Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes.
Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes.
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DOI：
10.3389/fimmu.2017.00167
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发表时间：
2017
影响因子：
7.3
通讯作者：
Oliveira MC
中科院分区：
文献类型：
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作者：
Malmegrim KC;de Azevedo JT;Arruda LC;Abreu JR;Couri CE;de Oliveira GL;Palma PV;Scortegagna GT;Stracieri AB;Moraes DA;Dias JB;Pieroni F;Cunha R;Guilherme L;Santos NM;Foss MC;Covas DT;Burt RK;Simões BP;Voltarelli JC;Roep BO;Oliveira MC
自体造血干细胞移植（AHSCT）可增加1型糖尿病患者的C肽水平并诱导胰岛素依赖性。本研究旨在探讨临床结局与免疫状态的关系，特别是免疫调节和自身反应性之间的平衡。21例1型糖尿病患者在AHSCT后进行监测，每6个月评估一次胰岛素依赖性持续时间、C肽水平、胰岛特异性自身反应性CD 8 + T细胞（CTL）频率、调节性淋巴细胞亚群、胸腺功能和T细胞库多样性。在中位随访78个月（范围15-106），所有患者成为胰岛素依赖，恢复胰岛素后，中位数43个月（范围6-100）。根据胰岛素非依赖性持续时间，将患者回顾性分为短期或长期缓解组。在整个随访期间，两组的CD 3 + CD 4 + T细胞数量均低于基线水平，而CD 3 + CD 8 + T细胞水平无变化，导致CD 4/CD 8比值倒置。AHSCT后长期随访的患者中，记忆性CTL包含了大部分的T细胞。两个患者组的B细胞在AHSCT后2-3个月重建至基线水平。在延长缓解组中，移植后基线胰岛特异性T细胞自身反应性持续存在，但调节性T细胞计数增加。与自身反应性胰岛特异性T细胞频率较低的患者相比，这些细胞频率较低的患者保持无胰岛素状态的时间更长，C肽水平更高。因此，免疫监测确定了AHSCT具有上级临床结局的患者亚组。我们的研究表明，改善免疫调节可能平衡自身反应性，支持胰岛特异性T细胞频率较低的患者更好的代谢结果。AHSCT新策略的开发对于增加接受移植的1型糖尿病患者中T和B调节细胞的频率和功能以及有效减少自身反应性胰岛特异性T和B记忆细胞是必要的。
Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8+ T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity. In median follow-up of 78 (range 15–106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6–100) months. Patients were retrospectively divided into short- or prolonged-remission groups, according to duration of insulin independence. For the entire follow-up, CD3+CD4+ T-cell numbers remained lower than baseline in both groups, whereas CD3+CD8+ T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CTL comprehended most of T cells detected on long-term follow-up of patients after AHSCT. B cells reconstituted to baseline levels at 2–3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T cell counts increased. Patients with lower frequencies of autoreactive islet-specific T cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.