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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Chimerism and tolerance in transplantation
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Chimerism and tolerance in transplantation

机译：嵌合和移植耐受

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Studies in experimental models (1953-1956) demonstrated that acquired donor-specific allotolerance in immunologically immature or irradiated animals is strongly associated with donor leukocyte chimerism. Bone marrow transplantation in immune-deficient or cytoablated human recipients was a logical extension (1968), In contrast clinical (1959) and then experimental organ transplantation was systematically accomplished in the apparent absence of leukocyte chimerism. Consequently, it was assumed for many years that success with organ and bone marrow transplantation involved fundamentally different mechanisms. With the discovery in 1992 of small numbers of donor leukocytes in the tissues or blood of long-surviving organ recipients (microchimerism), we concluded that organ engraftment was a form of leukocyte chimerism-dependent partial tolerance. In this initially controversial paradigm, alloengraftment after both kinds of transplantation is the product of a double immune reaction in which responses, each to the other, of coexisting donor and recipient immune systems results in variable reciprocal clonal exhaustion, followed by peripheral clonal deletion. It was proposed with Rolf Zinkernagel that the individual alloresponses are the equivalent of the MHC-re-stricted T cell recognition of, and host response to, intracellular parasites and that the mechanisms of immune responsiveness, or nonresponsiveness, are governed by the migration and localization of the respective antigens. Elucidation of the mechanisms of nonresponsiveness (clonal exhaustion-deletion and immune ignorance) and their regulation removed much of the historical mystique of transplantation. The insight was then applied to improve the timing and dosage of immunosuppression of current human transplant recipients.
机译：实验模型（1953-1956）中的研究表明，在免疫学上不成熟或受辐照的动物中获得的供体特异性同种异体耐受与供体白细胞嵌合密切相关。在有免疫缺陷或细胞消融的人类受体中进行骨髓移植是一个合理的扩展（1968年），相反，在临床上（1959年），然后在明显缺乏白细胞嵌合体的情况下系统地完成了实验器官移植。因此，多年来一直认为器官和骨髓移植的成功涉及根本不同的机制。 1992年发现长期存活的器官接受者的组织或血液中有少量供体白细胞（微嵌合体），我们得出结论，器官植入是白细胞嵌合体依赖性部分耐受的一种形式。在这种最初引起争议的范例中，两种移植后的同种异体移植都是双重免疫反应的产物，其中，供体和受体免疫系统共存的相互反应导致不同的互性克隆耗竭，继而导致外周克隆缺失。与Rolf Zinkernagel一起提出，个体的过敏反应等同于MHC限制的T细胞对细胞内寄生虫的识别和宿主应答，并且免疫应答或无应答的机制受迁移和定位的支配相应抗原。对无反应性机制（克隆性精疲力竭和免疫无知）的阐明及其调节消除了许多移植的历史神秘性。然后将这一见解应用于改善当前人类移植受者免疫抑制的时机和剂量。

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