Mechanism of tolerance to class I mismatched renal allografts in miniature swine -: Regulation of interleukin-2 receptor α-chain expression on CD8 peripheral blood lymphocytes of tolerant animals
Mechanism of tolerance to class I mismatched renal allografts in miniature swine -: Regulation of interleukin-2 receptor α-chain expression on CD8 peripheral blood lymphocytes of tolerant animals
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DOI：
10.1097/00007890-199808270-00007
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发表时间：
1998-08-27
期刊：
影响因子：
6.2
通讯作者：
Sachs, DH
中科院分区：
文献类型：
--
作者：
Ierino, FL;Yamada, K;Sachs, DH
背景资料。小型猪对移植肾的供者特异性耐受是通过环孢素1天的疗程，通过两个单倍型I类加上次要的组织相容抗原差异来统一诱导的。最近的研究表明，胸腺对于快速稳定的耐受诱导是必不可少的，因为之前的胸腺切除或一系列胸腺活检在环孢素1d疗程后会诱发自发的可逆排斥危象。本研究通过分析耐受动物外周血淋巴细胞(PBL)中的细胞毒效应途径，探讨耐受的外周细胞机制。用一系列肾功能稳定的耐受动物(无胸腺操作)或在排斥危象期间(胸腺活检诱导)，研究了同种异体抗原激活的PBL细胞的表型和细胞毒T淋巴细胞反应。体外实验结果与实验动物体内的临床病程相关。结果表明，体内和体外耐受与供体I类同种异体抗原刺激耐受动物的PBL时，高表达CD8的CD8单阳性(SP)T细胞的白介素α受体(IL-SR)α链的特异性缺失有关。第三方I类同种异体抗原或排斥危象时供者抗原的刺激可产生高效的细胞毒性T淋巴细胞反应和CD8(高)SP细胞上IL-2Rα的表达。CD8(高)SP PBL上IL-2Rα表达的抗原特异性调节是与这种临床前大型动物模型的耐受机制相关的主要事件，并可能参与其机制。
Background. Donor-specific tolerance to renal allografts in miniature swine is uniformly induced across a two-haplotype class I plus minor histocompatibility antigen disparity by a la-day course of cyclosporine. Recent studies have demonstrated that the thymus is essential for rapid and stable tolerance induction, because either prior thymectomy or a series of thymic biopsies induce a spontaneously reversible rejection crisis after the la-day course of cyclosporine. The present study examined the peripheral cellular mechanisms of tolerance by analyzing cytotoxic effector pathways in peripheral blood lymphocytes (PBL) of tolerant animals.Methods. The phenotype and cytotoxic T lymphocyte response of alloantigen-activated PBL cultures using cells from a series of tolerant animals with stable renal function (no thymic manipulation), or during a rejection crisis (induced by thymic biopsies), were studied. The in vitro findings were correlated with the in vivo clinical course of experimental animals.Results. The data demonstrated that in vivo and in vitro tolerance was associated with a specific deficiency of interleukin-alpha receptor (IL-SR) alpha-chain upregulation on CD8 single-positive (SP) T cells expressing high levels of CD8 (CD8(high)) when PBL from tolerant animals are stimulated with donor class I alloantigen. Stimulation by third party class I alloantigen, or by donor antigen during a rejection crisis, produced efficient cytotoxic T lymphocyte responses and expression of IL-2R alpha on CD8(high) SP cells.Conclusion. Antigen-specific regulation of the IL-2R alpha expression on CD8(high) SP PBL is a principal event associated with and potentially involved in the mechanism of tolerance in this preclinical large animal model.