Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody
Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody
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DOI：
10.1046/j.1600-6143.2003.00351.x
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发表时间：
2004-03-01
影响因子：
8.8
通讯作者：
Bluestone, JA
中科院分区：
文献类型：
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作者：
Hering, BJ;Kandaswamy, R;Bluestone, JA
我们试图确定优化胰腺保存、胰岛加工和诱导免疫抑制是否有助于单供者胰岛移植后持续的糖尿病逆转。从两层保存的胰腺中分离胰岛，纯化，培养2天；并移植到 6 名 C 肽阴性、非尿毒症、1 型糖尿病患者中，且患者没有意识到自己患有低血糖。诱导免疫抑制在移植前 2 天开始，包括不结合 Fc 受体的人源化抗 CD3 单克隆抗体 hOKT3gamma1 (Ala-Ala) 和西罗莫司。用西罗莫司和减少剂量的他克莫司维持免疫抑制。在我们的 6 名接受者中，4 名实现并保持了胰岛素独立性，HbA1c 水平正常且没有低血糖； 1例具有部分胰岛移植功能；移植后 2 周，1 例胰岛移植物功能丧失。 4 名胰岛素非依赖型患者表现出长期的 CD4(+) T 细胞淋巴细胞减少症； CD4：CD8 比率倒置； CD4(+) CD25(+) T 细胞的百分比增加。这些细胞抑制了对供体细胞的体外增殖反应，并在较小程度上抑制了第三方细胞的增殖反应。严重不良事件仅限于一名接受者出现短暂皮疹，三名接受者出现暂时性中性粒细胞减少。因此，我们的初步结果表明，最大化活胰岛产量、移植前胰岛培养和先发性免疫抑制的结合可以导致成功的单供体胰岛移植。
We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single-donor islet transplants. Islets were isolated from two-layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C-peptide-negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti-CD3 monoclonal antibody hOKT3gamma1 (Ala-Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced-dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post-transplant. The four insulin-independent patients showed prolonged CD4(+) T-cell lymphocytopenia; inverted CD4: CD8 ratios; and increases in the percentage of CD4(+) CD25(+) T cells. These cells suppressed the in-vitro proliferative response to donor cells and, to a lesser extent, to third-party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single-donor islet transplants.