Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance
Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance
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DOI：
10.1073/pnas.1408686111
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发表时间：
2015-01-13
影响因子：
11.1
通讯作者：
Kishimoto, Takashi Kei
中科院分区：
文献类型：
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作者：
Maldonado, Roberto A.;LaMothe, Robert A.;Kishimoto, Takashi Kei
目前控制病理性或不想要的免疫反应的治疗通常使用广泛的免疫抑制药物。诱导控制细胞和体液免疫反应的抗原特异性免疫耐受的新方法是可取的。在这里，我们描述了使用合成的、可生物降解的纳米颗粒携带蛋白质或肽抗原和耐受原性免疫调节剂雷帕霉素，以诱导持久的和抗原特异性免疫耐受，甚至在强效toll样受体激动剂存在的情况下。在血友病A小鼠中，甚至在先前对抗原敏感的动物中，使用耐受性纳米颗粒治疗可抑制CD4+和CD8+ t细胞活化，增加调节性细胞，持久的b细胞耐受性，抵抗多种免疫原性挑战，抑制抗原特异性超敏反应、实验性自身免疫性脑脊髓炎复发和针对凝血因子VIII的抗体反应。只有包封的雷帕霉素能诱导免疫耐受，而非游离的雷帕霉素。耐受性纳米颗粒治疗代表了治疗过敏、自身免疫性疾病和预防抗药物抗体对抗生物疗法的潜在新方法。
Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.