Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Rep. 2022 Nov 8;41(6):111615. doi: 10.1016/j.celrep.2022.111615.
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.
混合造血嵌合可以促进供体匹配的移植组织（如胰岛）的免疫耐受。然而，这种策略的采用受到使供体造血细胞植入的标准治疗毒性的限制。在这里，我们通过非清髓性调理方案解决了这些问题，该方案可实现造血嵌合和完全不匹配的主要组织相容性复合体（MHC）障碍的同种异体移植物耐受。用靶向 c-Kit 的 αCD117 抗体联合 T 细胞耗竭抗体和低剂量辐射治疗，可使免疫功能正常的小鼠在接受造血细胞移植后获得持久的多谱系嵌合。在糖尿病小鼠中，供体匹配的胰岛和造血细胞共移植可在没有慢性免疫抑制且没有明显移植物抗宿主病（GVHD）证据的情况下持久纠正糖尿病。供体来源的胸腺抗原呈递细胞和宿主来源的外周调节性 T 细胞可能是同种异体耐受的介导者。这些发现为建立造血嵌合和胰岛同种异体移植物耐受的更安全的骨髓调理和细胞移植方案提供了基础。
