Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection
Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection
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DOI：
10.1172/jci200112976
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发表时间：
2001-09-01
影响因子：
15.9
通讯作者：
Charo, IF
中科院分区：
文献类型：
--
作者：
Haskell, CA;Hancock, WW;Charo, IF
Fractalkine（Fk）是趋化因子家族中结构上不寻常的成员。为了确定其在体内的作用，我们产生了具有CX（3）CR 1（Fk受体）靶向破坏的小鼠。在无病原体的环境中，CX（3）CR 1（-/-）小鼠与野生型小鼠在表型上无法区分。对于抗体诱导的肾小球肾炎，CX（3）CR 1（-/-）和CX（3）CR 1（+/+）小鼠的蛋白尿和损伤水平相似。CX（3）CR 1（-/-）和CX（3）CR 1（+/+）小鼠在髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎中也发生了相似程度的疾病。我们进行了从BALB/c小鼠到C57 BL/6小鼠的异位MHC I/II类心脏移植。在没有环孢素A（CsA）的情况下，CX（3）CR 1（-/-）和CX（3）CR 1（+/+）受体小鼠之间的移植物存活时间没有差异。然而，在亚治疗水平的CsA存在下，CX（3）CR 1（-/-）小鼠的移植物存活时间显著增加。对浸润移植物的细胞的表征显示，在没有CsA的情况下，CX（3）CR 1（-/-）受体中的自然杀伤细胞选择性减少，而在有CsA的情况下，巨噬细胞、自然杀伤细胞和其他白细胞减少。我们的结论是Fk在移植排斥反应中起着重要的作用。CX（3）CR 1拮抗剂的开发可能会减少移植中使用的免疫抑制药物的剂量。
Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX(3)CR1, the receptor for Fk. CX(3)CR1(-/-) mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX(3)CR1(-/-) and CX(3)CR1(+/+) mice had similar levels of proteinuria and injury. CX(3)CR1(-/-) and CX(3)CR1(+/+) mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX(3)CR1(-/-) and CX(3)CR1(+/+) recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX(3)CR1(-/-) mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX(3)CR1(-/-) recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX(3)CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation.