A recombinant heavy chain antibody approach blocks ART2 mediated deletion of an iNKT cell population that upon activation inhibits autoimmune diabetes
A recombinant heavy chain antibody approach blocks ART2 mediated deletion of an iNKT cell population that upon activation inhibits autoimmune diabetes
复制标题
DOI：
10.1016/j.jaut.2009.08.012
复制
发表时间：
2010-03-01
影响因子：
12.8
通讯作者：
Serreze, David V.
中科院分区：
文献类型：
--
作者：
Scheuplein, Felix;Rissiek, Bjoern;Serreze, David V.
胞外酶ADP-核糖基转移酶2.2（ART2.2）可以特异性地删除各种T细胞亚群。根据所涉及的凋亡T细胞亚群，增强的ART2.2活性可能导致免疫抑制或自身免疫。通常代表NAD底物的反调节竞争剂的CD 38胞外酶的活性降低代表了增强ART 2.2活性的一种机制。因此，需要开发一种在体内有效阻断ART2.2活性的试剂。虽然美洲驼衍生的重组s+16单结构域抗体克服了特异性靶向ART2.2催化位点的困难，但由于体内持久性短，该试剂的潜在治疗用途受到限制。因此，我们测试了掺入鼠IgG 1 Fc尾（s+16 Fc）的s+16的修饰形式是否介导了ART 2.2的长期有效体内抑制。我们推断，测试s+16 Fc试剂的理想模型是NOD小鼠，其中CD 38的遗传消融导致ART 2.2介导的免疫调节性自然杀伤T-（NKT）细胞数量减少至当被超级激动剂α-半乳糖神经酰胺（α-GalCer）激活时不再允许它们引起抑制自身免疫性1型糖尿病（T1 D）发展的作用的水平。用s+16 Fc处理有效地介导了NOD.CD38（null）小鼠中ART2.2活性的长期体内抑制，使其iNKT细胞数量恢复到在α-GalCer活化后能够抑制T1 D发展的水平。(C)2009爱思唯尔有限公司保留所有权利。
The ectoenzyme ADP-ribosyltransferase 2.2 (ART2.2) can apoptotically delete various T-cell subsets. Depending on the involved apoptotic T-cell subset, enhanced ART2.2 activity could result in immunosuppression or autoimmunity. Diminished activity of the CD38 ectoenzyme that normally represents a counter-regulatory competitor for the NAD substrate represents one mechanism enhancing ART2.2 activity. Hence, it would be desirable to develop an agent that efficiently blocks ART2.2 activity in vivo. While the llama derived recombinant s+16 single domain antibody overcame the difficulty of specifically targeting the ART2.2 catalytic site potential therapeutic use of this reagent is limited due to short in vivo persistence. Thus, we tested if a modified version of s+16 incorporating the murine IgG1 Fc tail (s+16Fc) mediated long-term efficient in vivo suppression of ART2.2. We reasoned an ideal model to test the s+16Fc reagent were NOD mice in which genetic ablation of CD38 results in an ART2.2 mediated reduction in already sub-normal numbers of immunoregulatory natural killer T-(NKT) cells to a level that no longer allows them when activated by the super-agonist alpha-galactosylceramide (alpha-GalCer) to elicit effects inhibiting autoimmune type 1 diabetes (T1D) development. Treatment with s+16Fc efficiently mediated long-term in vivo inhibition of ART2.2 activity in NOD.CD38(null) mice, restoring their iNKT cell numbers to levels that upon alpha-GalCer activation were capable of inhibiting T1D development. (C) 2009 Elsevier Ltd. All rights reserved.