Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts.
Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts.
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DOI：
10.1111/ajt.13584
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Wong W
中科院分区：
文献类型：
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作者：
Brown K;Nowocin AK;Meader L;Edwards LA;Smith RA;Wong W
供体器官的排斥取决于供体过客白细胞迁移至受体的次级淋巴器官，通过直接抗原呈递途径引发免疫反应。因此，清除过客白细胞作为一种提高移植物存活率的策略在临床上可能具有应用价值。由于主要组织相容性复合体（MHC）II类阳性细胞在诱导免疫反应方面最为有效，从供体移植物中选择性清除这一群体可能会抑制同种免疫反应并延长移植物存活时间。在一个完全MHC不匹配的小鼠肾移植模型中，我们描述了一种免疫毒素的合成，它由针对供体MHC II类分子I - Ak的单克隆抗体的F(ab′)2片段与植物来源的核糖体失活蛋白多花白树毒蛋白结合而成。这种抗I - Ak多花白树毒蛋白免疫毒素在体外和体内都能特异性地清除表达I - Ak的细胞。当给予肾移植受体时，它能使移植物无限期存活且功能正常，供体移植物内存在Foxp3阳性细胞，供体特异性抗体形成减少，以及对后续供体类型皮肤移植物的排斥延迟。使用免疫毒素等药物针对免疫系统的供体端的策略可能是对现有以受体为导向的免疫抑制的一种有用辅助手段。
MHC II类特异性免疫毒素可使小鼠肾移植长期存活且无明显的保护性免疫效应。
Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II+ cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab′)2 fragment of a monoclonal antibody against the donor MHC class II molecule I‐Ak conjugated with the plant‐derived ribosomal inactivating protein gelonin. This anti–I‐Ak gelonin immunotoxin depletes I‐Ak expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3+ cells within donor grafts, diminished donor‐specific antibody formation, and delayed rejection of subsequent donor‐type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient‐orientated immunosuppression. MHC class II–specific immunotoxin allows long‐term murine kidney allograft survival without apparent protective immune effects.