Sands R Warren, Tabansky Inna, Verbeke Catia S, Keskin Derin, Michel Samuel, Stern Joel, Mooney David J
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, United States.
Wyss Institute, Boston, Massachusetts 02115, United States.
Bioconjug Chem. 2020 Dec 16;31(12):2779-2788. doi: 10.1021/acs.bioconjchem.0c00582. Epub 2020 Dec 7.
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.
免疫性疾病，包括自身免疫性疾病如多发性硬化症、移植排斥反应、过敏和哮喘，普遍存在且发病率不断上升。它们导致了显著的发病率和死亡率；然而，几乎没有治愈性疗法，现有的疗法要么缺乏效力，要么缺乏特异性。树突状细胞（DCs）是免疫系统的哨兵，连接先天性和适应性免疫系统，是免疫和耐受的关键调节因子。我们推测，可以利用DC的致耐受性潜力，通过将自身抗原原位递送至足够数量的致耐受性DCs，从而抑制致病性效应T细胞反应，来开发更具特异性和效力的免疫性疾病疗法。具体而言，我们假设与肽抗原共价偶联的类固醇地塞米松可被DCs加工，诱导致耐受性DCs，并减弱抗原特异性致病性T细胞反应。为了验证这一假设，我们通过标准固相肽合成法合成了一系列地塞米松-肽免疫缀合物。免疫缀合物的抗原部分可由DCs呈递，且该免疫缀合物在DCs中诱导出一种致耐受性表型，进而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给予免疫缀合物时，与以未偶联成分形式给予的地塞米松和肽相比，可以减轻疾病。总之，这项工作证明了免疫缀合物在诱导耐受性方面的实用性，同时为未来探索富集和靶向DCs进行致耐受性治疗方法的研究奠定了基础。
