GAD65和IA2自身抗体对异体胰岛移植存活的影响

Joana R. N. Lemos, Raffaella Poggioli, Jonathan Ambut, Nujen C. Bozkurt, Ana M. Alvarez, Nathalia Padilla, Francesco Vendrame, Camillo Ricordi, David A. Baidal, Rodolfo Alejandro
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Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade’s nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value <0.05 indicated statistical significance. Results ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 – 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 – 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 – 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status. Conclusion The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. 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引用次数: 0

摘要

胰岛移植(ITx)显示出治疗T1D的希望,但胰岛自身抗体在移植物存活中的作用尚未明确阐明。我们的目的是分析GAD65和IA2自身抗体水平对接受ITx治疗的T1D患者移植物存活和胰岛素独立性的影响。方法对2000 - 2018年47例ITx患者进行回顾性队列研究。通过肝内门静脉输注胰岛(n=44)或通过腹腔镜入路输注网膜(n=3)。38名受试者(80.9%)的免疫抑制包括抗il - 2受体抗体、抗tnf和西罗莫司、他克莫司或霉酚酸酯(埃德蒙顿样)的双重联合。9名受试者(19%)采用埃德蒙顿样维持法诱导t细胞消耗。在移植前和移植后(每月)评估GAD65和IA2自身抗体,直到移植失败,并将其分类为持续阴性、持续阳性或血清转化。采用U-Mann-Whitney检验分析移植物存活,并对混杂因素进行Quade非参数ANCOVA校正。Kaplan-Meier检验和Log-Rank检验分析胰岛素独立性的实现情况。P值<0.05表示有统计学意义。结果持续自身抗体阴性的ITx受体(n = 21)比持续自身抗体阳性的ITx受体(n = 18;38[13 - 163]个月),甚至在调整免疫抑制诱导方案后(P = 0.027)。血清转换者(n=8)的中位移植物生存时间为73(7.7 - 167)个月,与其他两组无显著差异。与胰岛自身抗体(GAD65/IA2)阴性的受试者相比,GAD65单抗体持续呈阳性的受试者(n = 8)移植物存活时间较短(n = 21;P = 0.016)。IA2单抗体阳性受试者的移植物存活时间无差异。无论自身抗体状况如何,获得胰岛素独立性的比例相似。结论胰岛自身抗体的持续存在,作为胰岛自身免疫的标志,可能是移植β细胞失败的一个未被充分认识的因素。在我们的队列中,无法评估t细胞耗损诱导是否会导致移植物存活率的提高,而不依赖于胰岛自身抗体状态。需要更大的前瞻性研究来进一步研究胰岛自身抗体状态在胰岛移植物存活中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Impact of GAD65 and IA2 autoantibodies on islet allograft survival
Introduction Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx. Method We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3). Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade’s nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value &lt;0.05 indicated statistical significance. Results ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 – 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 – 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 – 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status. Conclusion The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival.
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