Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
Vaccine Innovation Laboratory, RIKEN Cluster for Science, Technology and Innovation Hub (RCSTI), Yokohama, Japan.
Acta Diabetol. 2019 May;56(5):541-550. doi: 10.1007/s00592-019-01289-7. Epub 2019 Feb 13.
Islet transplantation is an effective therapeutic option for type 1 diabetes. Although maintenance immunosuppression therapy is required to prevent allogeneic rejection and recurrence of autoimmunity, long-term allograft survival has not yet been achieved partly because of its adverse effects. The induction of donor-specific immunotolerance is a promising approach for long-term allograft survival without maintenance immunosuppression therapy. We previously reported that combination therapy using a liposomal ligand for invariant natural killer T cells, RGI-2001, and anti-CD154 antibody established mixed hematopoietic chimerism for the induction of donor-specific immunotolerance. This study investigated whether the protocol could promote islet allograft acceptance in experimental diabetes.
Streptozotocin-induced diabetic BALB/c mice were transplanted with bone marrow cells from C57BL/6 donors and received combination therapy of RGI-2001 and anti-CD154 antibody after 3-Gy total body irradiation. 3 Weeks after bone marrow transplantation, islets isolated from C57BL/6 donors were transplanted under the kidney capsule.
Mixed chimerism was established in diabetic mice receiving the tolerance induction protocol. After islet transplantation, blood glucose levels improved and normoglycemia persisted for over 100 days. Hyperglycemia recurred after islet grafts were removed. Histopathological examinations showed insulin-positive staining and absence of cellular infiltration in the islet grafts. T cells of recipients showed donor-specific hyporesponsiveness, and anti-donor antibodies were not detected.
The tolerance induction protocol with combination therapy of RGI-2001 and anti-CD154 antibody promoted islet allograft acceptance in a mouse diabetic model. This protocol may be clinically applied to islet transplantation for type 1 diabetes mellitus.
胰岛移植是治疗 1 型糖尿病的有效治疗方法。虽然需要维持免疫抑制治疗来预防同种异体排斥和自身免疫的复发，但由于其不良反应，尚未实现长期移植物存活。诱导供体特异性免疫耐受是一种在不进行维持免疫抑制治疗的情况下实现长期移植物存活的有前途的方法。我们之前报道过，使用脂联素配体 RGI-2001 和抗 CD154 抗体的联合治疗方案，建立混合造血嵌合体，以诱导供体特异性免疫耐受。本研究探讨了该方案是否能促进实验性糖尿病中胰岛移植物的接受。
链脲佐菌素诱导的糖尿病 BALB/c 小鼠接受 C57BL/6 供者的骨髓细胞移植，并在全身照射 3Gy 后接受 RGI-2001 和抗 CD154 抗体的联合治疗。骨髓移植 3 周后，将来自 C57BL/6 供者的胰岛分离物移植到肾包膜下。
接受耐受诱导方案的糖尿病小鼠建立了混合嵌合体。胰岛移植后，血糖水平改善，且持续 100 天以上的正常血糖水平。移植物去除后，血糖再次升高。组织病理学检查显示胰岛移植物有胰岛素阳性染色，无细胞浸润。受者的 T 细胞表现出供体特异性低反应性，且未检测到抗供体抗体。
RGI-2001 和抗 CD154 抗体联合治疗的耐受诱导方案促进了糖尿病小鼠胰岛移植物的接受。该方案可能在 1 型糖尿病的胰岛移植中得到临床应用。
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