Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with unrestrained T-cell and B-cell activity towards self-antigens. Evidence shows that apoptotic cells (ApoCells) trigger an autoreactive response against nuclear antigens in susceptible individuals. In this study, we focus on generating and characterizing tolerogenic dendritic cells (tolDCs) to restore tolerance to ApoCells. Monocyte-derived dendritic cells (DCs) from healthy controls and patients with SLE were treated with dexamethasone and rosiglitazone to induce tolDCs. Autologous apoptotic lymphocytes generated by UV irradiation were given to tolDCs as a source of self-antigens. Lipopolysaccharide (LPS) was used as a maturation stimulus to induce the expression of co-stimulatory molecules and secretion of cytokines. TolDCs generated from patients with SLE showed a reduced expression of co-stimulatory molecules after LPS stimulation compared with mature DCs. The same phenomenon was observed in tolDCs treated with ApoCells and LPS. In addition, ApoCell-loaded tolDCs stimulated with LPS secreted lower levels of interleukin-6 (IL-6) and IL-12p70 than mature DCs without differences in IL-10 secretion. The functionality of tolDCs was assessed by their capacity to prime allogeneic T cells. TolDCs displayed suppressor properties as demonstrated by a significantly reduced capacity to induce allogeneic T-cell proliferation and activation. ApoCell-loaded tolDCs generated from SLE monocytes have a stable immature/tolerogenic phenotype that can modulate CD4 T-cell activation. These properties make them suitable for an antigen-specific immunotherapy for SLE.

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

“…In fact, DCs from SLE patients display an increased expression of maturation markers (CD86/CD80) indicating an inflammatory profile in comparison to healthy donors . Interestingly, a tolerogenic phenotype can be successfully induced in DCs from patients by pharmacological modulation with Dexa and Rgz . Tolerogenic DCs with similar properties have been loaded with autoantigens and employed in randomized clinical trials to induce tolerance in multiple sclerosis, rheumatoid arthritis and type I diabetes patients …”

“…Our results support the notion that, since different mechanisms of action are associated with each drug, the pharmacological combination could result in additive and synergistic effects. Indeed, it has been demonstrated that treatment with Dexa blocks DC maturation and it has been previously used together with Rgz, which is a known nuclear factor‐ κ B inhibitor . HO‐1 is a critical enzyme involved in renal protection and its expression is reduced in SLE patients .…”

“…Tolerogenic dendritic cells (tolDCs) are characterized by reduced expression of co‐stimulatory molecules, the up‐regulation of inhibitory molecules and increased production of anti‐inflammatory cytokines . A stable tolDC phenotype can be genetic and pharmacologically generated in vitro by treatments that block or prevent DC maturation . These in vitro treatments reduce both the production of pro‐inflammatory cytokines and the expression of co‐stimulatory molecules, leading to a lower CD4 + T‐cell priming .…”

“…1 A stable tolDC phenotype can be genetic and pharmacologically generated in vitro by treatments that block or prevent DC maturation. 1,3,4 These in vitro treatments reduce both the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules, leading to a lower CD4 + T-cell priming. 3,5 Hence, tolDCs pulsed with antigens can lead to antigen-specific T-cell hyporesponsiveness and as a result self-antigen selection is a central issue for the appropriate design of immunotherapy by using antigen-presenting cells in immune-mediated diseases.…”

“…1,3,4 These in vitro treatments reduce both the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules, leading to a lower CD4 + T-cell priming. 3,5 Hence, tolDCs pulsed with antigens can lead to antigen-specific T-cell hyporesponsiveness and as a result self-antigen selection is a central issue for the appropriate design of immunotherapy by using antigen-presenting cells in immune-mediated diseases. 1,6,7 Heme-oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism and can be induced by its natural substrate or by synthetic metalloporphyrins.…”