Matured Tolerogenic Dendritic Cells Effectively Inhibit Autoantigen Specific CD4+ T Cells in a Murine Arthritis Model

Abstract

Tolerogenic dendritic cells (tolDCs) are a promising treatment modality for diseases caused by a breach in immune tolerance, such as rheumatoid arthritis. Current medication for these diseases is directed toward symptom suppression but no real cure is available yet. TolDC-based therapy aims to restore immune tolerance in an antigen-specific manner. Here we used a mouse model to address two major questions: (i) is a maturation stimulus needed for tolDC function in vitro and in vivo and is maturation required for functioning in experimental arthritis and (ii) can tolDCs modulate CD4 + T cell responses? To answer these questions, we compared matured and immature dexamethasone/vitamin D3-generated tolDCs in vitro . Subsequently, we co-transferred these tolDCs with naïve or effector CD4 + T cells to study the characteristics of transferred T cells after 3 days with flow cytometry and Luminex multiplex assays. In addition, we tested the suppressive capabilities of tolDCs in an experimental arthritis model. We found that tolDCs cannot only modulate naïve CD4 + T cell responses as shown by fewer proliferated and activated CD4 + T cells in vivo , but also effector CD4 + T cells. In addition, Treg (CD4 + CD25 + FoxP3 + ) expansions were seen in the proliferating cell population in the presence of tolDCs. Furthermore, we show that administered tolDCs are capable to inhibit arthritis in the proteoglycan-induced arthritis model. However, a maturation stimulus is needed for tolDCs to manifest this tolerizing function in an inflammatory environment. Our data will be instrumental for optimization of future tolDC therapies for autoimmune diseases.

Innate immunity drives pathogenesis of rheumatoid arthritis

“…Additional research is exploring how to optimize this process. For instance, maturation of TolDC in vitro after stimulation with PAMPs (Monophosphoryl Lipid A (MPLA) or lipopolysaccharide (LPS)) leads to enhanced stability of the tolerant phenotype as well as the ability to suppress CD4 T cell responses in an experimental arthritis model [ 98 ]. Another group showed that preloading TolDC with heat shock proteins (HSP40-, HSP60- and HSP70-derived peptides) may be a promising tool to restore immune tolerance in RA patients by converting HSP-specific CD4 T cells into anti-inflammatory T Reg [ 99 ].…”

Retinoic Acid-Containing Liposomes for the Induction of Antigen-Specific Regulatory T Cells as a Treatment for Autoimmune Diseases

“…However, some specialized sub-types of immune cells, such as tolerogenic dendritic cells (tolDCs), can help maintain immune tolerance. tolDCs are derived from immature dendritic cells upon encountering a tolerogenic stimulus and an activation stimulus [11,12]. These tolDCs can induce T-cell anergy, inhibit the proliferation of effector T cells (such as the pro-inflammatory CD4+ T helper subsets Th1, Th2 and Th17) and can promote regulatory T cell (Treg) differentiation [13].…”

“…To assess the antigen specificity of these nanocarriers, a mouse model in which the T cells of the animal only express T-cell receptors specific for human proteoglycan (hPG) was used. The hPG antigen has been widely used for the induction of proteoglycan-induced arthritis (PGIA) in mice [12], which is a model for autoimmunity. This study aimed to see whether liposomes can be suitable carriers for the hPG antigen and RA and if these liposomes are as effective in vivo as using antigen-specific RA tolDCs.…”

Goals in Nutrition Science 2020-2025

“…Although it may depend on timing of exposure and dose, Vitamin D3 is also recognized as a regulator of immune function. DCs that were treated ex vivo with VitD3 adopt a tolerant phenotype and are currently studied as a possible cell therapy in autoimmune diseases such as type 1 diabetes and rheumatoid arthritis ( 34 ). Preliminary clinical trials have already shown the potential of such VitD3 produced tolerant DCs in rheumatoid arthritis ( 35 ).…”