自身免疫性疾病影响大约5-10%的总人口,女性比男性受影响更大。自身免疫性或自身炎症性疾病的标准治疗一直是免疫抑制剂,直到免疫调节生物药物出现,旨在阻断炎症介质,包括促炎细胞因子。这些生物药物的前沿是TNF-α阻滞剂。这些疗法抑制TNF-α在常见自身免疫性疾病如类风湿性关节炎中的促炎作用,牛皮癣,溃疡性结肠炎,和克罗恩病。由于与广谱免疫抑制剂相比,TNF-α阻断剂在控制疾病和降低患者不良风险方面的有效性,因此迅速成为这些自身免疫性疾病的“护理标准”。然而,抗TNF-α治疗有局限性,包括已知的不良安全风险,由于耐药性而失去治疗功效,在许多自身免疫性疾病中缺乏疗效,包括多发性硬化症.下一波真正的变革性疗法应该渴望通过选择性地抑制致病性自身抗原特异性免疫应答同时保持免疫系统的其余部分完整以控制传染病和恶性肿瘤来提供治愈。在这次审查中,我们将集中在三个主要领域积极研究免疫耐受。首先,旨在强健的致耐受性疫苗,持久的自身抗原特异性免疫耐受。第二,使用Tregs的T细胞疗法(无论是多克隆,抗原特异性,或基因工程以表达嵌合抗原受体)以建立活跃的显性免疫耐受或T细胞(工程化以表达嵌合抗原受体)以删除致病性免疫细胞。第三,旨在在体内扩增免疫抑制调节性T细胞的IL-2疗法。
Autoimmune diseases affect roughly 5-10% of the total population, with women affected more than men. The standard treatment for autoimmune or autoinflammatory diseases had long been immunosuppressive agents until the advent of immunomodulatory biologic drugs, which aimed at blocking inflammatory mediators, including proinflammatory cytokines. At the frontier of these biologic drugs are TNF-α blockers. These therapies inhibit the proinflammatory action of TNF-α in common autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn\'s disease. TNF-α blockade quickly became the \"standard of care\" for these autoimmune diseases due to their effectiveness in controlling disease and decreasing patient\'s adverse risk profiles compared to broad-spectrum immunosuppressive agents. However, anti-TNF-α therapies have limitations, including known adverse safety risk, loss of therapeutic efficacy due to drug resistance, and lack of efficacy in numerous autoimmune diseases, including multiple sclerosis. The next wave of truly transformative therapeutics should aspire to provide a cure by selectively suppressing pathogenic autoantigen-specific immune responses while leaving the rest of the immune system intact to control infectious diseases and malignancies. In this review, we will focus on three main areas of active research in immune tolerance. First, tolerogenic vaccines aiming at robust, lasting autoantigen-specific immune tolerance. Second, T cell therapies using Tregs (either polyclonal, antigen-specific, or genetically engineered to express chimeric antigen receptors) to establish active dominant immune tolerance or T cells (engineered to express chimeric antigen receptors) to delete pathogenic immune cells. Third, IL-2 therapies aiming at expanding immunosuppressive regulatory T cells in vivo.