Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model.
Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model.
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Lewis-to-F344 慢性心脏同种异体移植排斥模型中的胸腺内耐受。
DOI：
10.1097/00007890-199506270-00001
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发表时间：
1995
期刊：
影响因子：
6.2
通讯作者：
Karnovsky,MJ
中科院分区：
文献类型：
--
作者：
Shin,YT;Adams,DH;Wyner,LR;Akalin,E;Sayegh,MH;Karnovsky,MJ
在几种实验性急性排斥模型中，通过胸腺内接种同种异体抗原成功诱导供体特异性无反应性，这使我们假设在Lewis至F344大鼠慢性心脏同种异体移植排斥模型中，类似的免疫操作可以预防慢性排斥和移植物动脉硬化的发展。在异位刘易斯心脏移植前2周和6周，用供体（刘易斯）脾细胞通过胸腺内注射（it）单独处理（10 × 106个细胞/叶）;用供体脾细胞it加一次性剂量的ALS（1 mg）通过腹膜内注射（ip）处理;或用ALS单独ip（1 mg）处理。对照F344受体接受生理盐水，通过每日触诊监测同种异体移植物，并在第90天收获长期存活的移植物用于组织病理学分析。对照同种异体移植物的长期存活率为28.6%（> 90天），平均移植物存活率为46.7+/-12.2天。在第90天，存活的对照同种异体移植物增大并纤维化，几乎无法触及心跳（平均心跳等级0.29+/-0.18），组织学显示弥漫性中度单核细胞浸润和晚期移植物动脉硬化（平均血管评分3.57+/-0.10和89+/-1%血管病变）。胸腺内供者脾细胞单独给药显著延长了移植物存活（89%长期存活;平均83.8 ± 6.2天，P< 0.04），但没有显著抑制移植物动脉硬化的发展（评分2.98 ± 0.53和79 ± 8%患病，P= NS）。相比之下，在移植前2周用供体脾细胞加ALS治疗可延长移植物存活（100%长期;平均90.0 ± 0.0天，P< 0.04），并显著抑制移植物动脉硬化（评分0.80 ± 0.14，P< 0.05; 27 ± 4%患病，P< 0.05）。移植前两周单独给予ALS也延长了移植物存活（100%长期;平均90.0 ± 0.0天，P< 0.04），并抑制了移植物动脉硬化（评分0.89 ± 0.31，P< 0.05; 25 ± 7%患病，P< 0.05）。然而，当在心脏移植前6周给予ALS时，单独的ALS的有益作用被消除，这表明淋巴细胞耗竭可能是当在2周给予ALS时观察到的作用的原因。有趣的是，在移植前6周给予胸腺内供体脾细胞加ALS，另一方面，显示出显著的移植物存活延长（100%长期，平均90.0 ± 0.0天，P< 0.04），并抑制移植物动脉硬化（评分0.41 ± 0.02，P< 0.05; 16 ± 2%患病，P< 0.05）。我们的研究结果表明，细胞介导的免疫反应在启动和介导慢性排斥反应和移植物动脉硬化的发展的重要性，并建议旨在诱导耐受的策略可能是有效的预防。
Successful induction of donor-specific unresponsiveness by intrathymic inoculation of alloantigen in several experimental acute rejection models has led us to hypothesize that similar immune manipulations can prevent chronic rejection and development of graft arteriosclerosis in the Lewis-to-F344 rat chronic cardiac allograft rejection model. Recipient F344 rats were treated with donor (Lewis) splenocytes by intrathymic injection (it) alone (10x106 cells/lobe); with donor splenocytes it plus a one-time dose of ALS (1 mg) by intraperitoneal injection (ip); or with ALS ip (1 mg) alone 2 and 6 weeks prior to heterotopic Lewis heart transplantation. Control F344 recipients received saline it Allografts were monitored by daily palpation, and long-term surviving grafts were harvested on day 90 for histopathologic analysis. Control allografts had 28.6% long-term survival (> 90 days) with mean graft survival of 46.7+/-12.2 days. At day 90 the surviving control allografts were enlarged and fibrotic with barely palpable heartbeat (mean heartbeat grade 0.29+/-0.18), and histologically showed diffuse moderate mononuclear cell infiltrates and advanced graft arteriosclerosis (mean vessel score 3.57+/-0.10 and 89+/-1% vessels diseased). Recipient treatment with intrathymic donor splenocytes alone significantly prolonged graft survival (89% long-term survival; mean 83.8+/-6.2 days, P< 0.04), but did not significantly inhibit the development of graft arteriosclerosis (score 2.98+/-0.53 and 79+/-8% diseased, P= NS). By contrast, treatment with it donor splenocytes plus ALS 2 weeks prior to transplantation prolonged graft survival (100% long-term; mean 90.0+/-0.0 days, P< 0.04), and markedly inhibited graft arteriosclerosis (score 0.80+/-0.14, P< 0.05; 27+/-4% diseased, P< 0.05). ALS alone given two weeks prior to transplantation also prolonged graft survival (100% long-term; mean 90.0+/-0.0 days, P< 0.04), and inhibited graft arteriosclerosis (score 0.89+/-0.31, P< 0.05; 25+/-7% diseased, P< 0.05). However, when ALS was given 6 weeks prior to heart transplantation the beneficial effect of ALS alone was abolished, suggesting that lymphocyte depletion may have been responsible for the observed effects when ALS was administered at 2 weeks. Interestingly, intrathymic donor splenocytes plus ALS given 6 weeks prior to transplantation, on the other hand, showed significant prolongation of allograft survival (100% long-term, mean 90.0+/-0.0 days, P< 0.04), and inhibited graft arteriosclerosis (score 0.41+/-0.02, P< 0.05; 16+/-2% diseased, P< 0.05). Our results indicate the importance of the cell-mediated immune response in initiating and mediating development of chronic rejection and graft arteriosclerosis, and suggest that strategies aimed at induction of tolerance may be effective in their prevention.