한빛사논문
Charles A. Chang1,5, Preksha Bhagchandani1,5, Jessica Poyser2, Brenda J. Velasco2, Weichen Zhao1, Hye-Sook Kwon2, Everett Meyer2,3,4, Judith A. Shizuru2,3,4, Seung K. Kim1,3,4,6
1Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
2Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
3Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA
4Northern California JDRF Center of Excellence, Stanford University School of Medicine, Stanford, CA 94305, USA
5These authors contributed equally
6Lead contact
Corresponding author; Seung K. Kim
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.
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