[en] Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs ( approximately 2 x 10(6)/kg) on day 3 +/- 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m(2), compared to 32.5 ml/min/1.73m(2)in controls and 29.3 ml/min/1.73m(2)in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied.
Disciplines :
Urology & nephrology Surgery Hematology
Author, co-author :
ERPICUM, Pauline ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de néphrologie
WEEKERS, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de néphrologie
DETRY, Olivier ; Centre Hospitalier Universitaire de Liège - CHU > Département de chirurgie > Chirurgie abdo, sénologique, endocrine et de transplantation
BONVOISIN, Catherine ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de néphrologie
DELBOUILLE, Marie-Hélène ; Centre Hospitalier Universitaire de Liège - CHU > Département de chirurgie > Chirurgie abdo, sénologique, endocrine et de transplantation
GREGOIRE, Céline ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
BAUDOUX, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Laboratoire de thérapie cellulaire et génique (LTCG)
BRIQUET, Alexandra ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Laboratoire de thérapie cellulaire et génique (LTCG)
LECHANTEUR, Chantal ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Laboratoire de thérapie cellulaire et génique (LTCG)
MAGGIPINTO, Gianni ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Laboratoire immunologie de la transplantation
SOMJA, Joan ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Service d'anatomie et cytologie pathologiques
Legendre, C., Canaud, G., Martinez, F., Factors influencing long-term outcome after kidney transplantation. Transpl Int 27 (2014), 19–27.
Chandran, S., Tang, Q., Sarwal, M., et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 17 (2017), 2945–2954.
Moreau, A., Alliot-Licht, B., Cuturi, M., et al. Tolerogenic dendritic cell therapy in organ transplantation. Transpl Int 30 (2017), 754–764.
Alagesan, S., Griffin, M.D., Autologous and allogeneic mesenchymal stem cells in organ transplantation: what do we know about their safety and efficacy?. Curr Opin Organ Transplant 19 (2014), 65–72.
Reinders, M.E., van Kooten, C., Rabelink, T.J., et al. Mesenchymal stromal cell therapy for solid organ transplantation. Transplantation 102 (2018), 35–43.
Erpicum, P., Detry, O., Weekers, L., et al. Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion. Nephrol Dial Transplant 29 (2014), 1487–1493.
Dominici, M., Le Blanc, K., Mueller, I., et al. Minimal criteria for defining multipotent mesenchymal stromal cells: the International Society for Cellular Therapy position statement. Cytotherapy 8 (2006), 315–317.
Galipeau, J., Krampera, M., The challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria. Cytotherapy 17 (2015), 125–127.
Erpicum, P., Rowart, P., Poma, L., et al. Administration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and may modulate renal lipid metabolism in rats. Sci Rep, 7, 2017, 8687.
Togel, F., Hu, Z., Weiss, K., et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Physiol 289 (2005), F31–F42.
Chen, Y.-T., Sun, C.-K., Lin, Y.-C., et al. Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med, 9, 2011, 51.
Gatti, S., Bruno, S., Deregibus, M.C., et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant 26 (2011), 1474–1483.
Souidi, N., Stolk, M., Seifert, M., Ischemia–reperfusion injury: beneficial effects of mesenchymal stromal cells. Curr Opin Organ Transplant 18 (2013), 34–43.
De Martino, M., Zonta, S., Rampino, T., et al. Mesenchymal stem cells infusion prevents acute cellular rejection in rat kidney transplantation. Transplant Proc 42 (2010), 1331–1335.
Hara, Y., Stolk, M., Ringe, J., et al. In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia. Transpl Int 24 (2011), 1112–1123.
Wu, X., Yan, T., Wang, Z., et al. BM-MSCs-derived microvesicles promote allogeneic kidney graft survival through enhancing micro-146a expression of dendritic cells. Immunol Lett 191 (2017), 55–62.
Wang, Y., Zhang, A., Ye, Z., et al. Bone marrow–derived mesenchymal stem cells inhibit acute rejection of rat liver allografts in association with regulatory T-cell expansion. Transplant Proc 41 (2009), 4352–4356.
