2. Academic Validation
  3. Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning

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

  • Cell Rep. 2022 Nov 8;41(6):111615. doi: 10.1016/j.celrep.2022.111615.
Charles A Chang 1,  Preksha Bhagchandani 1,  Jessica Poyser 2,  Brenda J Velasco 2,  Weichen Zhao 1,  Hye-Sook Kwon 2,  Everett Meyer 3,  Judith A Shizuru 3,  Seung K Kim 4
Affiliations

Affiliations

  • 1 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Northern California JDRF Center of Excellence, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Northern California JDRF Center of Excellence, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 36351397 DOI: 10.1016/j.celrep.2022.111615
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.

Keywords

CP: Cell biology; CP: Immunology; allogeneic transplantation; bone marrow; diabetes mellitus; hematopoietic cell transplantation; immunologic tolerance; islet transplantation; mixed chimerism.

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