Searching for the Transcriptomic Signature of Immune Tolerance Induction—Biomarkers of Safety and Functionality for Tolerogenic Dendritic Cells and Regulatory Macrophages

Abstract

The last years have witnessed a breakthrough in the development of cell-based tolerance-inducing cell therapies for the treatment of autoimmune diseases and solid-organ transplantation. Indeed, the use of tolerogenic dendritic cells (tolDC) and regulatory macrophages (Mreg) is currently being tested in Phase I and Phase II clinical trials worldwide, with the aim of finding an effective therapy able to abrogate the inflammatory processes causing these pathologies without compromising the protective immunity of the patients. However, there exists a wide variety of different protocols to generate human tolDC and Mreg and, consequently, the characteristics of each product are heterogeneous. For this reason, the identification of biomarkers able to define their functionality (tolerogenicity) is of great relevance, on the one hand, to guarantee the safety of tolDC and Mreg before administration and, on the other hand, to compare the results between different cell products and laboratories. In this article, we perform an exhaustive review of protocols generating human tolDC and Mreg in the literature, aiming to elucidate if there are any common transcriptomic signature or potential biomarkers of tolerogenicity among the different approaches. However, and although several effectors seem to be induced in common in some of the most reported protocols to generate both tolDC or Mreg, the transcriptomic profile of these cellular products strongly varies depending on the approach used to generate them.

MAP7 and MUCL1 Are Biomarkers of Vitamin D3-Induced Tolerogenic Dendritic Cells in Multiple Sclerosis Patients

“…On the other hand, these biomarkers would enable the comparison of results with other research groups, hereby accelerating the translation of tolDC therapies into the clinic in a collaborative endeavor (6). However, although many efforts have been made in this regard, and despite several genes and molecules have been identified for a variety of tolDC protocols separately, such as IDO1, GILZ , or ANXA1 , the definition of universal biomarkers of tolerance-inducing cell products has not been possible so far, and it seems unlikely provided the wide heterogenicity of approaches being used (34). For this reason, in this study we have analyzed the transcriptomic profile of vitD3-tolDC in order to select and validate several differentially expressed genes (DEG) that may be used as transcriptomic biomarkers of these cells in a clinical trial for MS patients.…”

Generation of Powerful Human Tolerogenic Dendritic Cells by Lentiviral-Mediated IL-10 Gene Transfer

“…TolDC can be differentiated in vitro by treatment with immunosuppressive compounds, anti-inflammatory cytokines, or by genetic modifications ( 14 – 16 ). Among the different approaches used for inducing tolDC, IL-10 has been shown to potently modulate the differentiation and functions of myeloid cells ( 17 ), leading to the generation of the tolDC with the most powerful tolerogenic characteristics ( 18 ).…”

Ways Forward for Tolerance-Inducing Cellular Therapies- an AFACTT Perspective

“…Others demonstrated that C-lectin receptor CLEC-2 upregulation by DC is associated with Treg induction (51). So far, however, gene expression studies comparing different tolDC and Mreg protocols have not been able to identify common biomarkers of tolerance induction [reviewed by (52, 53) and (54)].…”