Ex vivo inhibition of NF-kappaB signaling in alloreactive T-cells prevents graft-versus-host disease.
Ex vivo inhibition of NF-kappaB signaling in alloreactive T-cells prevents graft-versus-host disease.
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DOI：
10.1111/j.1600-6143.2008.02533.x
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Blazar BR
中科院分区：
文献类型：
--
作者：
O'Shaughnessy MJ;Vogtenhuber C;Sun K;Sitcheran R;Baldwin AS;Murphy WJ;Dang L;Jaffee B;Palmer E;Serody JS;Blazar BR
通过共刺激通路阻断或暴露于免疫调节细胞因子，体外诱导异体抗原特异性低反应性已被证明可抑制过继转移t细胞的增殖、IL-2产生和GVHD能力。我们假设抑制同种异体反应性T细胞的细胞内NF-κB通路可能导致同种异体抗原反应性降低和GVHD能力丧失，这对包括IL-2转录在内的T细胞活化事件至关重要。我们证明了用PS1145（一种有效的NF-κB激活抑制剂）处理混合淋巴细胞反应（MLR）培养物，可以在原发性和继发性反应中诱导T细胞对同种异体抗原的低反应性，同时保留对强效有丝分裂刺激的体外反应。体外ps1145处理细胞受体的GVHD致死率被显著抑制。将对照或PS1145处理的MLR细胞放置在同源Rag - / -受体中，可产生完整的接触超敏反应。然而，GVHD的致死能力也得到了恢复，这表明淋巴细胞减少扩张不耦合同种异体抗原低反应性。这些结果表明，NF-κB通路是同种异体反应的关键调节因子，并提供了一种新的基于小分子抑制剂的方法，可有效预防移植后早期GVHD致死，但也允许供体T细胞反应在淋巴细胞减少扩张一段时间后恢复。
The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the GVHD capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-κB pathway in alloreactive T-cells, which is critical for T cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-κB activation, can induce T cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control- or PS1145- treated MLR cells in syngeneic Rag−/− recipients resulted in intact contact hypersensitivity responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-κB pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early post-transplant GVHD lethality but that also permits donor T cell responses to recover after a period of lymphopenic expansion.
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影响因子：
20.3
作者：
Godfrey, WR;Krampf, MR;Blazar, BR
通讯作者：
Blazar, BR
DOI：
10.1097/00042560-199811010-00002
发表时间：
1998-11-01
期刊：
JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY
影响因子：
--
作者：
Brice, GT;Riley, JL;Ansari, AA
通讯作者：
Ansari, AA
影响因子：
20.3
作者：
Gribben, JG;Guinan, EC;Nadler, LM
通讯作者：
Nadler, LM
影响因子：
15.3
作者：
Janssen, R;van Wengen, A;Lankester, A
通讯作者：
Lankester, A
影响因子：
64.5
作者：
Ruland, J;Duncan, GS;Mak, TW
通讯作者：
Mak, TW