Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.

Keywords: Autoimmunity; Cell therapy; Dendritic cells; Immune tolerance; Immunotherapy.; Type 1 diabetes.

Figure 1

Phenotypic and functional hallmarks describing the immunobiology of the tolerogenic state of dendritic cells. Tolerogenic dendritic cells (tolDCs) display a semimature state with high antigen uptake capability and bear low/intermediate surface levels of factors essential for T cell priming. In contrast, tolDCs bear high surface levels of inhibitory markers, allowing them to inhibit autoreactive T cells. Further, tolDCs display reduced secretion of inflammatory/immunomodulatory agents accompanied by the high secretion of anti-inflammatory/suppressive modulators. All those features are essential for inducing specific tolerance for self, microbiome, and environmental derived antigens by mechanisms such as anergy, deletion, phenotype skewing, and/or expansion of regulatory T cells. Additionally, tolDCs display optimal migratory capability, which has been documented to be essential to inducing periphery tolerance in vivo. HLA: Human leukocyte antigen; IFN: Interferon; IL: Interleukin; TGF: Transforming growth factor; tolDC: Tolerogenic dendritic cells; TNF: Tumor necrosis factor; MHC: Major histocompatibility complex; PD-L1: Programmed death-ligand 1.

Figure 2

Tolerogenic dendritic cells in type 1 diabetes therapy: manufacturing and tolerogenic mechanisms described in preclinical and clinical trials. A: Tolerogenic dendritic cells (tolDCs) are alternatively generated from peripheral blood monocytes, or bone marrow precursors, which are subjected in culture with sequentially stimulation processes. Immature DC differentiation is firstly generated with growth factors, which in turn, owing to their plasticity, are subjected to tolerogenic stimulation with immunomodulatory agents to obtain tolDCs. Besides, some protocols perform the manufacturing with additional maturation stimuli, such as lipopolysaccharide or tumor necrosis factor-α previous to or after the tolerogenic stimulus to obtain stable tolDCs; B: According to their regulatory mechanism, tolDCs may induce an increased frequency of interleukin (IL)-10-expressing T cells and expand the antigen-specific regulatory T cell population, which show optimal suppressive activity; further, tolDCs reduce the activation and proliferation of autoreactive naïve and memory CD4+ and CD8+ T cells, otherwise becoming anergic. Additionally, the regulatory roles of tolDCs also reach B cells, since a high level of regulatory B cells expressing IL-10 are expanded by tolDCs, which are associated to a protective role in type 1 diabetes, being the only described immunoregulatory mechanism obtained from a clinical trial. BMDC: Bone marrow-derived dendritic cell; GM-CSF: Granulocyte-macrophage colony-stimulating factor; IFN: Interferon; PGE₂: Prostaglandin E₂; PB: Peripheral blood; IL: Interleukin; tolDC: Tolerogenic dendritic cell; TGF: Transforming growth factor; LPS: Lipopolysaccharide.