treated for severe acute GVHD, six had complete responses, four showed improvement and one had stable disease. Three were not evaluable: two due to early death and one due to short follow-up. MSC donor DNA was detected in lymph node and colon in one of the patients who died. Among the 14 patients treated for severe acute GVHD, nine are alive between two months up to three years after transplantation. Four of these patients have extensive chronic GVHD. One patient transplanted for AML in relapse has recurrent leukaemia. The two patients treated for extensive chronic GVHD had transient responses. One of them died of Epstein-Barr virus lymphoma. We conclude that MSC have immune-modulatory and tissue repairing effects and therefore may be used for treatment of severe 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.

Mesenchymal Stem Cells for Treatment of Refractory Chronic Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4968-4968
Author(s):  
Weng Jianyu ◽  
Xin Du ◽  
Xiang Peng ◽  
Zhang Xiumin ◽  
Suijin Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Refractory extensive chronic graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation (SCT) is associated with high mortality [Margolis J., SeminOncol 2000].However, conventional therapies including steroids are often unsuccessful in those patients with multiorgan involvement and are associated with significant therapy-related complications and poorly life quality. Mesenchymal stem cells (MSCs) have immunomodulatory effects [Tse WT et al., Transplantation 2003; Spees JI et al.,Proc Natl Acad Sci USA 2003]. Recently MSCs have been given intravenously to treat seven steroid resistant acute GVHD patients and one patient with chronic GVHD. MSCs effects in chronic GVHD is rarely known, although this successfully experience suggests that MSCs have been well tolerated and had a powerful immunosuppressive effects on acute GVHD. [Katarina Le Blanc et al., Lancet 2004; Olle Ringden., Transplantation 2006 ]. Here, we present our experience of using MSCs for treatment of Thirteen patients with refractory chronic GVHD. Between May 2005 and March 2007, thirteen patients (8 male, 5female) with hematological malignancies with a median age of 26(range:15 to 40) years who had received peripheral stem cells from sibling donors. All patients developed steroid resistant or extensive chronic GVHD, with progressive involvement of the skin(13), liver(10), oral mucosa(12),ocular glands(12), and thrombocytopenia (1) when the immunosuppressive agents were taped after five to twenty-four months. The MSC dose was median 1.0 ×106 cells/kg body weight of the recipient. In all, thirteen patients had at least received one dose, seven patients received more than two doses. MSC donors were in seven cases HLA-identical siblings, six unrelated mismatched donors. No side-effects were seen after MSCs infusions. All patients have responded after follow-up of the median time 15 months. One patient with moderate cGVHD had a complete responses, and discontinued all of the immunosuppressive agents without relapse more than 18.4 months after MSC infusion. Three moderate and two patients with severe chronic GVHD improved to mild degree, and six severe turned to moderate degree. Complete resolution was seen in gut(2/3), liver(5/10), skin(5/13), oral(6/12) and eye(2/12). One patient responded in skin, liver, oral mucose and eye, but developed in lung (bronchiolitis obliterans, BO) score of 2 which are considered severe chronic GVHD. Mean follow-up periods was 27m (rang: 14 to48m), Leukemia free survival(LFS)rate were 85%(11/13), and the overall survival (OS)rate were 92.3%(12/13). Our experience suggests that MSC infusion is a safe and effective adjunct therapy for refractory extensive chronic GVHD with resistance to conventional therapy. But more prospective, controlled studies with MSCs for treatment of GVHD should be performanced to evaluate this new treatment exactly.

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

scholarly journals Mesenchymal Stem Cells Improve the Structure and Function of the Graft-Versus-Host Disease Receptor Thymus: CCR9 Plays an Important Role in Its Homing Thymus

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5599-5599
Author(s):  
Xin Zhang ◽  
Ke Zhao ◽  
Jiabao He ◽  
Andy Peng Xiang ◽  
Qifa Liu
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Untreated Group ◽  
Thymic Epithelial Cells ◽  
Frozen Sections ◽  
Host Disease ◽  
Graft Versus Host

