Molecular and cellular events implicated in local tolerance to kidney allografts in miniature swine
Molecular and cellular events implicated in local tolerance to kidney allografts in miniature swine
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DOI：
10.1097/00007890-199701150-00006
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发表时间：
1997-01-15
期刊：
影响因子：
6.2
通讯作者：
LeGuern, C
中科院分区：
文献类型：
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作者：
Blancho, G;Gianello, PR;LeGuern, C
短期环孢素A（CsA）治疗可诱导小型猪对I类错配肾移植物的长期耐受。接受CsA治疗的肾受体和未接受治疗的对照肾受体均表现出单核细胞对移植肾的浸润，在术后8 - 11天达到最大值。在该模型中，未接受耐受化方案的受体在术后8天至12天之间排斥其移植物。细胞因子基因表达的动力学，包括白细胞介素（IL）-1 α，IL-1 β，IL-2，IL-6，IL-10，肿瘤坏死因子，和干扰素-γ（IFN-γ），在移植肾排斥和受体动物，使用北方印迹杂交测定。观察到排斥反应和IFN-γ基因上调之间的强相关性，而具有长期耐受性的动物显示出低水平的IFN-γ，但高水平的IL-10基因转录。其他细胞因子基因均未表现出与同种异体移植物接受/排斥相关的可重复表达模式。从移植肾纯化的单核细胞中细胞因子基因转录模式的分析证实了活检的初步观察结果。移植物浸润细胞（GIC）的表型显示CD8（+）细胞占优势，平均66%的单阳性细胞和19%的CD4/CD8双阳性细胞，而外周血细胞分别为30%和14%。CD 8（+）GIC的主导地位既不取决于MHC抗原差异，也不取决于拒绝者/接受者状态。因此，这些结果表明，GIC代表了单核细胞产生局部免疫介质的调节组合，其在一定程度上控制了该大型动物模型中同种异体移植物的命运。
Long-term tolerance to class I-mismatched renal allografts can be induced in miniature swine by treatment with a short course of cyclosporine (CsA). Kidney recipients treated with CsA and untreated control kidney recipients both demonstrated infiltration of the transplanted kidney by mononuclear cells, which reached a maximum between postoperative days 8 and 11. Recipients that did not receive the tolerizing regimen rejected their grafts between postoperative days 8 and 12 in this model. The kinetics of cytokine gene expression, including interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-6, IL-10, tumor necrosis factor, and interferon-gamma (IFN-gamma), within the grafted kidney of rejector and acceptor animals, were determined using Northern blot hybridization. A strong correlation between rejection and up-regulation of the IFN-gamma gene was observed, whereas animals with long-term tolerance showed low levels of IFN-gamma, but high levels of IL-10 gene transcription. None of the other cytokine genes demonstrated a reproducible pattern of expression that correlated with acceptance/rejection of allografts. Analysis of transcription patterns of cytokine genes in mononuclear cells purified from renal grafts confirmed the initial observations made on biopsies. The phenotype of graft-infiltrating cells (GIC) showed a dominance of CD8(+) cells, with an average of 66% single-positive cells and 19% CD4/CD8 double-positive cells, compared with 30% and 14%, respectively, for peripheral cells. Predominance of CD8(+) GIC was dictated neither by the MHC antigen disparity nor the rejector/acceptor status. These results, therefore, suggest that GIC represent a regulated combination of mononuclear cells producing local immune mediators that, in part, control the fate of allografts in this large animal model.