Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration

Casiraghi, Federica; Perico, Norberto; Gotti, Eliana; Todeschini, Marta; Mister, Marilena; Cortinovis, Monica; Portalupi, Valentina; Plati, Anna Rita; Gaspari, Flavio; Villa, Alessandro; Introna, Martino; Longhi, Elena; Remuzzi, Giuseppe

doi:10.1002/sctm.19-0185

Cited by 24 publications

(23 citation statements)

References 30 publications

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“…Long-term follow-up highlighted a sustained increase in the ratio between Treg and CD8 + effector T cells in one of these patients, which was associated with a B-cell profile consistent with the pro-tolerogenic signature identified in other cohorts of spontaneously tolerant kidney transplant recipients ( 129 ). This patient consented to gradual tapering of immunosuppression, which was successfully completed without any evidence of rejection (the patient has been off immunosuppression for over two years), thus supporting the hypothesis that a single administration of MSC may induce a long-term, self-sustaining immunoregulatory process responsible for tolerance induction ( 130 ). Other groups reported similar immunomodulating effects after the administration of autologous BM-MSC, which were safe and induced an increase in Treg frequency and a reduction in T-cell proliferation ( 131 ); nevertheless, so far immunosuppression withdrawal has not been attempted in any other study on renal transplant recipients.…”

Section: Introductionsupporting

confidence: 52%

Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation

2021

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Transplantation is the gold-standard treatment for the failure of several solid organs, including the kidneys, liver, heart, lung and small bowel. The use of tailored immunosuppressive agents has improved graft and patient survival remarkably in early post-transplant stages, but long-term outcomes are frequently unsatisfactory due to the development of chronic graft rejection, which ultimately leads to transplant failure. Moreover, prolonged immunosuppression entails severe side effects that severely impact patient survival and quality of life. The achievement of tolerance, i.e., stable graft function without the need for immunosuppression, is considered the Holy Grail of the field of solid organ transplantation. However, spontaneous tolerance in solid allograft recipients is a rare and unpredictable event. Several strategies that include peri-transplant administration of non-hematopoietic immunomodulatory cells can safely and effectively induce tolerance in pre-clinical models of solid organ transplantation. Mesenchymal stromal cells (MSC), non-hematopoietic cells that can be obtained from several adult and fetal tissues, are among the most promising candidates. In this review, we will focus on current pre-clinical evidence of the immunomodulatory effect of MSC in solid organ transplantation, and discuss the available evidence of their safety and efficacy in clinical trials.

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Section: Introductionsupporting

confidence: 52%

Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation

2021

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“…As mentioned above, it was demonstrated that timing of MSC infusion was of importance as an engraftment syndrome with infiltration of immune cells and C3 deposits were found when MSC were administered at 7 days after kidney transplantation, which was not observed when MSC were given before transplantation [24]. Moreover, an interesting case provided evidence that in a renal transplant recipient, infusion of autologous bone marrow MSC was associated with safe complete discontinuation of maintenance immunosuppression after transplantation allowing a state of immune tolerance [36]. Progression of the field is also influenced by logistic and regulatory issues, which accompany cell‐based therapy such as clinical grade cell production facilities and associated costs.…”

Section: Mesenchymal Stromal Cell Therapiesmentioning

confidence: 99%

Cellular therapies in organ transplantation

et al. 2021

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Summary Cellular therapy is a promising tool for improving the outcome of organ transplantation. Various cell types with different immunoregulatory and regenerative properties may find application for specific transplant rejection or injury‐related indications. The current era is crucial for the development of cellular therapies. Preclinical models have demonstrated the feasibility of efficacious cell therapy in transplantation, early clinical trials have shown safety of several of these therapies, and the first steps towards efficacy studies in humans have been made. In this review, we address the current state of the art of cellular therapies in clinical transplantation and discuss monitoring tools and endpoints for these studies.

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“…By contrast, autologous BM-derived MSC infusion induced a significant prolongation of kidney graft survival by a T cell regulatory-dependent mechanism when a protocol biopsy showed signs of subclinical rejection and/or an increase in interstitial fibrosis/tubular atrophy 4 weeks or 6 months posttransplantation [ 61 ]. Additionally, autologous BM-derived MSC, when injected before living-related kidney transplant, led to a decrease in the circulating memory CD8 + T lymphocytes and donor-specific CD8 + T lymphocyte cytolytic response [ 62 ] and might induce tolerance [ 63 ].…”

Section: Mesenchymal Stem Cells (Mscs)mentioning

confidence: 99%

Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells

Sávio-Silva

Beyerstedt

Soinski-Sousa

et al. 2020

Stem Cells International

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Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus (DM) and comprises multifactorial pathophysiologic mechanisms. Despite current treatment, around 30-40% of individuals with type 1 and type 2 DM (DM1 and DM2) have progressive DKD, which is the most common cause of end-stage chronic kidney disease worldwide. Mesenchymal stem cell- (MSC-) based therapy has important biological and therapeutic implications for curtailing DKD progression. As a chronic disease, DM may impair MSC microenvironment, but there is compelling evidence that MSC derived from DM1 individuals maintain their cardinal properties, such as potency, secretion of trophic factors, and modulation of immune cells, so that both autologous and allogeneic MSCs are safe and effective. Conversely, MSCs derived from DM2 individuals are usually dysfunctional, exhibiting higher rates of senescence and apoptosis and a decrease in clonogenicity, proliferation, and angiogenesis potential. Therefore, more studies in humans are needed to reach a conclusion if autologous MSCs from DM2 individuals are effective for treatment of DM-related complications. Importantly, the bench to bedside pathway has been constructed in the last decade for assessing the therapeutic potential of MSCs in the DM setting. Laboratory research set the basis for establishing further translation research including preclinical development and proof of concept in model systems. Phase I clinical trials have evaluated the safety profile of MSC-based therapy in humans, and phase II clinical trials (proof of concept in trial participants) still need to answer important questions for treating DKD, yet metabolic control has already been documented. Therefore, randomized and controlled trials considering the source, optimal cell number, and route of delivery in DM patients are further required to advance MSC-based therapy. Future directions include strategies to reduce MSC heterogeneity, standardized protocols for isolation and expansion of those cells, and the development of well-designed large-scale trials to show significant efficacy during a long follow-up, mainly in individuals with DKD.

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Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration

Cited by 24 publications

References 30 publications

Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation

Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation

Cellular therapies in organ transplantation

Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells

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