Bone Marrow–Derived Mesenchymal Stem Cells Inhibit Acute Rejection of Rat Liver Allografts in Association With Regulatory T-Cell Expansion

Wang, Y.; Zhang, A.; Ye, Z.; Xie, Haiyang; Zheng, Shu-Sen

doi:10.1016/j.transproceed.2009.08.072

Cited by 97 publications

(77 citation statements)

References 16 publications

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“…Evidence from experimental models of solid organ transplantation suggests that the mechanisms of MSC-induced tolerance include regulatory T cells (17,45,46). Despite the two patients given MSCs were receiving CsA, known to prevent the development of Treg by the inhibition of IL-2 (10,47), a progressive expansion of Treg was documented posttransplant.…”

Section: Discussionmentioning

confidence: 99%

Autologous Mesenchymal Stromal Cells and Kidney Transplantation

Perico

Casiraghi

Introna³

et al. 2011

Clinical Journal of the American Society of Nephrology

279

287

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SummaryBackground and objectives Mesenchymal stromal cells (MSCs) abrogate alloimmune response in vitro, suggesting a novel cell-based approach in transplantation. Moving this concept toward clinical application in organ transplantation should be critically assessed.Design, setting, participants & measurements A safety and clinical feasibility study (ClinicalTrials.gov, NCT00752479) of autologous MSC infusion was conducted in two recipients of kidneys from living-related donors. Patients were given T cell-depleting induction therapy and maintenance immunosuppression with cyclosporine and mycophenolate mofetil. On day 7 posttransplant, MSCs were administered intravenously. Clinical and immunomonitoring of MSC-treated patients was performed up to day 360 postsurgery.Results Serum creatinine levels increased 7 to 14 days after cell infusion in both MSC-treated patients. A graft biopsy in patient 2 excluded acute graft rejection, but showed a focal inflammatory infiltrate, mostly granulocytes. In patient 1 protocol biopsy at 1-year posttransplant showed a normal graft. Both MSCtreated patients are in good health with stable graft function. A progressive increase of the percentage of CD4 ϩ CD25 high FoxP3 ϩ CD127 Ϫ Treg and a marked inhibition of memory CD45RO ϩ RA Ϫ CD8 ϩ T cell expansion were observed posttransplant. Patient T cells showed a profound reduction of CD8 ϩ T cell activity. ConclusionsFindings from this study in the two patients show that MSC infusion in kidney transplant recipients is feasible, allows enlargement of Treg in the peripheral blood, and controls memory CD8 ϩ T cell function. Future clinical trials with MSCs to look with the greatest care for unwanted side effects is advised.

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Section: Discussionmentioning

confidence: 99%

Autologous Mesenchymal Stromal Cells and Kidney Transplantation

Perico

Casiraghi

Introna³

et al. 2011

Clinical Journal of the American Society of Nephrology

279

287

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“…In addition, MSCs mediated their effects in part through shifting the balance of T helper 1 cell phenotype to a more anti-inflammatory Th2 phenotpye producing IL-4 and IL-10 (Ge et al 2010;Jia et al 2012). Importantly, MSCs also have the capacity to expand or induce Treg in the setting of SOT (Casiraghi et al 2008(Casiraghi et al , 2012Wang et al 2009;Jia et al 2012) and in some cases to generate a state of Treg-dependent tolerance (Ge et al 2010;Casiraghi et al 2012). Both of these studies elegantly show the importance of Treg in MSC induced tolerance using Treg depletion studies.…”

Section: Mesenchymal Stromal Cell Suppression Of Allogeneic T-cell Rementioning

confidence: 99%

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

English

Wood

2013

Cold Spring Harbor Perspectives in Medicine

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Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cellbased immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.

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“…The immunosuppressive effect and low immunogenicity of mesenchymal stem cells (MSCs) make them ideal candidates for immunosuppressive strategies [3,4]. Adult MSCs have been used widely in the allogeneic heart [5][6][7][8][9][10][11], liver [12], islet [13][14][15][16][17], kidney [18,19], and composite tissue transplants [20,21]. Bone marrow mesenchymal stem cells (BM-MSCs) alone prolong heart allograft survival [8].…”

Section: Introductionmentioning

confidence: 99%

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Cheng

Xiao-cun

et al. 2015

Stem Cells and Development

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Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1 · 10 6 iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival ( > 100 days). Histopathological analysis revealed that iPSCMSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4 + and CD8 + T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-g was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-b was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSCMSCs in islet transplantation.

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Bone Marrow–Derived Mesenchymal Stem Cells Inhibit Acute Rejection of Rat Liver Allografts in Association With Regulatory T-Cell Expansion

Cited by 97 publications

References 16 publications

Autologous Mesenchymal Stromal Cells and Kidney Transplantation

Autologous Mesenchymal Stromal Cells and Kidney Transplantation

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

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