Effect of immune tolerance induced by immature dendritic cells and CTLA4-Ig on systemic lupus erythematosus: An in�vivo study

Abstract

Abstract. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease in which tissue damage is caused by autoantibodies. The induction of specific immune tolerance, including the utilization of immune regulatory cells, may enhance the therapeutic effects of organ transplantation in patients with SLE. Furthermore, inhibiting immune responses has been reported to be an effective treatment for SLE. However, few studies have explored the association between an increased immune tolerance and a decreased immune response in SLE treatment. Dendritic cells (DCs), which are highly efficient antigen-presenting cells, are able to induce specific tolerance, while cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig) inhibits the immune response. In the present study, interleukin (IL)-10-treated DCs and CTLA4-Ig were administered to mice with SLE alone or in combination and the therapeutic effects were investigated. IL-10 was added into the culture medium of bone marrow-derived DCs to prevent them from differentiating into mature cells. Low levels of major histocompatibility complex II, cluster of differentiation (CD)40, CD80 and CD86 were detected, which indicated that the immature state of DCs was maintained. IL-10-treated DCs were subsequently injected into the caudal vein of B6.MRL-Fas lpr /J lupus mice, which are an established animal model of SLE. To amplify the tolerance effect, mice were simultaneously injected with CTLA4-Ig. Compared with the IL-10-treated DC and CTLA4-Ig groups, combined treatment with IL-10-treated DCs and CTLA4-Ig strongly induced immune tolerance in mice with SLE, as indicated by the significantly reduced levels of urine protein, anti-nuclear antibody, double-stranded DNA and IL-17A. A significant decrease in the proportion of T helper cells and an increase in the proportion of CD4 + forkhead box protein P3 + Treg cells was also observed, further confirming the induction of immune tolerance. These results suggest that combined treatment with IL-10-DCs and CTLA4-Ig may be a promising novel therapeutic strategy for the treatment of SLE.

Astaxanthin Protects Dendritic Cells from Lipopolysaccharide-Induced Immune Dysfunction

“…Moreover, DCs can easily mature into inflammatory DCs, thereby sustaining a continuous activation of the adaptive immune response at inflammation sites [ 43 ]. However, iDCs were able to induce immune tolerance, and have therefore been introduced as a therapy for systemic lupus erythematosus (SLE) [ 44 , 45 ]. In our data, astaxanthin can effectively inhibit LPS-induced phenotypic markers of DCs, including MHCII, CD40, CD80, and CD86, suggesting that astaxanthin was able to prevent the transformation from iDCs into mDCs.…”

Immunomodulation for the Treatment of Chronic Chagas Disease Cardiomyopathy: A New Approach to an Old Enemy

“…Tolerogenic dendritic cells (tDCs) have been tested as a therapeutic tool to reduce or prevent autoimmune diseases (Hermansson et al, 2011;Lee et al, 2014;Choo et al, 2017;Huang et al, 2017;Aragão-Franca et al, 2018) prevented RV dilation when applied one month after the infection.…”

Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

“…CTLA4-Ig binding to CD80/CD86 also transmitted a reverse signal to DCs, resulting in expression of IDO and induction of regulatory phenotypes in DCs [155,156]. In addition, combined treatment with IL-10-induced tolDCs and CTLA4-Ig efficiently ameliorated chronic lupus nephritis in MRL-Fas lpr mice [157]. Nonetheless, a clinical trial study of CTLA4-Ig (Abatacept) and low dose cyclophosphamide combination therapy in patient with lupus nephritis has demonstrated a drug safety but was not effective to improve the clinical outcome of renal responses which may be due to the dose inadequacy of CTLA4-Ig [158].…”