Allegheny Health Network Institute of Cellular Therapeutics, Allegheny General Hospital, Pittsburgh, PA, United States.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States.
Front Immunol. 2019 Feb 6;10:148. doi: 10.3389/fimmu.2019.00148. eCollection 2019.
Tolerogenic dendritic cells and T-regulatory cells are two immune cell populations with the potential to prevent the onset of clinical stage type 1 diabetes, and manage the beginning of underlying autoimmunity, at the time-at-onset and onwards. Initial phase I trials demonstrated that the administration of a number of these cell populations, generated from peripheral blood leukocytes, was safe. Outcomes of some of these trials also suggested some level of autoimmunity regulation, by the increase in the numbers of regulatory cells at different points in a network of immune regulation . As these cell populations come to the cusp of pivotal phase II efficacy trials, a number of questions still need to be addressed. At least one mechanism of action needs to be verified as operational, and through this mechanism biomarkers predictive of the underlying autoimmunity need to be identified. Efficacy in the regulation of the underlying autoimmunity also need to be monitored. At the same time, the absence of a common phenotype core among the different dendritic cell and T-regulatory cell populations, that have completed phase I and early phase II trials, necessitates a better understanding of what makes these cells tolerogenic, especially if a uniform phenotypic core cannot be identified. Finally, the inter-relationship of tolerogenic dendritic cells and T-regulatory cells for survival, induction, and maintenance of a tolerogenic state that manages the underlying diabetes autoimmunity, raises the possibility to co-administer, or even to serially-administer tolerogenic dendritic cells together with T-regulatory cells as a cellular co-therapy, enabling the best possible outcome. This is currently a knowledge gap that this review aims to address.
耐受性树突状细胞和调节性 T 细胞是两种具有潜在作用的免疫细胞群体，它们能够预防 1 型糖尿病临床期的发生，并在发病时及以后管理潜在自身免疫的开始。初步的 I 期临床试验表明，从外周血白细胞中生成的许多这些细胞群体的给药是安全的。这些试验的一些结果还表明，通过在免疫调节网络的不同点增加调节性细胞的数量，在某种程度上调节了自身免疫。随着这些细胞群体进入关键性 II 期疗效试验的关键时刻，仍有许多问题需要解决。至少需要验证一种作用机制是否可行，并且需要通过该机制来确定预测潜在自身免疫的生物标志物。还需要监测对潜在自身免疫的调节作用的疗效。同时，在已经完成 I 期和早期 II 期试验的不同树突状细胞和调节性 T 细胞群体中，缺乏共同的表型核心，这需要更好地了解是什么使这些细胞具有耐受性，特别是如果不能确定统一的表型核心。最后，耐受性树突状细胞和调节性 T 细胞之间的相互关系，对于生存、诱导和维持管理潜在糖尿病自身免疫的耐受性状态，提出了共同给药，甚至序贯给药耐受性树突状细胞与调节性 T 细胞作为细胞联合治疗的可能性，以实现最佳结果。这是目前知识空白，本综述旨在解决这一问题。
