Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study

Hartleif, Steffen; Schumm, Michael; Döring, Michaela; Mezger, Markus; Lang, Peter; Dahlke, Marc H.; Riethmüller, Joachim; Königsrainer, Alfred; Handgretinger, Rupert; Nadalin, Silvio; Sturm, Ekkehard

doi:10.1155/2017/2352954

Cited by 24 publications

(11 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the variation in cell product and the heterogeneity of tissue origin makes interpretation of previous clinical studies challenging, MSC therapy is certainly promising. Currently the ongoing mYSTEP1 trial is testing safety and efficacy of donor derived bone marrow MSC pediatric living-donor liver transplantation ( 158 ).…”

Section: Future Therapeutic Strategies To Induce Long Term Tolerancementioning

confidence: 99%

The Immunological Basis of Liver Allograft Rejection

et al. 2020

View full text Add to dashboard Cite

Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.

show abstract

Section: Future Therapeutic Strategies To Induce Long Term Tolerancementioning

confidence: 99%

The Immunological Basis of Liver Allograft Rejection

et al. 2020

View full text Add to dashboard Cite

show abstract

“…However, no further follow-up data was reported (152). An open-label, prospective pilot trial of two intravenous infusions of 1 × 10 6 cells/kg of donor-derived MSC in pediatric living-donor transplant recipients who will receive standard immunosuppression is currently ongoing (153).…”

Section: Ongoing and Novel Therapeutic Approaches To Promote Liver Trmentioning

confidence: 99%

Transplant Tolerance Induction: Insights From the Liver

2020

View full text Add to dashboard Cite

A comparison of pre-clinical transplant models and of solid organs transplanted in routine clinical practice demonstrates that the liver is most amenable to the development of immunological tolerance. This phenomenon arises in the absence of stringent conditioning regimens that accompany published tolerizing protocols for other organs, particularly the kidney. The unique immunologic properties of the liver have assisted our understanding of the alloimmune response and how it can be manipulated to improve graft function and survival. This review will address important findings following liver transplantation in both animals and humans, and how these have driven the understanding and development of therapeutic immunosuppressive options. We will discuss the liver's unique system of immune and non-immune cells that regulate immunity, yet maintain effective responses to pathogens, as well as mechanisms of liver transplant tolerance in pre-clinical models and humans, including current immunosuppressive drug withdrawal trials and biomarkers of tolerance. In addition, we will address innovative therapeutic strategies, including mesenchymal stem cell, regulatory T cell, and regulatory dendritic cell therapy to promote liver allograft tolerance or minimization of immunosuppression in the clinic.

show abstract

“…Interestingly this may be further proof of the pre-clinical studies suggesting that the MSC/HSC niche is controlled in part by the sympathetic nervous system (30). The ongoing MYSTEP1 trial is not only testing safety and efficacy of donor derived bone marrow MSC, but also the intraportal route of administration in pediatric liver transplantation (102). Due to the inherent complexity and heterogeneity of clinical conditions, coupled with the variation in cell therapeutic products due to differences in donor, batch and cell tissue origin, the conduct and interpretation of clinical trials of MSC is complex and challenging.…”

Section: Clinical Trialsmentioning

confidence: 87%

“…In patients treated with MSC in combination with standard immunosuppression protocols for acute rejection there was a significant increase in PGE 2 and TGF-β1, as well as an significant increase in FoxP3 + T regulatory cells isolated from peripheral blood (101). The MYSTEP1 trial currently nearing completion may provide safety information on the use of donor derived bone marrow MSC in pediatric living donor liver transplantation, paving the way for more extensive study in this cohort (102).…”

Section: Therapeutic Strategies Utilizing Msc In Liver Transplantationmentioning

confidence: 97%

Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation?

Owen

Newsome

2020

Front. Immunol.

View full text Add to dashboard Cite

In response to the global burden of liver disease there has been a commensurate increase in the demand for liver transplantation. However, due to a paucity of donor organs many centers have moved toward the routine use of marginal allografts, which can be associated with a greater risk of complications and poorer clinical outcomes. Mesenchymal stromal cells (MSC) are a multi-potent progenitor cell population that have been utilized to modulate aberrant immune responses in acute and chronic inflammatory conditions. MSC exert an immunomodulatory effect on innate and adaptive immune systems through the release of both paracrine soluble factors and extracellular vesicles. Through these routes MSC can switch the regulatory function of the immune system through effects on macrophages and T regulatory cells enabling a switch of phenotype from injury to restoration. A key benefit seems to be their ability to tailor their response to the inflammatory environment without compromising the host ability to fight infection. With over 200 clinical trials registered to examine MSC therapy in liver disease and an increasing number of trials of MSC therapy in solid organ transplant recipients, there is increasing consideration for their use in liver transplantation. In this review we critically appraise the potential role of MSC therapy in the context of liver transplantation, including their ability to modulate reperfusion injury, their role in the reduction of medium term complications in the biliary tree and their potential to enhance tolerance in transplanted organs.

show abstract

Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study

Cited by 24 publications

References 64 publications

The Immunological Basis of Liver Allograft Rejection

The Immunological Basis of Liver Allograft Rejection

Transplant Tolerance Induction: Insights From the Liver

Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation?

Contact Info

Product

Resources

About