The effect of clinically relevant doses of immunosuppressive drugs on human mesenchymal stem cells

Javorková, Eliška; Vackova, Julie; Hájková, Michaela; Heřmánková, Barbora; Zajı́cová, Alena; Holáň, Vladimı́r; Krulová, Magdaléna

doi:10.1016/j.biopha.2017.10.114

Cited by 20 publications

(16 citation statements)

References 42 publications

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“…MMF was chosen for several reasons. Firstly, unlike other immunosuppressive drugs such as corticosteroids, it does not alter the expression of MSC immunomodulatory factors ( 42 ) and has been shown to exert a synergistic effect with MSC in a pre-clinical heart transplant model ( 21 ). Secondly, MMF is currently prescribed to patients receiving high-risk cornea transplants including re-grafts ( 43 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

et al. 2018

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High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals (p = < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45+CD11b+ B220+ monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4+ FoxP3+ regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In in vitro experiments, third-party allo-MSC polarized primary lung-derived CD11b/c+ myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E2 and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers.

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Section: Discussionmentioning

confidence: 99%

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

et al. 2018

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“…Our data extend previous studies that have examined the effects of combinations of MSCs and the calcineurin inhibitor cyclosporine A, FK506-binding protein inhibitor tacrolimus, mTOR inhibitor rapamycin, and IMPDH inhibitor MMF [ 17 – 19 ]. Most studies showed that these compounds did not affect the viability and immunosuppressive capacity of MSCs [ 17 , 18 ]. However, several studies showed inconsistent results: tacrolimus increased MSC inhibitory capacity [ 17 ], cyclosporine A increased the inhibition of lymphocyte proliferation by MSCs [ 17 ] and enhanced MSC viability [ 20 ], and MMF promoted the inhibitory activity of MSCs, whereas cyclosporine A, tacrolimus, and rapamycin antagonized it [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, several studies showed inconsistent results: tacrolimus increased MSC inhibitory capacity [ 17 ], cyclosporine A increased the inhibition of lymphocyte proliferation by MSCs [ 17 ] and enhanced MSC viability [ 20 ], and MMF promoted the inhibitory activity of MSCs, whereas cyclosporine A, tacrolimus, and rapamycin antagonized it [ 21 ]. Glucocorticoids, such as dexamethasone and PD, are widely used in SLE patients because of their potent anti-inflammatory properties, although they have severe side effects [ 18 ]. Dexamethasone enhances human growth factor production by MSCs [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Glucocorticoids, such as dexamethasone and PD, are widely used in SLE patients because of their potent anti-inflammatory properties, although they have severe side effects [ 18 ]. Dexamethasone enhances human growth factor production by MSCs [ 18 ]. PD increases indoleamine 2,3-dioxygenase production by MSCs without affecting other immunosuppressive capacities [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Dexamethasone enhances human growth factor production by MSCs [ 18 ]. PD increases indoleamine 2,3-dioxygenase production by MSCs without affecting other immunosuppressive capacities [ 18 ]. Several studies also showed the efficacy of combinations of immunosuppressants and MSCs [ 19 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of a Combination of Prednisone or Mycophenolate Mofetil and Mesenchymal Stem Cells on Lupus Symptoms in MRL.Fas^lpr Mice

Lee

Kim

et al. 2018

Stem Cells International

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The combination of immunosuppressants and mesenchymal stem cells (MSCs) is a promising therapeutic strategy for systemic lupus erythematosus, since this approach reduces doses of immunosuppressants while maintaining the same therapeutic outcome. However, it is unavoidable for MSCs to be exposed to immunosuppressants. Here, we examined the combination effect of prednisone (PD) or mycophenolate mofetil (MMF) and MSCs. We showed that PD or MMF in combination with MSCs showed better therapeutic effect than single therapy in lupus-prone MRL.Faslpr mice, as assessed by using the following readouts: prolongation of survival, decrease in anti-dsDNA and total IgG levels in serum, decrease in cytokine gene expression in spleen cells, and decrease in inflammatory cell infiltration into the kidney. In vitro, immunosuppressants and MSCs inhibited T cell proliferation in a synergistic manner. However, immunosuppressants did not affect MSC viability and functions such as TGF-β1 and PGE2 production, migration, and immunosuppressive capacity. In summary, our study demonstrates that a combination of immunosuppressants and MSCs is a good strategy to reduce the side effects of PD and MMF without the loss of therapeutic outcome.

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Mesenchymal stem cell therapy in hypertrophic and keloid scars

Bojanic

Hatoum

et al. 2021

Cell Tissue Res

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Scars are the normal outcome of wound repair and involve a co-ordinated inflammatory and fibrotic process. When a scar does not resolve, uncontrolled chronic inflammation can persist and elicits excessive scarring that leads to a range of abnormal phenotypes such as hypertrophic and keloid scars. These pathologies result in significant impairment of quality of life over a long period of time. Existing treatment options are generally unsatisfactory, and there is mounting interest in innovative cell-based therapies. Despite the interest in mesenchymal stem cells (MSCs), there is yet to be a human clinical trial that investigates the potential of MSCs in treating abnormal scarring. A synthesis of existing evidence of animal studies may therefore provide insight into the barriers to human application. The aim of this PRISMA systematic review was to evaluate the effectiveness of MSC transplantation in the treatment of hypertrophic and keloid scars in in vivo models. A total of 11 case-control studies were identified that treated a total of 156 subjects with MSCs or MSC-conditioned media. Ten studies assessed hypertrophic scars, and one looked at keloid scars. All studies evaluated scars in terms of macroscopic and histological appearances and most incorporated immunohistochemistry. The included studies all found improvements in the above outcomes with MSC or MSC-conditioned media without complications. The studies reviewed support a role for MSC therapy in treating scars that needs further exploration. The transferability of these findings to humans is limited by factors such as the reliability and validity of the disease model, the need to identify the optimal MSC cell source, and the outcome measures employed.

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The effect of clinically relevant doses of immunosuppressive drugs on human mesenchymal stem cells

Cited by 20 publications

References 42 publications

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

Effect of a Combination of Prednisone or Mycophenolate Mofetil and Mesenchymal Stem Cells on Lupus Symptoms in MRL.Fas^lpr Mice

Mesenchymal stem cell therapy in hypertrophic and keloid scars

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The effect of clinically relevant doses of immunosuppressive drugs on human mesenchymal stem cells

Cited by 20 publications

References 42 publications

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

Effect of a Combination of Prednisone or Mycophenolate Mofetil and Mesenchymal Stem Cells on Lupus Symptoms in MRL.Faslpr Mice

Mesenchymal stem cell therapy in hypertrophic and keloid scars

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Product

Resources

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Effect of a Combination of Prednisone or Mycophenolate Mofetil and Mesenchymal Stem Cells on Lupus Symptoms in MRL.Fas^lpr Mice