Casiraghi, F., Azzollini, N., Todeschini, M., et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant 12 (2012), 2373–2383.
Merino, A., Ripoll, E., de Ramon, L., et al. The timing of immunomodulation induced by mesenchymal stromal cells determines the outcome of the graft in experimental renal allotransplantation. Cell Transplant 26 (2017), 1017–1030.
Popp, F.C., Eggenhofer, E., Renner, P., et al. Mesenchymal stem cells can affect solid organ allograft survival. Transplantation 87 (2009), S57–S62.
Hoogduijn, M.J., Popp, F.C., Grohnert, A., et al. Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT). Transplantation 90 (2010), 124–126.
Franquesa, M., Hoogduijn, M.J., Reinders, M.E., et al. Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting. Transplantation 96 (2013), 234–238.
Perico, N., Casiraghi, F., Remuzzi, G., Clinical transplantation of mesenchymal stromal cell therapies in nephrology. J Am Soc Nephrol 29 (2018), 362–375.
Tan, J., Wu, W., Xu, X., et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants. JAMA 307 (2012), 1169–1177.
Peng, Y., Ke, M., Xu, L., et al. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation 95 (2013), 161–168.
Pan, G., Chen, Z., Xu, L., et al. Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study. Oncotarget 7 (2016), 12089–12101.
Mudrabettu, C., Kumar, V., Rakha, A., et al. Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study. Nephrology 20 (2015), 25–33.
Perico, N., Casiraghi, F., Gotti, E., et al. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transpl Int 26 (2013), 867–878.
Perico, N., Casiraghi, F., Introna, M., et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol 6 (2011), 412–422.
Detry, O., Vandermeulen, M., Delbouille, M.-H., et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I–II, open-label, clinical study. J Hepatol 67 (2017), 47–55.
Shi, M., Liu, Z., Wang, Y., et al. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection. Stem Cells Transl Med 6 (2017), 2053–2061.
Reinders, M.E.J., de Fijter, J.W., Roelofs, H., et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med 2 (2013), 107–111.
Griffin, M.D., Ryan, A.E., Alagesan, S., et al. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far?. Immunol Cell Biol 91 (2013), 40–51.
Baron, F., Lechanteur, C., Willems, E., et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant 16 (2010), 838–847.
Zangi, L., Margalit, R., Reich-Zeliger, S., et al. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells 27 (2009), 2865–2874.
Chan, W.K., Lau, A.S.-Y., Li, J.C.-B., et al. MHC expression kinetics and immunogenicity of mesenchymal stromal cells after short-term IFN-γ challenge. Exp Hematol 36 (2008), 1545–1555.
Eliopoulos, N., Stagg, J., Lejeune, L., et al. Allogeneic marrow stromal cells are immune rejected by MHC class I– and class II–mismatched recipient mice. Blood 106 (2005), 4057–4065.
Lee, H., Park, J.B., Lee, S., et al. Intra-osseous injection of donor mesenchymal stem cell (MSC) into the bone marrow in living donor kidney transplantation: a pilot study. J Transl Med, 11, 2013, 96.
Sun, Q., Huang, Z., Han, F., et al. Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trial. J Transl Med, 16, 2018, 52.
Lohan, P., Treacy, O., Griffin, M., et al. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells and their extracellular vesicles: are we still learning?. Front Immunol, 8, 2017, 1626.
Lalu, M.M., McIntyre, L., Pugliese, C., et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One, 7, 2012, e47559.
Tögel, F., Yang, Y., Zhang, P., et al. Bioluminescence imaging to monitor the in vivo distribution of administered mesenchymal stem cells in acute kidney injury. Am J Physiol Physiol 295 (2008), F315–F321.
Jung, J.W., Kwon, M., Choi, J.C., et al. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J 54 (2013), 1293–1296.
Gleeson, B.M., Martin, K., Ali, M.T., et al. Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by antithrombin therapy. Stem Cells 33 (2015), 2726–2737.
Christy, B.A., Herzig, M.C., Montgomery, R.K., et al. Procoagulant activity of human mesenchymal stem cells. J Trauma Acute Care Surg 83 (2017), S164–S169.
