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.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in the joints which causes cartilage and bone destruction [1]
The PD-L1/CD86 ratio is considered indicative of a tolerogenic phenotype as described in multiple studies [20, 25, 26] MPLA stimulation of Tolerogenic dendritic cells (tolDCs) did not induce a proinflammatory cytokine profile as shown by the trend toward a higher IL-10 production and lower IL-12 and IL-6 (Figure 2C) which is important since cytokine signaling is one of the mechanisms of dendritic cells (DCs) to communicate
Peptide pulsed itolDCs or mtolDCs were co-cultured with naïve CD4+ T cells from a TCR transgenic mouse [27]
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in the joints which causes cartilage and bone destruction [1]. There is no cure available and treatment is directed toward mitigating symptoms (non-steroidal anti-inflammatory drugs) or dampening the immune response (disease modifying anti-rheumatic drugs) [2, 3]. These therapies mtolDCs Inhibit Autoreactive T Cells suppress the immune system non- and are not completely effective and have side effects. Regulatory T cells (Tregs), mainly CD4+ T cells, are able to restore immune tolerance by suppressing effector cells in an antigen-specific manner. Antigen specific Tregs are able to suppress this excessive inflammation by suppressing the immune cells that cause the pathological autoimmune response while leaving protective immunity intact
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