Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA.
Diabetes. 2010 Apr;59(4):947-57. doi: 10.2337/db09-0498. Epub 2010 Jan 19.
To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.
We monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays.
Autoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells.
We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used.
研究在 3 例免疫抑制的胰肾联合移植（SPK）受者中，是否反复发生的自身免疫导致高血糖和 C 肽丢失。
我们监测了自身抗体和自身反应性 T 细胞（使用四聚体），并进行了活检。通过体外和体内试验研究了自身反应性 T 细胞的功能。
一位患者移植前存在自身抗体，并在随访中持续存在。另外两名患者在移植后数年、高血糖发生前出现了自身抗体。在高血糖复发后大约 1 年内对胰腺移植活检进行了检查，发现β细胞丢失和胰岛炎。我们从活检时开始研究自身反应性 T 细胞，并在进一步随访中反复证明了它们的存在，同时还有自身抗体。用 T 细胞靶向治疗（所有患者用胸腺球蛋白和达珠单抗），或联合 B 细胞靶向治疗（两例患者用利妥昔单抗）单独或联合治疗，非特异性地耗竭了 T 细胞，与 C 肽分泌持续超过 1 年相关。随后在接下来的 2 年中，随着进一步的 C 肽丢失，出现了具有相同自身抗原特异性和保守 T 细胞受体的自身反应性 T 细胞。从两名患者中纯化的自身反应性 CD4 T 细胞与 HLA 错配的人胰岛一起移植到免疫缺陷小鼠中。在接受自身反应性 T 细胞的小鼠中移植物出现了β细胞丢失，而在接受对照 T 细胞的小鼠中没有。
我们在 3 例这样的患者中证明了反复发生自身免疫的主要特征，包括能够介导β细胞破坏的 CD4 T 细胞再次出现。自身免疫的标志物有助于诊断这种被低估的移植物丢失原因。治疗期间的免疫监测表明，免疫抑制剂不能解决自身免疫问题。
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