Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.
Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.
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DOI：
10.2337/db09-0498
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发表时间：
2010-04
期刊：
影响因子：
7.7
通讯作者：
Pugliese A
中科院分区：
文献类型：
--
作者：
Vendrame F;Pileggi A;Laughlin E;Allende G;Martin-Pagola A;Molano RD;Diamantopoulos S;Standifer N;Geubtner K;Falk BA;Ichii H;Takahashi H;Snowhite I;Chen Z;Mendez A;Chen L;Sageshima J;Ruiz P;Ciancio G;Ricordi C;Reijonen H;Nepom GT;Burke GW 3rd;Pugliese A
研究是否复发性自身免疫解释高血糖和c肽丢失在三个免疫抑制同时胰肾（SPK）移植受者。我们监测自身抗体和自身反应性t细胞（使用四聚体）并进行活检。通过体外和体内实验研究了自身反应性t细胞的功能。1例患者在移植前存在自身抗体，并在随访中持续存在。它们在移植后数年出现，但在其余患者出现高血糖之前。在高血糖复发后1年内进行胰腺移植活检，发现β细胞丢失和胰岛素炎。我们研究了活检时的自身反应性t细胞，并在进一步的随访中反复证明了它们与自身抗体的存在。接受t细胞定向治疗（胸腺球蛋白和daclizumab，所有患者），单独或加用b细胞定向治疗（利妥昔单抗，2例患者），非特异性耗尽t细胞，并与c肽分泌相关，治疗期为10年。具有相同自身抗原特异性和保守的t细胞受体的自身反应性t细胞随后再次出现，并在接下来的2年中进一步丢失c肽。来自两名患者的纯化的自身反应性CD4 t细胞与hla不匹配的人胰岛共移植到免疫缺陷小鼠体内。在接受自身反应性t细胞而非控制性t细胞的小鼠中，移植物显示β细胞丢失。我们在三个这样的患者中展示了复发性自身免疫的主要特征，包括能够介导β细胞破坏的CD4 t细胞的再现。自身免疫标志物可以帮助诊断这种未被充分认识的移植物丧失的原因。治疗期间的免疫监测显示，使用的免疫抑制剂不能解决自身免疫问题。
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 ∼1 year from hyperglycemia recurrence and revealed β-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 β-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 β-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.
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影响因子：
4.4
作者：
Kupfer, TM;Crawford, ML;Gill, RG
通讯作者：
Gill, RG
DOI：
10.1073/pnas.0508621102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Pinkse, GGM;Tysma, OHM;Roep, BO
通讯作者：
Roep, BO
影响因子：
7.7
作者：
Bingley, PJ;Bonifacio, E;Mueller, PW
通讯作者：
Mueller, PW
影响因子：
7.7
作者：
Herold KC;Gitelman SE;Masharani U;Hagopian W;Bisikirska B;Donaldson D;Rother K;Diamond B;Harlan DM;Bluestone JA
通讯作者：
Bluestone JA
影响因子：
158.5
作者：
Herold, KC;Hagopian, W;Bluestone, JA
通讯作者：
Bluestone, JA