Secondary Logo

Institutional members access full text with Ovid®

Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes

A Pilot Randomized Trial

Maffi, Paola, MD1; Nano, Rita1; Monti, Paolo, PhD1; Melzi, Raffaella1; Sordi, Valeria, PhD1; Mercalli, Alessia1; Pellegrini, Silvia, PhD1; Ponzoni, Maurilio, MD2,3; Peccatori, Jacopo, MD4; Messina, Carlo, MD4; Nocco, Angela, MD5; Cardillo, Massimo, MD5; Scavini, Marina, MD1; Magistretti, Paola1; Doglioni, Claudio, MD2,3; Ciceri, Fabio, MD4,3; Bloem, Stef J., PhD6; Roep, Bart O., MD6,7; Secchi, Antonio, MD8,3; Piemonti, Lorenzo, MD1,3

doi: 10.1097/TP.0000000000002416
Original Clinical Science—General

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 posttransplantation 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 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity.

Conclusions. Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.

1 San Raffaele Diabetes Research Institute, IRCCS Scientific Institute San Raffaele, Milan, Italy.

2 Department of Pathology, IRCCS Scientific Institute San Raffaele, Milan, Italy.

3 Vita-Salute San Raffaele University, Milan, Italy.

4 Hematology and Bone Marrow Transplantation Unit, IRCCS Scientific Institute San Raffaele, Milan, Italy.

5 Transplantation Immunology, Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy.

6 Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.

7 Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute at the City of Hope, Duarte, CA.

8 Clinical Transplant Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.

Received 27 April 2018. Revision received 11 June 2018.

Accepted 1 July 2018.

Trial registration. NCT01345227 and NCT01722682.

The authors declare no conflicts of interest.

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.

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 article 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 article, 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.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (

Correspondence: Lorenzo Piemonti, MD, Diabetes Research Institute, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. (

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.