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Case Report Suggests that MSC Pretreatment Supports Long‐term Kidney Transplant Tolerance

Review of  “Kidney transplant tolerance associated with remote autologous mesenchymal stromal cells administration” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Researchers from the laboratory of Giuseppe Remuzzi (Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy) previously described how syngeneic and allogeneic mesenchymal stem cells (MSCs) induced regulatory T‐cell‐mediated tolerance in a cardiac transplant murine model [1]. While their initial human clinical studies testing the administration of autologous bone marrow‐derived MSC following living‐donor kidney transplants failed to provide acceptable results [2], subsequent research in a mouse model established that the administration of syngeneic MSCs before kidney transplantation permitted MSC migration to the lymphoid organs and the early expansion of T-regulatory cells (T-regs), which inhibited the deterioration of graft function and maintained the immunomodulatory tolerogenic effects [3]. Encouragingly, the implementation of the early administration of MSCs to the human clinical protocol led to successful kidney transplants with no evidence of engraftment syndrome or other adverse side effects [4, 5].

Now, the team returns with a new STEM CELLS Translational Medicine study that delves into the mechanism regarding the immunomodulatory properties of MSCs and explores their long‐term graft tolerance induction capacity with regards to kidney transplant [6]. 

Casiraghi et al. reported on a 37‐year‐old male patient with end-stage renal disease who received an intravenous administration of autologous BM-MSCs before a living‐donor kidney transplant. The patient rapidly recovered normal renal function with stable graft function observed for the next two years; importantly, a surveillance protocol biopsy found no evidence of subclinical rejection at one year, and the patient failed to generate de novo donor‐specific antibodies. Additionally, the patient developed a sustained pro‐tolerogenic immune environment during this follow-up period, including a high T-reg/memory CD8+ T‐cell ratio and an expansion of naïve and transitional B cells in the peripheral blood. This immune status permitted the authors to gradually reduce patient immunosuppressive therapy until complete discontinuation after approximately five years, and, encouragingly, the patient displayed stable graft function and maintained pro‐tolerogenic immune status for a further 18 months. 

Overall, this exciting case report provides evidence that MSC pretreatment can modulate the immune environment sufficiently to permit the long term function of kidney transplants. The authors note that the implementation of a panel of non-invasive immunomonitoring tools in addition to clinical criteria may help to identify a pro‐tolerogenic signature associated with MSC administration that could allow the identification of those patients amenable to the safe discontinuation of immunosuppressive drug treatment. 

For more on how MSCs may support the long-term function of transplants, stay tuned to the Stem Cells Portal!

References

  1. Casiraghi F, Azzollini N, Cassis P, et al., Pretransplant Infusion of Mesenchymal Stem Cells Prolongs the Survival of a Semiallogeneic Heart Transplant through the Generation of Regulatory T Cells. Journal of Immunology 2008;181:3933.
  2. Perico N, Casiraghi F, Introna M, et al., Autologous Mesenchymal Stromal Cells and Kidney Transplantation: A Pilot Study of Safety and Clinical Feasibility. Clinical Journal of the American Society of Nephrology 2011;6:412.
  3. Casiraghi F, Azzollini N, Todeschini M, et al., Localization of Mesenchymal Stromal Cells Dictates Their Immune or Proinflammatory Effects in Kidney Transplantation. American Journal of Transplantation 2012;12:2373-2383.
  4. Perico N, Casiraghi F, Todeschini M, et al., Long-Term Clinical and Immunological Profile of Kidney Transplant Patients Given Mesenchymal Stromal Cell Immunotherapy. Frontiers in Immunology 2018;9:1359.
  5. Perico N, Casiraghi F, Gotti E, et al., Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transplant International 2013;26:867-878.
  6. Casiraghi F, Perico N, Gotti E, et al., Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration. STEM CELLS Translational Medicine 2020;9:427-432.