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Τρίτη 21 Αυγούστου 2018

Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial

Background Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation. Methods We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n=4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n=6) or BM (n=3) to evaluate islet transplant function and survival Results We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable post transplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except one lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immuno-monitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity. Conclusion BM is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes Correspondence to: Lorenzo Piemonti, Diabetes Research Institute, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan. Fax: 39 02 26432871. Tel: 39 02 26432706. E-mail: piemonti.lorenzo@hsr.it Trial registration. ClinicalTrials.gov NCT01345227 and NCT01722682 Authorship page P.M. and A.S. managed patients. M.P. and C.D performed the histopathological analysis of the bone marrow. R.N., R.M. and A.M. performed islet isolations. V.S. and S.P performed the molecular analysis of the bone marrow biopsy samples. M.S. reviewed and edited the manuscript and contributed to the discussion. J.P., C.M. and F.C. developed the intrabone marrow islet infusion method and performed the transplantations. P.M., S.B., B.R, A.N. and M.C. performed the cellular and humoral immunomonitoring. L.P. conceived the intrabone marrow strategy, developed the concept, designed the experiments, wrote the manuscript, promoted the study, and researched data. L.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Funding This study was supported by the Italian Minister of Health (Ricerca Finalizzata RF-2009-1469691) and by the European Commission (FP7 241883 and H2020 681070). P.M. is supported by a Career Development Award (5-CDA-2015-85-A-N) from JDRF. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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