Background: Insufficient thymic function of allogeneic hematopoietic stem cell transplantation (allo-HSCT) receptors results in continuous production of alloreactive T cells, which leads to the development of graft-versus-host disease (GVHD), especially chronic GVHD (cGVHD). We have previously found that patients with acute GVHD (aGVHD) treated with mesenchymal stem cells (MSCs) have increased thymic output and decreased incidence of cGVHD, thus hypothesized that MSCs may reduce the incidence of cGVHD by remodeling the thymus. Chemokine receptor 9 (CCR9), the receptor that specifically guides migration of T-lineage precursors into thymus, is also expressed on MSCs, and thus may be a key factor mediating MSCs homing to the thymus. This in turn allows MSCs to reduce GVHD by repairing thymus tissue structure and saving thymus function. Methods: We carried out studies in a murine GVHD model of fully MHC-mismatched myeloablative bone marrow transplantation (C57BL/6 to BALB/c), a model that can observe the prolongation of aGVHD to cGVHD. We randomly divided GVHD mice into four groups, including three MSCs treated groups and one untreated group. CCR9 over-expressed (MSC/CCR9+), knocked-down (MSC/CCR9-) and empty-load MSCs (MSC/Control) were generated and administrated intravenously at dose of 5 × 105 cells/infusion at 7th and 21th day post HCT to the treated groups respectively to compare their thymic homing ability, and therapeutic effects of GVHD with the untreated group. Clinical scores were recorded once every five days to evaluate GVHD symptoms. Mice of MSCs treated groups and the untreated group were sacrificed at 30d, 45d and 60d after HCT. Thymuses of each group were collected and assessed for size and weight before being manufactured into frozen sections or thymic single-cell suspension. We then analyzed the number and distribution of MSCs in the thymus of the treated groups to assess the role of CCR9 in thymic homing, and analyzed the expression of thymic T cells subsets (CD4+CD8-, CD4-CD8+, CD4+CD8+ T, CD4+CD25+Foxp3+Tregs), thymic epithelial cells (TECs) substes (CD45-CD326+Ly51+ cortical TECs and CD45-CD326+UEA-1+ medullary TECs) and the level of T cell receptor rearrangement excision circles (TRECs) in thymus among the four groups to evaluate the repair effect of MSCs for thymus. Radiation-pretreated murine TECs were cultured alone or co-cultured with murine MSCs in vitro to assess the effect of MSCs on damaged TECs. Results: The infusion of MSC/CCR9+ potently alleviated the clinical signs of GVHD and prolonged the survival of GVHD mice (P<0.05 versus MSC/CCR9- and untreated group). Significant increases in thymus size and weight were observed in the MSC/CCR9+ group, as well as the number of total thymocytes and the more organized cortical medullary structure compared to the other groups. MSCs enter the thymus from the microvascular region at the cortex-medium junction. MSC/CCR9+ were found to appear in the cortex-medium junction of thymus in a greater amount 24 hours after the first infusion, then distribute throughout the whole thymus and relocate in proximity with TECs 48 hours thereafter. MSC/Control could be observed in the cortical and cortex-medium junction, whereas MSC/CCR9- was observed only in the cortex-medium junction with a small amount of distribution. Immunofluorescence of thymus frozen sections showed that, compared with other groups, TECs had decreased apoptosis and significantly increased proliferation and maturation levels in MSC/CCR9+ group, indicating MSCs potently repaired injured TECs and promoted their proliferation and maturation. The number of TECs and its proportion of thymus stroma were significantly improved, including cortical TEC and medullary TECs. As for thymocyte, MSC/CCR9+ infusion significantly increased the number and proportion of CD4+CD8+T cells and Tregs, which were reported deficiency in GVHD thymus. Furthermore, MSC/CCR9+ administration resulted in a remarkable increase in the levels of TRECs in the thymocyte at 45d and 60d after HCT (P<0.05 versus MSC/CCR9- and untreated group). In vitro study showed co-cultured TECs had a decreased apoptosis and increased proliferation compared to TECs cultured alone. Conclusion: This study demonstrates that CCR9 plays an important role in guiding migration of MSCs to thymus and thus highly intensify their issue repair and immunomodulatory effect to rescue thymus function in GVHD model. Disclosures No relevant conflicts of interest to declare.

scholarly journals Third-party Wharton’s jelly mesenchymal stem cells for treatment of steroid-resistant acute and chronic graft-versus-host disease: a report of 10 cases

2016 ◽  
Vol 40 ◽  
pp. 493-500 ◽  
Author(s):  
Dariusz BORUCZKOWSKI ◽  
Dominika GŁADYSZ ◽  
Sławomir RUMIŃSKI ◽  
Iwona CZAPLICKA-SZMAUS ◽  
Magdalena MURZYN ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Wharton’S Jelly ◽  
Third Party ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Wharton's Jelly

IL10-Transduced Mesenchymal Stem Cells Attenuate Experimental Acute Graft-Versus-Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5247-5247
Author(s):  
Chang-Ki Min ◽  
Bo-Kyung Kim ◽  
Gyeongsin Park ◽  
Bin Cho ◽  
Il-Hoan Oh
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Acute Gvhd ◽  
Serum Levels ◽  
Host Disease ◽  
Graft Versus Host ◽  
Adult Mesenchymal Stem Cells ◽  
Immunosuppressive Microenvironment

Abstract Recent data suggest that, due to their immunosuppressive nature, adult mesenchymal stem cells (MSCs) may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease (GVHD). Using a murine model of acute GVHD, this study investigated whether the immunosuppressive properties of MSCs could reduce the severity of experimental GVHD. In a MHC-mismatched C57BL/6→B6D2F1 model, recipient animals were transplanted with bone marrow (BM) cells (10x106) plus 20x106 splenocytes after 1100 cGy on day 0. Various doses (1~3x106) of donor BM-derived MSCs were given intravenously from day 1 to day 5 and subsequently evaluated the clinical and immunologic parameters. MSCs did not attenuate the severity of acute GVHD. Using GFP expressing MSCs, we were unable to detect labeled cells in liver, spleen, lymph nodes and lung day 7 post-BMT. Because MSCs fail to display any immunosuppression in this experimental GVHD model and induce an immunosuppressive microenvironment through the production of IL10, we investigated whether the use of genetically modified MSCs expressing IL10 (IL10-transduced MSCs, IL10 MSCs) could improve the GVHD protection. Lethally irradiated recipients were transplanted and injected with 2x106 IL10 MSCs, MSC expressing MIG as a vector (MIG MSCs), or diluent on day 1. Compared with MIG MSCs or controls, recipients of IL10 MSCs demonstrated significantly reduced mortality at day 50 after BMT (percent survival, 0% or 10% vs 70%, P&lt;0.001). The reduction in mortality was confirmed by the semi-quantitative GVHD score (P&lt;0.01). It was associated with decreased serum levels of pro-inflammatory cytokines, IFNγ on day 7 (IL10 MSCs vs MIG MSCs; 297±116 pg/ml vs 681±87 pg/ml, P=0.015). Serum levels of TNFα or splenic donor CD3+ cell numbers were not different between the groups. Thus, benefical effects on GVHD could be observed when MSCs were engineered to express an anti-inflammatory cytokine, IL10. The mechanisms for the GVHD protection effect of IL10 MSCs in this murine model are currently under investigation.

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