Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance induction in rhesus macaques
Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance induction in rhesus macaques
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DOI：
10.1016/s0198-8859(01)00235-x
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发表时间：
2001-05-01
期刊：
影响因子：
2.7
通讯作者：
Thomas, JM
中科院分区：
文献类型：
--
作者：
Hubbard, WJ;Moore, JK;Thomas, JM
利用特异性抗体减少T细胞已广泛应用于人类移植，并且是非人灵长类动物中多种耐受诱导策略的基石。我们已经建立了一个人口的长期耐受恒河猴诱导抗CD3 γ免疫毒素（IT）。这种治疗对血液和淋巴组织中的T细胞产生短暂的、特异性的和深刻的消融。在大多数情况下，IT与NF-κ B抑制剂15-脱氧精胍菌素联合使用。这个2周长的方案产生了耐受化的"机会窗口"，其中动物表现出对同种异体移植物无反应的持久静止状态，所有这些都在没有维持免疫抑制药物的情况下完成。在该诱导期期间，经治疗的免疫系统与新生儿的免疫系统有一些相似之处，因为T细胞数量异常低，并且树突状细胞的抗原呈递被其NF-κ B依赖性成熟的阻滞所阻止。此外，IL-4的产生是突出的期间和之后的耐受性诱导间隔。在这项研究中，我们专注于测量猴子重新填充T细胞的能力，特别强调记忆T细胞表型。使用三种"记忆"表型; CD3（+）CD45RO（+）、CD3（+）CRTH2（+）和CD3（+）CD4（+）CD8（+）。所有这三种表型表现出不同的恢复模式，所有这些都包括短暂的爆发在其数量在重新种群。我们还使用新描述的RTE或近期胸腺移行表型（初始CD8（+）CD103（+）T细胞）评估了T细胞消融后的胸腺活性。该标志物揭示了RTE细胞的产生，包括在移植后约6个月的超正常水平，暗示了T细胞再增殖中的胸腺功能。最后，我们测量了对一组抗原（疫苗、环境抗原和外源蛋白）的抗体应答，这表明在耐受诱导期期间或之后没有明显的免疫功能丧失。T细胞受体库表达的研究结果表明预处理库的保留，这与对测试抗原的免疫能力的快速恢复一致。综上所述，这些结果表明，虽然具有侵略性，但这种耐受性诱导方案似乎不会引起延长的免疫受损状态，如果有的话。(C)美国组织相容性和免疫遗传学学会，2001年。出版社：Elsevier Science Inc.
T-cell reduction utilizing specific antibody has been widely used in human transplantation, and is a cornerstone of several tolerance induction strategies in nonhuman primates. We have established a population of long-term tolerant rhesus macaques induced with an anti-CD3 epsilon immunotoxin (IT). This treatment effects transient, specific and profound ablation of T cells in blood and lymphoid tissues. Tn most instances the IT was used in combination with the NF-kappaB inhibitor, 15-Deoxyspergualin. This 2-week long protocol produces a "window of opportunity" for tolerization in which the animal exhibits an enduring quiescent state of unresponsiveness to the allograft, all accomplished without maintenance immunosuppressive drugs. During this induction period, the treated immune system bears some resemblance to that of the neonate, in that T cell numbers are abnormally low and antigen presentation by dendritic cells is precluded by an arrest in their NF-kappaB dependant maturation. In addition, IL-4 production is prominent during and after the tolerance induction interval. For this study we focused on measuring the monkey's ability to repopulate T cells with particular emphasis on the memory T-cell phenotype. Three "memory" phenotypes were utilized; CD3(+)CD45RO(+), CD3(+)CRTH2(+), and CD3(+)CD4(+)CD8(+). All three phenotypes exhibited different patterns of recovery, all of which included transient bursts in their numbers during repopulation. We also estimated thymic activity after T-cell ablation with the use of a newly-described RTE or recent thymic emigre phenotype (a naive CD8(+)CD103(+) T cell). This marker revealed production of RTE cells including supranormal levels at approximately 6 months post-transplant, implicating thymic function in the repopulation of T-cells. Finally, we measured antibody responses to a panel of antigens (vaccines, environmental antigen, and foreign proteins) that indicated there was no apparent loss of immunologic function during or after the tolerance induction period. Results of studies of T-cell receptor repertoire expression suggest preservation of the pretreatment repertoire, which is consistent with rapid recovery of immune competence to the test antigens. Taken together, these results suggest that while aggressive, this tolerance induction prorocol does not appear to incur a prolonged immunologically-compromised state, if at all. (C) American Society for Histocompatibility and Immunogenetics, 2001. Published by Elsevier Science Inc.