Indoleamine 2,3-dioxygenase and inducible nitric oxide synthase mediate immune tolerance induced by CTLA4Ig and anti-CD154 hematopoietic stem cell transplantation in a sensitized mouse model.
Indoleamine 2,3-dioxygenase and inducible nitric oxide synthase mediate immune tolerance induced by CTLA4Ig and anti-CD154 hematopoietic stem cell transplantation in a sensitized mouse model.
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吲哚胺2,3-双加氧酶和诱导型一氧化氮合酶介导致敏小鼠模型中CTLA4Ig和抗CD154造血干细胞移植诱导的免疫耐受
DOI：
10.3892/etm.2017.4722
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发表时间：
2017-09
影响因子：
2.7
通讯作者：
Fang JP
中科院分区：
文献类型：
--
作者：
Ye QX;Xu LH;Shi PJ;Xia T;Fang JP
细胞毒性 T 淋巴细胞相关蛋白 4 免疫球蛋白 (CTLA4Ig) 和抗分化簇 154（抗 CD154）能够阻断 T 细胞中的 B7/CD28 和 CD40/CD154 共刺激信号。此外，它们还能促进致敏受体的造血干细胞移植（HSCT），并能够诱导免疫耐受和完全造血重建。吲哚胺 2, 3-双加氧酶 (IDO) 和一氧化氮 (NO) 与 T 细胞免疫耐受有关。本报告的目的是研究 CTLA4Ig 和抗 CD154 诱导接受 HSCT 的小鼠移植存活的体内耐受机制。 BALB/c 小鼠通过脾细胞输注致敏，并在第 7 天用 CTLA4Ig 加抗 CD154 预处理。第7天至第0天应用IDO和诱导型一氧化氮合酶（iNOS）抑制剂，将小鼠分为4组（n=10），每隔一天注射IDO。在第 0 天处死小鼠，分离脾细胞以鉴定 CD11c+ 抗原呈递细胞，随后评估其 IDO 表达和活性。使用硝酸还原酶试剂盒测试NO的浓度。接受同种异体 HSCT 后，对小鼠进行归巢和移植以及存活率测试。 IDO抑制剂的应用增加了NO的浓度，而NO的减少导致IDO活性增加。在 IDO 和 iNOS 抑制剂同时存在的情况下，免疫耐受被消除，而单独使用任一化合物均未观察到这种效应。 CTLA4Ig和抗CD154可能通过影响IDO和iNOS的活性来诱导免疫耐受。当 IDO 和 iNOS 抑制剂同时存在时，这种耐受性被消除。在IDO和NO途径之间观察到交叉调节途径，其中IDO的抑制刺激iNOS途径，反之亦然。
Cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig) and anti-cluster of differentiation 154 (anti-CD154) are able to block B7/CD28 and CD40/CD154 co-stimulatory signals in T cells. Additionally, they promote hematopoietic stem cell transplantation (HSCT) in sensitized recipients and are able to induce immune tolerance and complete hematopoietic reconstitution. Indoleamine 2, 3-dioxygenase (IDO) and nitric oxide (NO) have been implicated in T cell immune tolerance. The aim of the present report was to study the in vivo tolerogenic mechanisms by which CTLA4Ig and anti-CD154 induce transplantation survival in mice receiving HSCT. BALB/c mice were sensitized via splenocyte transfusion and pretreated with CTLA4Ig plus anti-CD154 on day-7. IDO and inducible nitric oxide synthase (iNOS) inhibitors were applied on days-7 to 0 and the mice were divided into 4 groups (n=10) and injected with IDO every other day. The mice were sacrificed on day 0, and splenocytes were separated to identify CD11c+ antigen-presenting cells, which were subsequently assessed for IDO expression and activity. The concentration of NO was tested using a nitrate reductase kit. Following the acceptance of allogeneic HSCT, mice were tested for homing and engraftment, as well as survival rate. Application of the IDO inhibitor increased the concentration of NO, whereas a decrease in NO resulted in increased IDO activity. Immune tolerance was abrogated in the presence of both IDO and iNOS inhibitors, whereas this effect was not observed with either compound alone. CTLA4Ig and anti-CD154 may induce immune tolerance by affecting the activity of IDO and iNOS. This tolerance was abrogated in the presence of both IDO and iNOS inhibitors. A cross-regulatory pathway was observed between the IDO and NO pathways, in which the inhibition of IDO stimulated the iNOS pathway and vice versa.
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影响因子：
3.1
作者：
Hucke, C;MacKenzie, CR;Däubener, W
通讯作者：
Däubener, W
影响因子：
30.5
作者：
Grohmann, U;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
DOI：
10.1016/s0006-291x(03)00814-3
发表时间：
2003-06-06
影响因子：
3.1
作者：
Ischiropoulos, H
通讯作者：
Ischiropoulos, H
影响因子：
3.3
作者：
Guan Y;Yaster M;Raja SN;Tao YX
通讯作者：
Tao YX
影响因子：
6.4
作者：
Bauer, H;Jung, T;Neumann, C
通讯作者：
Neumann, C