T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice.
T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice.
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人 CD3ε 转基因小鼠中抗人 CD3 免疫毒素诱导 T 细胞耗竭和移植物存活。
DOI：
10.1097/00007890-200205270-00023
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发表时间：
2002
期刊：
影响因子：
6.2
通讯作者：
Lake,
中科院分区：
文献类型：
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作者：
Weetall,Marla;Digan,MaryEllen;Hugo,Ronald;Mathew,Sheba;Hopf,Christine;Tart-Risher,Nicole;Zhang,Jin;Shi,Victor;Fu,Fumin;Hammond-McKibben,Denise;West,Susan;Brack,Richard;Brinkmann,Volker;Bergman,Reinhard;NevilleJr,David;Lake,
背景：抗CD3免疫毒素是多种器官移植动物模型中的广谱免疫抑制剂，可用于引发抗原特异性耐受。然而，动物研究中使用的抗CD3免疫毒素不会与人类T细胞发生交叉反应，限制了对人类的外推并阻碍了临床开发。方法。对三种抗人CD3定向免疫毒素DT389-scFv (UCHT1)、scFv (UCHT1)-PE38和UCHT1-CRM9进行了体外和转基因比较 小鼠，tgε600±，其 T 细胞同时表达人和鼠 CD3ε 抗原。结果。这些免疫毒素在体外针对人或转基因小鼠 T 细胞非常有效，细胞测定中的 IC 50 值范围为 pM 至 fM。这些免疫毒素的全身施用剂量依赖性地耗尽体内>99%的tgε600±淋巴结和脾T细胞。耗竭是 T 细胞特异的。免疫毒素处理的动物中伴刀豆球蛋白 A 诱导的脾增殖反应的丧失，而不是脂多糖诱导的脾增殖反应的丧失，进一步证明了 T 细胞功能的特异性丧失。免疫毒素治疗将 tgε600± 受体的完全同种异体皮肤移植存活期从未治疗动物的 10 天延长至 25 天。在有或没有皮肤移植的动物中，大约 22 天后，T 细胞恢复到正常水平的 50%； T 细胞恢复与皮肤移植排斥相关。所有三种免疫毒素均导致完全同种异体心脏移植物的中位生存期 > 100 天。 100 天时，这些动物中的 T 细胞恢复到正常数量，但移植物显示出慢性排斥反应。结论。这些免疫毒素在体内深度消耗 T 细胞，并有效延长同种异体移植物的存活时间。抗 CD3 免疫毒素已被证明在大型和小型动物器官移植模型（参见评论 1）以及其他器官移植模型中都是广谱免疫抑制剂。 T 细胞介导的反应，包括小鼠的移植物抗宿主病 (2) 和灵长类动物的过敏性脑脊髓炎 (3)。抗 T 细胞免疫毒素也可用于引发抗原特异性耐受 (4)。例如，抗灵长类 CD3 导向的化学偶联免疫毒素 FN18-CRM9 在同种异体肾移植模型中约三分之一的治疗动物中引起长期但不是无限期的移植物存活 (5, 6)。在这些研究中，肾移植最终因慢性血管病变而发生排斥反应。相比之下，当与 15-脱氧精胍菌素联合使用时，FN18-CRM9 可在灵长类动物模型中引发长期移植物存活，无需慢性免疫抑制，并预防肾移植物的血管病变 (6, 7)。
Background.Anti-CD3 immunotoxins are broad-spectrum immunosuppressive agents in a wide range of organ transplantation animal models with potential use in eliciting antigen-specific tolerance. However, the anti-CD3 immunotoxins used in animal studies do not cross-react with human T cells, limiting extrapolation to humans and hindering clinical development.Methods.Three anti-human CD3-directed immunotoxins, DT389-scFv (UCHT1), scFv (UCHT1)-PE38, and UCHT1-CRM9, were compared in vitro and in transgenic mice, tgε600±, that have T cells expressing both human and murine CD3ε antigens.Results.These immunotoxins were extraordinarily potent in vitro against human or transgenic mouse T cells, with IC 50 values in cellular assays ranging from pM to fM. Systemic administration of these immunotoxins dose-dependently depleted> 99% of tgε600±lymph node and spleen T cells in vivo. Depletion was specific for T cells. The loss of the concanavalin A-induced, but not the lipopolysaccharide-induced, splenic proliferative response from immunotoxin-treated animals further demonstrated specific loss of T-cell function. Immunotoxin treatment prolonged fully allogeneic skin graft survival in tgε600±recipients to 25 days from 10 days in untreated animals. T-cells recovered to∼ 50% of normal levels after approximately 22 days in animals with or without skin grafts; T-cell recovery correlated with skin graft rejection. All three immunotoxins elicited> 100 day median survival of fully allogeneic heterotopic heart grafts. By 100 days, T cells recovered to normal numbers in these animals, but the grafts showed chronic rejection.Conclusion.These immunotoxins profoundly deplete T cells in vivo and effectively prolong allogeneic graft survival.Anti-CD3 immunotoxins have been shown to be broad-spectrum immunosuppressive agents in both large and small animal models of organ transplantation (see for review 1), as well as in other T-cell-mediated responses including graft-versus-host disease in the mouse (2) and allergic encephalomyelitis in the primate (3). Anti-T-cell immunotoxins may also have use in eliciting antigen-specific tolerance (4). For example, the anti-primate CD3 directed chemically conjugated immunotoxin, FN18-CRM9, elicits long-term but not indefinite graft survival in approximately one-third of treated animals in models of allogeneic kidney transplantation (5, 6). In these studies, the kidney grafts eventually reject because of chronic vasculopathy. In contrast, when combined with 15-deoxyspergualin, FN18-CRM9 elicits long-term graft survival in primate models without chronic immunosuppression and prevents vasculopathy of kidney grafts (6, 7).