Absence of MyD88 signaling induces donor-specific kidney allograft tolerance.
Absence of MyD88 signaling induces donor-specific kidney allograft tolerance.
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DOI：
10.1681/asn.2012010052
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发表时间：
2012-10
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影响因子：
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通讯作者：
Hui-ling Wu;Gerda A. Noordmans;Maya R. O’Brien;Jin Ma;C. Zhao;Geoff Zhang;Tony K Kwan;S. Alexander-S.-Alex
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文献类型：
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作者：
Hui-ling Wu;Gerda A. Noordmans;Maya R. O’Brien;Jin Ma;C. Zhao;Geoff Zhang;Tony K Kwan;S. Alexander-S.-Alex
toll样受体（TLRs）在先天免疫中起着重要作用，并在对同种异体移植物的先天和适应性反应之间提供了联系；然而，急性和慢性同种异体移植排斥反应的发生是否需要TLR信号尚不清楚。在这里，我们研究了TLR信号在一个完全mhc错配的、维持生命的肾移植排斥小鼠模型中。TLR连接蛋白MyD88缺乏的小鼠产生了供体抗原特异性耐受性，这保护它们免受急性和慢性同种异体移植排斥反应，与野生型对照相比，移植后的存活率提高。对myd88缺陷受体给予抗CD25抗体，使CD4(+)CD25(+)FoxP3（+）细胞减少，并破坏耐受性。此外，体外和体内对同种异体抗原的Th17免疫反应发生缺陷，导致Tregs与Th17效应物的比例增加。因此，MyD88缺乏与Th17细胞上Tregs平衡的改变有关，促进耐受性而不是排斥。本研究提供的证据表明，靶向先天免疫可能是促进移植耐受的临床相关策略。
Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4(+)CD25(+)FoxP3(+) cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance.