Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source
Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source
复制标题
DOI：
10.1073/pnas.1520175113
复制
发表时间：
2016-03-15
影响因子：
11.1
通讯作者：
Nedospasov, Sergei A.
中科院分区：
文献类型：
--
作者：
Efimov, Grigory A.;Kruglov, Andrei A.;Nedospasov, Sergei A.
肿瘤坏死因子的过度表达参与了多种自身免疫性疾病的发病机制，是抗肿瘤坏死因子治疗取得显著成功的原因。肿瘤坏死因子由多种类型的细胞产生，它既可以起到有益的作用，也可以起到有害的作用。特别是，在自身免疫中，致病的肿瘤坏死因子可能来自有限的细胞来源。在这项研究中，我们评估了体内细胞类型限制性肿瘤坏死因子抑制的可行性。为此，我们设计了髓系特异性肿瘤坏死因子抑制物(Mysti)，这是一种与髓系细胞表面F4/80分子和人肿瘤坏死因子(HTNF)结合的重组双特异性抗体。在肿瘤坏死因子人源化小鼠的巨噬细胞培养中，Mysti可以捕获分泌的hTNF，限制了其生物利用度。此外，根据对肿瘤坏死因子人源化小鼠的评估，Mysti在保护小鼠免受内毒素/D-氨基半乳糖诱导的致命肝毒性方面优于其他类似的全身性肿瘤坏死因子抑制剂。我们的结果提示了一种新的、更特异的方法来抑制主要由巨噬细胞来源的肿瘤坏死因子驱动的病理过程中的肿瘤坏死因子。
Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)-a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.