Antithymocyte globulin facilitates alloreactive T-cell apoptosis by means of caspase-3: potential implications for monitoring rejection-free outcomes.
Antithymocyte globulin facilitates alloreactive T-cell apoptosis by means of caspase-3: potential implications for monitoring rejection-free outcomes.
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DOI：
10.1097/tp.0000000000000289
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发表时间：
2015-01
期刊：
影响因子：
6.2
通讯作者：
Sindhi R
中科院分区：
文献类型：
--
作者：
Ashokkumar C;Sun Q;Ningappa M;Higgs BW;Mazariegos G;Zeevi A;Sindhi R
同种异体反应性t细胞凋亡可能解释了促凋亡免疫抑制和无排斥受体中免疫抑制需求的减少。这种可能性尚未得到证实。在健康成人hla错配的外周血淋巴细胞（PBL）混合淋巴细胞共培养（MLC）中加入兔抗胸腺细胞球蛋白（rATG）前后，观察其凋亡（caspase-3+、cathepsinb +）和炎症（CD154+） t细胞亚群的变化。在肝（LTx-20）和肠（ITx-13）移植儿童的随机样本中，使用caspase-3底物phiphilux评估凋亡t细胞与无排斥反应结果的关系。在正常人PBL之间的MLC中，1)记忆频率(M)和naïve频率(N)表达活化caspase-3的Th和Tc频率在同种异体刺激和rATG联合作用下比单独刺激增强最多。这些发现被活化caspase-3抗体、philphilux和TUNEL实验证实，2)表达活化cathepsin-B的Th亚群频率在联合刺激下同样增加。Tc对组织蛋白酶- b活化表现出抗性。3)随着rATG浓度的增加，同种异体CD154+TcM存活的比例高于TcM，导致同种异体CD154+TcM相对富集。在随机血液样本中，14名无排斥的LTx和ITx受体中philphilux + t细胞亚群频率更高，并且与19名排斥者相比，体外rATG预处理显示出更大的增加。在logistic回归分析中，philphilux +TcM与无排斥反应的结果相关性最好，敏感性和特异性分别为57%和89%。rATG通过caspase-3激活促进同种异体反应性t细胞凋亡，这可能解释了其在儿童肝脏和肠道受体中的类固醇节省作用。抵抗组织蛋白酶b激活的t细胞毒性记忆细胞的凋亡敏感性可能区分无排斥和易排斥的肝受体。
Alloreactive T-cell apoptosis may explain reduced immunosuppression requirements with pro-apoptotic immunosuppression and among rejection-free recipients. This possibility remains unproven. Apoptotic (caspase-3+, cathepsin-B+) and inflammatory (CD154+) T-cell subsets were evaluated before and after adding rabbit anti-thymocyte globulin (rATG) to mixed lymphocyte co-cultures (MLC) between HLA-mismatched peripheral blood lymphocytes (PBL) from healthy adults. In random samples from children with liver (LTx-20) and intestine (ITx-13) transplantation, apoptotic T-cells were evaluated for association with rejection-free outcomes using the caspase-3 substrate, phiphilux. In MLC between normal human PBL, 1) frequencies of memory (M) and naïve (N) Th and Tc, which expressed activated caspase-3, were enhanced most by the combination of allostimulation and rATG, than either stimulus alone. These findings were confirmed with antibody to activated caspase-3, phiphilux, and TUNEL assay, 2) frequencies of Th subsets, which expressed activated cathepsin-B, were similarly increased with combined stimulation. Tc appeared resistant to cathepsin-B activation. 3) with increasing rATG concentrations, proportionately more allospecific CD154+TcM survived than TcM, resulting in relative enrichment of allospecific CD154+TcM. In random blood samples, phiphilux+T-cell subset frequencies were higher among 14 rejection-free LTx and ITx recipients, and demonstrated a greater increase with ex-vivo rATG pre-treatment, than 19 rejectors. In logistic regression analysis, phiphilux+TcM associated best with rejection-free outcomes with sensitivity/specificity of 57%/89%, respectively. rATG facilitates apoptosis of alloreactive T-cells via caspase-3 activation, which may explain its steroid-sparing effect in pediatric liver and intestine recipients. Apoptotic susceptibility of T-cytotoxic memory cells, which resist cathepsin-B activation, may distinguish rejection-free and rejection-prone liver recipients.