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Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning.

Citation
Chang, C. A., et al. “Curative Islet And Hematopoietic Cell Transplantation In Diabetic Mice Without Toxic Bone Marrow Conditioning.”. Cell Reports, p. 111615.
Center Stanford University
Featured
Author Charles A Chang, Preksha Bhagchandani, Jessica Poyser, Brenda J Velasco, Weichen Zhao, Hye-Sook Kwon, Everett Meyer, Judith A Shizuru, Seung K Kim
Keywords CP: Cell biology, CP: Immunology, allogeneic transplantation, bone marrow, diabetes mellitus, hematopoietic cell transplantation, immunologic tolerance, islet transplantation, mixed chimerism
Abstract

Mixed hematopoietic chimerism can promote immune tolerance of donor-matched transplanted tissues, like pancreatic islets. However, adoption of this strategy is limited by the toxicity of standard treatments that enable donor hematopoietic cell engraftment. Here, we address these concerns with a non-myeloablative conditioning regimen that enables hematopoietic chimerism and allograft tolerance across fully mismatched major histocompatibility complex (MHC) barriers. Treatment with an αCD117 antibody, targeting c-Kit, administered with T cell-depleting antibodies and low-dose radiation permits durable multi-lineage chimerism in immunocompetent mice following hematopoietic cell transplant. In diabetic mice, co-transplantation of donor-matched islets and hematopoietic cells durably corrects diabetes without chronic immunosuppression and no appreciable evidence of graft-versus-host disease (GVHD). Donor-derived thymic antigen-presenting cells and host-derived peripheral regulatory T cells are likely mediators of allotolerance. These findings provide the foundation for safer bone marrow conditioning and cell transplantation regimens to establish hematopoietic chimerism and islet allograft tolerance.

Year of Publication
2022
Journal
Cell reports
Volume
41
Issue
6
Number of Pages
111615
Date Published
11/2022
ISSN Number
2211-1247
DOI
10.1016/j.celrep.2022.111615
Alternate Journal
Cell Rep
PMID
36351397
PMCID
PMC9922474
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