Kruglov A A, Nedospasov S A
Institut der Leibniz-Gemeinschaft, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Chariteplatz 1, 10117, Berlin, Deutschland.
Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, 119991, Moskau, Russland.
Z Rheumatol. 2017 Mar;76(2):163-165. doi: 10.1007/s00393-016-0244-6.
Currently, treatment of autoimmune diseases is based on manipulation of general control mechanisms, including those mediated by immunoregulatory cytokines. This approach is non-curative and may cause unwanted side effects due to numerous beneficial and non-redundant functions of a particular cytokine.
Techniques of reverse genetics, such as conditional gene targeting, were employed to uncover the contributions of two proinflammatory and immunomodulatory cytokines, tumour necrosis factor (TNF) and interleukin 6 (IL-6), in various disease states.
Several non-redundant functions of TNF from distinct cellular sources were identified. TNF from myeloid cells is pathogenic in several autoimmune diseases, whereas TNF produced by T cells showed non-redundant protective functions in experimental arthritis and in a Mycobacterium tuberculosis infection model. To test the idea of selective pharmacological inhibition of "bad" TNF produced by myeloid cells while sparing "good" TNF produced by T lymphocytes, a myeloid-specific TNF inhibitor (MYSTI) was designed - a recombinant mini-antibody with dual specificity that can bind to the surface molecule F4/80 on myeloid cells and to TNF. In vitro experiments confirmed retention of TNF on the surface of TNF-producing cells and in vivo experiments indicated that MYSTI can protect mice from lethal TNF-mediated hepatotoxicity. MYSTI is also effective in experimental arthritis.
The proposed therapeutic strategy may be more effective than systemic anti-cytokine therapy in several human autoimmune diseases, as it would preserve the potentially beneficial effects of the same cytokine produced by other cell types. Such bispecific biological agents may become interesting tools for experimental studies and, eventually, drug development.
目前，自身免疫性疾病的治疗基于对一般调控机制的操控，包括那些由免疫调节细胞因子介导的机制。这种方法无法治愈疾病，并且由于特定细胞因子具有众多有益且非冗余的功能，可能会导致不良副作用。
采用反向遗传学技术，如条件性基因靶向，来揭示两种促炎和免疫调节细胞因子，即肿瘤坏死因子（TNF）和白细胞介素6（IL-6），在各种疾病状态中的作用。
确定了来自不同细胞来源的TNF的几种非冗余功能。髓系细胞产生的TNF在几种自身免疫性疾病中具有致病性，而T细胞产生的TNF在实验性关节炎和结核分枝杆菌感染模型中显示出非冗余的保护功能。为了测试选择性药理抑制髓系细胞产生的“坏”TNF同时保留T淋巴细胞产生的“好”TNF这一想法，设计了一种髓系特异性TNF抑制剂（MYSTI）——一种具有双重特异性的重组微型抗体，它可以与髓系细胞表面分子F4/80以及TNF结合。体外实验证实TNF保留在产生TNF的细胞表面，体内实验表明MYSTI可以保护小鼠免受致死性TNF介导的肝毒性。MYSTI在实验性关节炎中也有效。
所提出的治疗策略在几种人类自身免疫性疾病中可能比全身抗细胞因子治疗更有效，因为它将保留其他细胞类型产生的相同细胞因子的潜在有益作用。这种双特异性生物制剂可能成为实验研究以及最终药物开发的有趣工具。
