Functional topography of discrete domains of human CD38
Functional topography of discrete domains of human CD38
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DOI：
10.1034/j.1399-0039.2000.560608.x
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发表时间：
2000-12-01
期刊：
影响因子：
--
通讯作者：
Malavasi, F
中科院分区：
文献类型：
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作者：
Ausiello, CM;Urbani, F;Malavasi, F
除了作为外NAD（+）糖水解酶（NADase）的催化活性外，CD 38还显示出转导生物相关信号的能力。事实上，通过激动性单克隆抗体（mAb）连接外周血单核细胞（PBMC）上的CD 38之后是大量调节性细胞因子的转录和分泌。目前的工作解决的问题，导致钙（Ca 2+）动员，淋巴细胞增殖和细胞因子的释放的信号是否依赖于由单个单克隆抗体识别的表位。竞争结合分析鉴定了两个mAb家族，即一侧的IB 4、IB 6和AT 2，另一侧的OKT 10、SUN-4 B7和AT 1。每个mAb家族结合完全或部分共同的表位。然而. CD 38分子的功能活性不能简单地归因于所结合的表位：例如，结合不同表位的IB 4和OKT 10单克隆抗体在诱导PBMC增殖和干扰素（IFN）-γ分泌中作为激动性单克隆抗体发挥作用。SUN-4 B7产生中等效果，而IB 6、ATI和AT 2 mAb完全无效。由IB 4和OKT 10 mAb介导的作用在80%的研究的健康个体中明显，而SUN-4 B7 mAb的作用仅在25%的供体中起作用。在分析的所有个体中观察到白细胞介素（IL）-6分泌，而不考虑触发的表位和用于连接CD 38分子的mAb。此外，IB 4是唯一能够诱导显著的细胞内Ca 2+通量的mAb。
In addition to its catalytic activities as ecto-NAD(+) glycohydrolase (NADase), CD38 displays the ability to transduce signals of biological relevance. Indeed, ligation of CD38 on peripheral blood mononuclear cells (PBMC) by agonistic monoclonal antibodies (mAbs) is followed by the transcription and secretion of a vast array of regulatory cytokines. The present work addresses the issue of whether the signals leading to calcium (Ca2+) mobilization, lymphocyte proliferation and release of cytokines is dependent on the epitopes recognized by the individual mAbs. Competition binding analysis identifies two families of mAbs, namely IB4, IB6 and AT2 on one side and OKT10, SUN-4B7 and AT1 on the other. Each mAb family binds epitopes that are completely or partially common. However. the functional activities of the CD38 molecule can not be simply attributed to the epitopes engaged: for instance, IB4 and OKT10 mAbs, which bind different epitopes, perform as agonistic mAbs in inducing PBMC proliferation and interferon (IFN)-gamma secretion. SUN-4B7 yields intermediate effects, whereas IB6, ATI and AT2 mAbs are totally ineffective. The effects mediated by IB4 and OKT10 mAbs are apparent in 80% of the healthy individuals studied, whereas the effects of SUN-4B7 mAb operate only in 25% of the donors. Interleukin (IL)-6 secretion was observed in all individuals analyzed, irrespective of the epitopes triggered and of mAbs used to ligate the CD38 molecule. In addition, IB4 is the only mAb able to induce significant intracellular Ca2+ fluxes.