Cytokine Receptor Laboratory, VIB Medical Biotechnology Center, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
Orionis Biosciences, 9052, Ghent, Belgium.
Sci Rep. 2021 Nov 3;11(1):21575. doi: 10.1038/s41598-021-00891-6.
Type I Interferon (IFN) was the very first drug approved for the treatment of Multiple Sclerosis (MS), and is still frequently used as a first line therapy. However, systemic IFN also causes considerable side effects, affecting therapy adherence and dose escalation. In addition, the mechanism of action of IFN in MS is multifactorial and still not completely understood. Using AcTaferons (Activity-on-Target IFNs, AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting, we have previously demonstrated that specific targeting of IFN activity to dendritic cells (DCs) can protect against experimental autoimmune encephalitis (EAE), inducing in vivo tolerogenic protective effects, evidenced by increased indoleamine-2,3-dioxygenase (IDO) and transforming growth factor β (TGFβ) release by plasmacytoid (p) DCs and improved immunosuppressive capacity of regulatory T and B cells. We here report that targeting type I IFN activity specifically towards B cells also provides strong protection against EAE, and that targeting pDCs using SiglecH-AFN can significantly add to this protective effect. The superior protection achieved by simultaneous targeting of both B lymphocytes and pDCs correlated with improved IL-10 responses in B cells and conventional cDCs, and with a previously unseen very robust IDO response in several cells, including all B and T lymphocytes, cDC1 and cDC2.
I 型干扰素（IFN）是最早被批准用于治疗多发性硬化症（MS）的药物，目前仍常被用作一线治疗药物。然而，全身性 IFN 也会引起相当多的副作用，影响治疗的依从性和剂量升级。此外，IFN 在 MS 中的作用机制是多因素的，仍不完全清楚。我们之前使用 AcTaferons（靶向作用 IFNs，AFNs），即基于 IFN 的优化免疫细胞因子，实现了细胞特异性靶向，已经证明针对树突状细胞（DCs）的 IFN 活性的特异性靶向可以预防实验性自身免疫性脑脊髓炎（EAE），诱导体内耐受保护作用，表现为浆细胞样（p）DCs 中吲哚胺 2,3-双加氧酶（IDO）和转化生长因子β（TGFβ）释放增加，以及调节性 T 和 B 细胞的免疫抑制能力增强。我们在此报告称，特异性针对 B 细胞的 I 型 IFN 活性也可以提供针对 EAE 的强大保护作用，并且使用 SiglecH-AFN 靶向 pDCs 可以显著增强这种保护作用。同时靶向 B 淋巴细胞和 pDCs 所实现的优越保护作用与 B 细胞和常规 cDCs 中 IL-10 反应的改善相关，并且在包括所有 B 和 T 淋巴细胞、cDC1 和 cDC2 在内的几种细胞中出现了以前未见的非常强烈的 IDO 反应。
