Zabludowicz center for autoimmune diseases, Sheba Medical Center, Ramat Gan. Israel; Reichman University, Herzelia, Israel.
Zabludowicz center for autoimmune diseases, Sheba Medical Center, Ramat Gan. Israel; Reichman University, Herzelia, Israel.
Autoimmun Rev. 2024 Oct;23(10):103601. doi: 10.1016/j.autrev.2024.103601. Epub 2024 Aug 17.
Autoimmune diseases (AIDs) affect 5 to 10% of the population. There are more than ∼100 different autoimmune diseases. The AIDs are one of the top 10 causes of death in women under 65; 2nd highest cause of chronic illness; top cause of morbidity in women in the US. The NIH estimates annual direct healthcare costs for autoimmune diseases about $100 billion, in comparison, with cancers investment of $57 billion, heart and stroke cost of $200 billion. The current treatments for autoimmune diseases encompasses: steroids, chemotherapy, immunosuppressants, biological drugs, disease specific drugs (like acethylcholine-estherase for myasthenia gravis). The treatments for autooimmune diseases supress the patient immune network, which leads the patients to be more susceptible to infections. Hence, there is a need to develop immunomodulatory small molecules with minimal side effects to treat autoimmune diseases. The helminths developed secreting compounds which modulate the human defense pathways in order to develop tolerance and survive in the host environment. We have imitated the immunomodulatory activity of the helminth by using a derivative of the helminth secretory molecule. A bi-functional small molecule -tuftsin (T)-phosphorylcholine (PC), coined as TPC, was constructed. This chimeric molecule showed its immunomodulatory activity in 4 murine models of autoimmune diseases, attenuating the clinical score and the inflammatory response by immunomodutating the host immune system. Ex-vivo in human peripheral blood mononuclear cells (PBMCs) and biopsies originated from arteries of patients with giant cell arteritis. This paper decipher the mode of action of TPC immunomodulatory activity. Our data propose the potential for this small molecule to be a novel therapy for patients with autoimmune diseases.
自身免疫性疾病（AIDs）影响了 5%至 10%的人口。有超过∼100 种不同的自身免疫性疾病。AIDs 是导致 65 岁以下女性死亡的前 10 大原因之一；是第二大导致慢性疾病的原因；是美国女性发病率最高的原因。NIH 估计自身免疫性疾病的年直接医疗费用约为 1000 亿美元，相比之下，癌症投资为 570 亿美元，心脏病和中风费用为 2000 亿美元。目前治疗自身免疫性疾病的方法包括：类固醇、化疗、免疫抑制剂、生物药物、针对特定疾病的药物（如乙酰胆碱酯酶用于重症肌无力）。这些治疗方法抑制了患者的免疫网络，使患者更容易感染。因此，需要开发具有最小副作用的免疫调节小分子来治疗自身免疫性疾病。寄生虫为了在宿主环境中生存和发展耐受，会产生调节人类防御途径的化合物。我们通过使用寄生虫分泌分子的衍生物来模拟寄生虫的免疫调节活性。一种双功能小分子——tuftsin（T）-磷酸胆碱（PC），被命名为 TPC，被构建出来。这种嵌合分子在 4 种自身免疫性疾病的小鼠模型中表现出免疫调节活性，通过调节宿主免疫系统来减轻临床评分和炎症反应。在人类外周血单核细胞（PBMCs）和来源于巨细胞性动脉炎患者动脉的活检中进行了体外实验。本文揭示了 TPC 免疫调节活性的作用机制。我们的数据表明，这种小分子有可能成为治疗自身免疫性疾病患者的新疗法。