Vulliet, P.R., Greeley, M., Halloran, S.M., et al. Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet 363 (2004), 783–784.
Puelacher, C., Lurati Buse, G., Seeberger, D., et al. Perioperative myocardial injury after noncardiac surgery: incidence, mortality, and characterization. Circulation 137 (2018), 1221–1232.
Arango-Rodriguez, M.L., Ezquer, F., Ezquer, M., et al. Could cancer and infection be adverse effects of mesenchymal stromal cell therapy?. World J Stem Cells 7 (2015), 408–417.
Borni-Duval, C., Caillard, S., Olagne, J., et al. Risk factors for BK virus infection in the era of therapeutic drug monitoring. Transplantation 95 (2013), 1498–1505.
Casiraghi, F., Remuzzi, G., Abbate, M., et al. Multipotent mesenchymal stromal cell therapy and risk of malignancies. Stem Cell Rev Rep 9 (2013), 65–79.
Zhang, J., Huang, X., Wang, H., et al. The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res Ther, 6, 2015, 234.
Le Blanc, K., Tammik, C., Rosendahl, K., et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31 (2003), 890–896.
Le Blanc, K., Tammik, L., Sundberg, B., et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57 (2003), 11–20.
Gu, L.-H., Zhang, T.-T., Li, Y., et al. Immunogenicity of allogeneic mesenchymal stem cells transplanted via different routes in diabetic rats. Cell Mol Immunol 12 (2015), 444–455.
Eggenhofer, E., Steinmann, J.F., Renner, P., et al. Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts. Transpl Immunol 24 (2011), 157–163.
Seifert, M., Stolk, M., Polenz, D., et al. Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection. Front Immunol, 3, 2012, 202.
Saadi, G., Fadel, F., El Ansary, M., et al. Mesenchymal stem cell transfusion for desensitization of positive lymphocyte cross-match before kidney transplantation: outcome of 3 cases. Cell Prolif 46 (2013), 121–126.
van de Berg, P.J.E.J., Hoevenaars, E.C., Yong, S., et al. Circulating lymphocyte subsets in different clinical situations after renal transplantation. Immunology 136 (2012), 198–207.
Glennie, S., Soeiro, I., Dyson, P.J., et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105 (2005), 2821–2827.
Corcione, A., Benvenuto, F., Ferretti, E., et al. Human mesenchymal stem cells modulate B-cell functions. Blood 107 (2006), 367–372.
Tabera, S., Pérez-Simón, J.A., Díez-Campelo, M., et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 93 (2008), 1301–1309.
Newell, K.A., Asare, A., Kirk, A.D., et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest 120 (2010), 1836–1847.
Svachova, V., Sekerkova, A., Hruba, P., et al. Dynamic changes of B-cell compartments in kidney transplantation: lack of transitional B cells is associated with allograft rejection. Transpl Int 29 (2016), 540–548.
Reinders, M.E.J., Dreyer, G.J., Bank, J.R., et al. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study. J Transl Med, 13, 2015, 344.
Braza, F., Durand, M., Degauque, N., et al. Regulatory T cells in kidney transplantation: new directions?. Am J Transplant 15 (2015), 2288–2300.
Maccario, R., Podestà, M., Moretta, A., et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90 (2005), 516–525.
Luz-Crawford, P., Kurte, M., Bravo-Alegría, J., et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther, 4, 2013, 65.
Chao, Y.-H., Wu, H.-P., Wu, K.-H., et al. An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis. PLoS One, 9, 2014, e110338.
Burr, S.P., Dazzi, F., Garden, O.A., Mesenchymal stromal cells and regulatory T cells: the Yin and Yang of peripheral tolerance?. Immunol Cell Biol 91 (2013), 12–18.
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. J Immunol 181 (2008), 3933–3946.
Ehx, G., Hannon, M., Beguin, Y., et al. Validation of a multicolor staining to monitor phosphoSTAT5 levels in regulatory T-cell subsets. Oncotarget, 6, 2015, 43255.
Schaier, M., Seissler, N., Schmitt, E., et al. DR high+ CD45RA − -Tregs potentially affect the suppressive activity of the total Treg Pool in renal transplant patients. PLoS One, 7, 2012, e34208.
