Phillips Brett Eugene, Garciafigueroa Yesica, Trucco Massimo, Giannoukakis Nick
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. 2017 Oct 12;8:1279. doi: 10.3389/fimmu.2017.01279. eCollection 2017.
Tolerogenic dendritic cell (tDC)-based clinical trials for the treatment of autoimmune diseases are now a reality. Clinical trials are currently exploring the effectiveness of tDC to treat autoimmune diseases of type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis (MS), and Crohn's disease. This review will address tDC employed in current clinical trials, focusing on cell characteristics, mechanisms of action, and clinical findings. To date, the publicly reported human trials using tDC indicate that regulatory lymphocytes (largely Foxp3+ T-regulatory cell and, in one trial, B-regulatory cells) are, for the most part, increased in frequency in the circulation. Other than this observation, there are significant differences in the major phenotypes of the tDC. These differences may affect the outcome in efficacy of recently launched and impending phase II trials. Recent efforts to establish a catalog listing where tDC converge and diverge in phenotype and functional outcome are an important first step toward understanding core mechanisms of action and critical "musts" for tDC to be therapeutically successful. In our view, the most critical parameter to efficacy is stability of the tolerogenic activity over phenotype. As such, methods that generate tDC that can induce and stably maintain immune hyporesponsiveness to allo- or disease-specific autoantigens in the presence of powerful pro-inflammatory signals are those that will fare better in primary endpoints in phase II clinical trials (e.g., disease improvement, preservation of autoimmunity-targeted tissue, allograft survival). We propose that pre-treatment phenotypes of tDC in the absence of functional stability are of secondary value especially as such phenotypes can dramatically change following administration, especially under dynamic changes in the inflammatory state of the patient. Furthermore, understanding the outcomes of different methods of cell delivery and sites of delivery on functional outcomes, as well as quality control variability in the functional outcomes resulting from the various approaches of generating tDC for clinical use, will inform more standardized generation methods. An understanding of these similarities and differences, with a reference point the large number of naturally occurring tDC populations with different immune profiles described in the literature, could explain some of the expected and unanticipated outcomes of emerging tDC clinical trials.
基于耐受性树突状细胞（tDC）治疗自身免疫性疾病的临床试验如今已成为现实。目前，临床试验正在探索tDC治疗1型糖尿病、类风湿性关节炎、多发性硬化症（MS）和克罗恩病等自身免疫性疾病的有效性。本综述将阐述当前临床试验中所应用的tDC，重点关注细胞特征、作用机制和临床研究结果。迄今为止，公开报道的使用tDC的人体试验表明，调节性淋巴细胞（主要是Foxp3 + T调节细胞，在一项试验中还包括B调节细胞）在循环中的频率大多有所增加。除此之外，tDC的主要表型存在显著差异。这些差异可能会影响近期启动及即将开展的II期试验的疗效结果。近期致力于建立一个目录清单，列出tDC在表型和功能结果方面的异同，这是朝着理解其核心作用机制以及tDC治疗成功的关键“必要条件”迈出的重要第一步。我们认为，对疗效而言，最关键的参数是耐受性活性相对于表型的稳定性。因此，那些能够在存在强大促炎信号的情况下诱导并稳定维持对同种异体或疾病特异性自身抗原的免疫低反应性的tDC生成方法，将在II期临床试验的主要终点（如疾病改善、自身免疫靶组织的保存、同种异体移植存活）中表现得更好。我们提出，缺乏功能稳定性的tDC预处理表型的价值次之，尤其是因为这些表型在给药后可能会发生显著变化，特别是在患者炎症状态的动态变化情况下。此外，了解不同细胞递送方法和递送部位对功能结果的影响，以及因用于临床的tDC生成的各种方法导致的功能结果中的质量控制变异性，将有助于形成更标准化的生成方法。以文献中描述的大量具有不同免疫特征的天然存在的tDC群体为参考点，理解这些异同，可以解释新兴tDC临床试验中一些预期和意外的结果。
