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ResearchIn-Press PreviewHematologyImmunology Open Access | 10.1172/jci.insight.194491

Improved conditioning for hematopoietic chimerism induces islet tolerance to cure diabetes

Stephan A. Ramos,1 Preksha Bhagchandani,1 Diego M. Burgos,1 Xueying Gu,1 Richard Rodriguez,1 Nadia Nourin,1 Martin Neukam,1 Shiva Pathak,2 Judith Shizuru,2 and Seung K. Kim3

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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

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

3Developmental Biology, Stanford School of Medicine, Stanford, United States of America

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Published April 21, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.194491.
Copyright © 2026, Ramos 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 April 21, 2026 - Version history
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Abstract

Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues. However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance. We sought agents that reduced conditioning intensity, while promoting durable mixed chimerism after HCT across complete major histocompatibility complex (MHC) mismatch in diabetic mice, permitting islet allotransplantation and diabetes reversal. We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and αCD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT. Combined with αCD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of GVHD. Thus, we have developed a conditioning regimen to promote allogeneic mixed hematopoietic chimerism and transplanted islet allotolerance that minimizes conditioning radiation and cures diabetes, a significant achievement.

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