Advertisement

ResearchIn-Press PreviewAutoimmunityEndocrinology Open Access | 10.1172/JCI190034

Curing autoimmune diabetes in mice with islet and hematopoietic cell transplantation after CD117 antibody-based conditioning

Preksha Bhagchandani,1 Stephan A. Ramos,1 Bianca Rodriguez,1 Xueying Gu,1 Shiva Pathak,2 Yuqi Zhou,1 Yujin Moon,1 Nadia Nourin,1 Charles A. Chang,1 Jessica Poyser,2 Brenda J. Velasco,2 Weichen Zhao,1 Hye-Sook Kwon,2 Richard Rodriguez,1 Diego M. Burgos,1 Mario A. Miranda,1 Everett Meyer,2 Judith A. Shizuru,2 and Seung K. Kim1

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Bhagchandani, P. in: PubMed | Google Scholar |

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Ramos, S. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Rodriguez, B. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Gu, X. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Pathak, S. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Zhou, Y. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Moon, Y. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Nourin, N. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Chang, C. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Poyser, J. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Velasco, B. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Zhao, W. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Kwon, H. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Rodriguez, R. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Burgos, D. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Miranda, M. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Meyer, E. in: PubMed | Google Scholar

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Shizuru, J. in: PubMed | Google Scholar |

1Department of Developmental Biology, Stanford School of Medicine, Stanford, United States of America

2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, United States of America

Find articles by Kim, S. in: PubMed | Google Scholar

Published November 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190034.
Copyright © 2025, Bhagchandani et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 18, 2025 - Version history
View PDF
Abstract

Mixed hematopoietic chimerism after allogeneic hematopoietic cell transplantation (HCT) promotes tolerance of transplanted donor-matched solid organs, corrects autoimmunity, and could transform therapeutic strategies for autoimmune type 1 diabetes (T1D). However, development of non-toxic bone marrow conditioning protocols is needed to expand clinical use. We developed a chemotherapy-free, non-myeloablative (NMA) conditioning regimen that achieves mixed chimerism and allograft tolerance across MHC barriers in NOD mice. We obtained durable mixed hematopoietic chimerism in prediabetic NOD mice using anti-c-Kit monoclonal antibody, T-cell depleting antibodies, JAK1/2 inhibition, and low-dose total body irradiation prior to transplantation of MHC-mismatched B6 hematopoietic cells, preventing diabetes in 100% of chimeric NOD:B6 mice. In overtly diabetic NOD mice, NMA conditioning followed by combined B6 HCT and islet transplantation durably corrected diabetes in 100% of chimeric mice without chronic immunosuppression or graft-versus-host disease (GVHD). Chimeric mice remained immunocompetent, as assessed by blood count recovery and rejection of 3rd party allogeneic islets. Adoptive transfer studies and analysis of autoreactive T cells confirmed correction of autoimmunity. Analysis of chimeric NOD mice revealed central thymic deletion and peripheral tolerance mechanisms. Thus, with NMA conditioning and cell transplantation, we achieved durable hematopoietic chimerism without GVHD, promoted islet allograft tolerance, and reversed established T1D.

Graphical Abstract
graphical abstract
Supplemental material

View

Version history
  • Version 1 (November 18, 2025): In-Press Preview
Advertisement
Advertisement