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MSCs May Aid Kidney Transplants

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“Autologous Bone Marrow-Derived Mesenchymal Stromal Cells for the Treatment of Allograft Rejection After Renal Transplantation”

 

From Stem Cells Translational Medicine

New means of improving for long-term survival of transplanted kidneys have been searched for unsuccessfully (Pascual et al), but mesenchymal stromal cells (MSCs), which have anti-inflammatory and antifibrotic properties (Franquesa et alNinichuk et al and Tolar et al) and prevent renal injury in preclinical models (Casiraghi et alGe et alInoue et al and Morigi et al) may constitute a new therapeutic option. A relative lack of information (Perico et al and Tan et al), led the group of Ton J. Rabelink at Leiden University Medical Center, Netherlands, in a study published in Stem Cells Translational Medicine, to perform a safety and feasibility study in kidney allograft recipients receiving intravenous infusions of autologous bone marrow (BM) MSCs. Overall they report that this is clinically feasible and safe, and the findings are suggestive of systemic immunosuppression (Reinders et al).

Of 15 patients who underwent kidney transplants, 6 patients with subclinical rejection (SCR) at 6 months received MSCs (two doses of 1–2 × 106 cells per kilogram of body weight) which were well-tolerated, and no treatment-related adverse events were reported. MSCs were taken from the iliac crest and were isolated, cultured and characterised as previously described (Duijvestein et al). Three patients developed an opportunistic viral infection; Patient 1 BK-virus associated nephropathy and a late primary CMV infection which were treated with antiviral therapy and reduction of immune suppression, although the third case of low-grade CMV viral load persisted in the months after MSC infusion. Excitingly, two patients who initially showed signs of borderline subclinical rejection and severe T-cell-mediated acute rejection of the kidney allograft and who were infused with MSCs showed resolution of tubulitis without interstitial fibrosis/tubular atrophy. Five of the six patients displayed a donor-specific downregulation of the peripheral blood mononuclear cell proliferation assay, not seen in untreated patients, suggesting a downregulation in the donor-specific immunity.

Overall, the authors report the first clinical observations to support the potential of MSCs to prevent allograft rejection and interstitial fibrosis/tubular atrophy, although immunosuppression after MSC infusions is a potential risk highlighted. Additionally, this is the first study to analyse the effects of MSCs after long term kidney transplantation, with previous studies concentrating on the use of autologous MSCs in the early period after renal transplantation (Perico et al and Tan et al). The authors also report that long-term follow up is required for a deeper understanding of the mechanisms behind MSC/based treatment and any unwanted side-effects.

References

  • Casiraghi F, et al. (2012) Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant 12:2373–2383.
  • Duijvestein M, et al.  (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: Results of a phase I study. Gut 59:1662–1669.
  • Franquesa M, et al. (2012) Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev 21:3125–3135.
  • Ge W, et al. (2009) Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant 9:1760–1772.
  • Inoue S, et al. (2006) Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 81:1589–1595.
  • Morigi M, et al. (2008) Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells 26:2075–2082.
  • Ninichuk V, et al. (2006) Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. Kidney Int 70:121–129.
  • Pascual M, et al. (2002) Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 346:580–590.
  • Perico N, et al. (2011) Autologous mesenchymal stromal cells and kidney transplantation: A pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol 6:412–422.
  • Tan J, et al. (2012) Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: A randomized controlled trial. JAMA 307:1169–1177.
  • Tolar J, et al. (2010) Concise review: Hitting the right spot with mesenchymal stromal cells. Stem Cells 28:1446–1455.

STEM CELLS correspondent Stuart P. Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.