Steroid-Peptide Immunoconjugates for Attenuating T Cell Responses in an Experimental Autoimmune Encephalomyelitis Murine Model of Multiple Sclerosis.
Steroid-Peptide Immunoconjugates for Attenuating T Cell Responses in an Experimental Autoimmune Encephalomyelitis Murine Model of Multiple Sclerosis.
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用于减弱多发性硬化症实验性自身免疫性脑脊髓炎小鼠模型中 T 细胞反应的类固醇肽免疫缀合物。
DOI：
10.1021/acs.bioconjchem.0c00582
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发表时间：
2020
影响因子：
4.7
通讯作者：
Mooney,DavidJ
中科院分区：
文献类型：
--
作者：
Sands,RWarren;Tabansky,Inna;Verbeke,CatiaS;Keskin,Derin;Michel,Samuel;Stern,Joel;Mooney,DavidJ
免疫疾病，包括多发性硬化症、移植物排斥、过敏和哮喘等自身免疫性疾病，非常普遍，而且患病率不断增加。它们导致显着的发病率和死亡率；然而，目前几乎没有治愈性疗法，而且现有疗法要么缺乏效力，要么缺乏特异性。树突状细胞 (DC) 是免疫系统的哨兵，连接先天性免疫系统和适应性免疫系统，是免疫和耐受性的关键调节因子。我们假设，可以利用 DC 的致耐受潜力，通过将自身抗原原位递送到足够数量的致耐受 DC，从而抑制致病性效应 T 细胞反应，从而开发针对免疫性疾病的更特异和有效的疗法。具体来说，我们假设与肽抗原共价偶联的类固醇地塞米松可以被 DC 加工，诱导耐受性 DC，并减弱抗原特异性致病性 T 细胞反应。为了检验这一假设，我们通过标准固相肽合成合成了一系列地塞米松-肽免疫缀合物。免疫偶联物的抗原部分可以由 DC 呈递，并且免疫偶联物在 DC 中诱导耐受表型，然后在体外抑制抗原特异性 T 细胞增殖。当在多发性硬化症的小鼠实验性自身免疫性脑脊髓炎模型中预防性施用免疫缀合物时，与作为非偶联组分递送的地塞米松和肽相比，疾病得到减轻。总之，这项工作证明了免疫缀合物在诱导耐受方面的效用，同时为未来研究探索富集和靶向树突状细胞以进行耐受性治疗的方法奠定了基础。
Diseases of immunity, including autoimmune diseases such as multiple sclerosis, transplantation graft rejection, allergy, and asthma, are prevalent and increasing in prevalence. They contribute to significant morbidity and mortality; however, few if any curative therapies exist, and those that are available lack either potency or specificity. Dendritic cells (DCs) are sentinels of the immune system that connect the innate and adaptive immune system and are critical regulators of both immunity and tolerance. We posited that the tolerogenic potential of DC could be harnessed to develop more specific and potent therapies for diseases of immunity by delivering autoantigen to a sufficient number of tolerogenic DCs in situ that could then inhibit pathogenic effector T cell responses. Specifically, we hypothesized that the steroid dexamethasone covalently coupled to a peptide antigen could be processed by DCs, induce tolerogenic DCs, and attenuate antigen-specific pathogenic T cell responses. To test this hypothesis, we synthesized a series of dexamethasone–peptide immunoconjugates by standard solid-phase peptide synthesis. The antigenic portion of the immunoconjugate could be presented by DCs, and the immunoconjugate induced a tolerogenic phenotype in DCs that then inhibited antigen-specific T cell proliferation in vitro. When the immunoconjugate was administered prophylactically in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis, disease was attenuated compared to dexamethasone and peptide delivered as uncoupled components. Together, this work demonstrates the utility of immunoconjugates for inducing tolerance while establishing the foundation for future studies exploring methods to enrich and target DCs for tolerogenic therapies.