A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.
A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.
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DOI：
10.1371/journal.ppat.1000948
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发表时间：
2010-06-10
期刊：
影响因子：
6.7
通讯作者：
Pelegrin M
中科院分区：
文献类型：
--
作者：
Michaud HA;Gomard T;Gros L;Thiolon K;Nasser R;Jacquet C;Hernandez J;Piechaczyk M;Pelegrin M
抗病毒单克隆抗体（mab）是一种很有前景的治疗方法。然而，到目前为止，大多数基于单克隆抗体的免疫疗法只考虑了病毒传播的钝化，而没有考虑其他独立于病毒中和的可能的治疗效果，即调节内源性免疫反应。由于诱导长期抗病毒免疫仍然是治疗慢性感染的首要挑战，我们在这里提出了一个问题，即除了抑制病毒传播外，中和的单克隆抗体是否还能发挥免疫调节作用并产生保护性结果。为了支持这一观点，我们在这里报道，在出生后第8天感染FrCasE小鼠逆转录病毒的小鼠在4-5个月内死于白血病，并产生非保护性免疫反应，而那些迅速接受短期免疫治疗的小鼠则健康存活，并产生持久的保护性抗病毒免疫，具有强烈的体液和细胞免疫反应。有趣的是，给药的mAb通过抗体依赖性细胞毒性（ADCC）机制介导感染细胞的裂解。此外，它与感染细胞形成免疫复合物（ic），通过fc γ r介导的与树突状细胞（dc）的结合增强抗病毒CTL反应。重要的是，在单抗处理小鼠中产生的内源性抗病毒抗体也显示出相同的特性，允许在给药单抗消失后遏制病毒传播并增强记忆细胞反应。因此，我们的数据表明，中和抗病毒单克隆抗体可以作为免疫调节剂，能够在治疗结束后长时间刺激保护性免疫。它们还显示了受感染细胞/抗体复合物通过增强初级和记忆抗病毒t细胞反应在诱导和维持保护性免疫中的重要作用。他们还指出，抗体针对受感染的细胞，而不仅仅是病毒，对于引发有效、持久的抗病毒t细胞反应至关重要。在设计基于单克隆抗体的抗病毒免疫疗法时必须考虑到这一点。单克隆抗体（mab）是生物治疗蛋白中最大的一类，越来越被认为是治疗急性和慢性严重人类病毒性疾病的药物。到目前为止，大多数基于单克隆抗体的抗病毒治疗，无论是在人类还是在动物模型中，都只考虑通过直接中和病毒来减弱病毒的传播。然而，单克隆抗体也可能通过互补机制起作用，因为它们能够与免疫系统的各种成分相互作用。利用逆转录病毒诱导的白血病致死性小鼠模型，我们在这里报道，除了对病毒传播的直接作用外，对感染小鼠短时间给予中和mAb，还可以诱导强烈、持久的抗病毒免疫反应，保护小鼠在治疗结束后很长一段时间内免于疾病发展。尽管这种长期免疫的启动和维持是多因素的，但我们证明了抗病毒抗体和感染细胞之间形成的免疫复合物在此过程中起着至关重要的作用。我们的工作揭示了抗病毒中和单克隆抗体迄今未被充分认识的疫苗样作用，这将在未来治疗危及生命的病毒感染时必须加以考虑。
Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies. Monoclonal antibodies (mAbs) constitute the largest class of bio-therapeutic proteins and are increasingly being considered as drugs to fight both acute and chronic severe human viral diseases. Most antiviral mAb-based treatments conducted so far, whether in humans or in animal models, have only considered the blunting of viral propagation through direct virus neutralization. However, mAbs might also operate via complementary mechanisms owing to their ability to interact with various components of the immune system. Using a lethal mouse model of retrovirally-induced leukemia, we report here that a neutralizing mAb administered to infected mice for a short period of time can, in addition to its direct effect on viral spread, induce a strong, long-lasting antiviral immune response protecting mice from disease development long after the end of the treatment. Although the initiation and maintenance of this long-term immunity is multi-factorial, we demonstrate a crucial role for the immune complexes formed between antiviral antibodies and infected cells in this process. Our work reveals a thus far underappreciated vaccine-like effect of antiviral neutralizing mAbs, which will have to be considered for future treatment of life-threatening viral infections.
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