Antagonist anti-human CD40 antibody inhibits germinal center formation in cynomolgus monkeys
Antagonist anti-human CD40 antibody inhibits germinal center formation in cynomolgus monkeys
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DOI：
10.1002/eji.200424973
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发表时间：
2004-12-01
影响因子：
5.4
通讯作者：
Larman, JD
中科院分区：
文献类型：
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作者：
de Vos, AF;Melief, MJ;Larman, JD
APC表面的CD40与活化的CD4(+)T细胞表达的CD154(CD40L)之间的相互作用在生发中心(GC)的形成和功能中起着至关重要的作用，但对这些相互作用的机制认识仍然有限。功能研究大多局限于对年轻成年近亲交配的SPF啮齿动物进行实验性免疫，而在人类身上的研究则不允许在体内进行操作。因此，我们研究了CD40的功能拮抗剂是否干扰了成年食蟹猴(Macaca Fascularis)暴露于其传统圈养环境抗原下的GC的自然形成。用不同剂量的嵌合拮抗剂抗CD40单抗(Ch5D12)处理动物，在最后一次注射后1周或7周进行分析。详细的原位分析显示，与PBS或低剂量治疗相比，高剂量抗CD40治疗增加了初级卵泡与次级卵泡的比例，表明CG反应受损。这种损害是可逆的，因为恢复的动物，除了那些残留的抗CD40水平的动物，有正常化的比率。抗CD40治疗与GC中抗体产生减少和凋亡细胞数量增加有关。这些数据表明，CD40-CD154相互作用在灵长类动物对环境抗原反应的生理性GC形成中起关键作用，它们支持使用拮抗剂抗CD40的免疫治疗策略。
Interactions between CD40 on APC and CD154 (CD40L) expressed by activated CD4(+) T cells are crucially involved in formation and function of germinal centers (GC), but mechanistic insight into these interactions remains limited. Functional studies have mostly been restricted to experimental immunization of young-adult inbred SPF rodents that are often genetically manipulated, while studies in humans disallow in vivo manipulation. Therefore, we asked whether a functional antagonist of CD40 interferes with natural GC formation in adult cynomolgus monkeys (Macaca fascicularis) exposed to the environmental antigens of their conventional housing in captivity. Animals were treated with different doses of a unique chimeric antagonist anti-CD40 mAb (ch5D12) and analyzed 1 week or 7 weeks after last injection. Detailed in situ analysis showed that high-dose anti-CD40 treatment increased the ratio of primary over secondary follicles compared to PBS or low-dose treatment, indicative of impairment of the CG reaction. This impairment was reversible since recovery animals, except those with residual anti-CD40 levels, had normalized ratios. Anti-CD40 treatment was associated with decreased antibody production and increased numbers of apoptotic cells in GC. These data demonstrate that CD40-CD154 interactions are pivotal in physiological GC formation in primates responding to environmental antigens, and they support immunotherapeutic strategies using antagonist anti-CD40.