Schaier, M., Seissler, N., Becker, L.E., et al. The extent of HLA-DR expression on HLA-DR+ Tregs allows the identification of patients with clinically relevant borderline rejection. Transpl Int 26 (2013), 290–299.
Duffy, M.M., Ritter, T., Ceredig, R., et al. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther, 2, 2011, 34.
Jitschin, R., Mougiakakos, D., Von Bahr, L., et al. Alterations in the cellular immune compartment of patients treated with third-party mesenchymal stromal cells following allogeneic hematopoietic stem cell transplantation. Stem Cells 31 (2013), 1715–1725.
Reinders, M.E.J., Hoogduijn, M.J., NK cells and MSCs: possible implications for MSC therapy in renal transplantation. J Stem Cell Res Ther, 4, 2014, 1000166.
Najar, M., Fayyad-Kazan, M., Meuleman, N., et al. Immunological impact of Wharton's Jelly mesenchymal stromal cells and natural killer cell co-culture. Mol Cell Biochem 447 (2018), 111–124.
Krampera, M., Cosmi, L., Angeli, R., et al. Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24 (2006), 386–398.
Spaggiari, G.M., Capobianco, A., Abdelrazik, H., et al. Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111 (2008), 1327–1333.
Sotiropoulou, P.A., Perez, S.A., Gritzapis, A.D., et al. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24 (2006), 74–85.
Selmani, Z., Naji, A., Zidi, I., et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25highFOXP3+ regulatory T cells. Stem Cells 26 (2008), 212–222.
Crop, M.J., Korevaar, S.S., de Kuiper, R., et al. Human mesenchymal stem cells are susceptible to lysis by CD8+ T cells and NK cells. Cell Transplant 20 (2011), 1547–1559.
Liu, J., Hu, X., Li, Z., et al. In vivo bioluminescence imaging of transplanted mesenchymal stromal cells and their rejection mediated by intrahepatic NK cells. Mol Imaging Biol 19 (2017), 31–40.
Trojan, K., Zhu, L., Aly, M., et al. Association of peripheral NK cell counts with Helios+ IFN-γ–Tregs in patients with good long-term renal allograft function. Clin Exp Immunol 188 (2017), 467–479.
Sagoo, P., Perucha, E., Sawitzki, B., et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest 120 (2010), 1848–1861.
Wang, Y., He, J., Pei, X., et al. Systematic review and meta-analysis of mesenchymal stem/stromal cells therapy for impaired renal function in small animal models. Nephrology 18 (2013), 201–208.
Bank, J.R., Rabelink, T.J., De Fijter, J.W., et al. Safety and efficacy endpoints for mesenchymal stromal cell therapy in renal transplant recipients. J Immunol Res, 2015, 2015, 391797.
Masson, I., Flamant, M., Maillard, N., et al. MDRD versus CKD-EPI equation to estimate glomerular filtration rate in kidney transplant recipients. Transplantation 95 (2013), 1211–1217.
Kasiske, B.L., Zeier, M.G., Chapman, J.R., et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 77 (2010), 299–311.
Sierra-Parraga, J.M., Eijken, M., Hunter, J., et al. Mesenchymal stromal cells as anti-inflammatory and regenerative mediators for donor kidneys during normothermic machine perfusion. Stem Cells Dev 26 (2017), 1162–1170.
Lechanteur, C., Briquet, A., Giet, O., et al. Clinical-scale expansion of mesenchymal stromal cells: a large banking experience. J Transl Med, 14, 2016, 145.
Haas, M., Loupy, A., Lefaucheur, C., et al. The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cell–mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 18 (2018), 293–307.
Balan, A., Lucchini, G., Schmidt, S., et al. Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease—friends or foes?. Leukemia 28 (2014), 1941–1948.
Streitz, M., Miloud, T., Kapinsky, M., et al. Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study. Transplant Res, 2, 2013, 17.
Abadja, F., Alamartine, E., Berthoux, F., et al. Quantification of circulating regulatory T cells by flow cytometry in kidney transplant patients after basiliximab induction therapy. Transplantation 89 (2010), 366–368.
