Generation of tolerogenic dendritic cells from Fcgr2b deficient lupus-prone mice for the model of SLE therapy

Abstract

Tolerogenic dendritic cells (tolDCs) are DCs with an immunoregulatory function, which can induce regulatory T cells (Tregs) and suppress the immune response. Currently, tolDCs-based treatment has become a promising therapeutic approach for organ transplantation and autoimmune disease. FcgRIIB is an inhibitory receptor widely expressed in B cells, myeloid cells, and DCs. The ablation of FcgRIIB in the murine model shows a spontaneous development of a lupus-like disease and might affect other immune cell regulation. There was limited information on tolDC induction in FcgRIIB defective mice. Thus, in this study, we studied the generation of tolDCs from the bone marrow-derived dendritic cells (BMDCs) of�Fcgr2b-/-�mice by various tolerogenic agents. As expected, when compared with wide-type (WT) control, bone marrow-derived DCs of�Fcgr2b-/-�mice showed higher activation and pro-inflammatory cytokine�productionupon LPS stimulation when compared with wide-type (WT) control. Tolerogenic agents can partially reduce the activation and cytokine production of LPS-stimulated�Fcgr2b-/-�BMDCs. Mainly, dexamethasone-treated�Fcgr2b-/-�BMDCs exhibited a notable decrease in pro-inflammatory cytokine production and showed an increase in IL-10 production in response to LPS stimulation. Furthermore, we demonstrated that dexamethasone-conditioned�Fcgr2b-/-�tolDCs could mediate Treg expansion�ex vivo.
 
 For the�in vivo�treatment of lupus disease, dexamethasone-conditioned�Fcgr2b-/-�tolDCs were adoptively transferred to�Fcgr2b-/-�lupus-prone mice, mediated Foxp3+�Treg expansion in the spleens and suppressed anti-double strand DNA autoantibodies in the serum. In addition, to generate tolDCs�in vivo�more conveniently, dexamethasone-loaded nanoparticles (DexaNPs) designed to target DCs were subcutaneously injected into�Fcgr2b-/-�lupus-prone mice. The DexaNPs-treated mice showed a significantly enhanced expression of PD-L1 on CD11c+�DCs, increased FoxP3+�Treg numbers, and decreased serum anti-double strand DNA autoantibodies.�
 
 ������������������In conclusion, our study demonstrated that dexamethasone is the most potent drug that can induce tolerogenic DCs and lead to better clinical outcome in�Fcgr2b-/-�lupus-prone mice. This may be helpful for DC-based treatment in SLE patients but not limited to�FcgrIIb�gene polymorphism.��

Potential clinical implications of molecular mimicry‐induced autoimmunity

“…81 Dendritic cell vaccines pulsed with nucleosomal antigens are being evaluated for their ability to delete or anergize autoreactive T cell clones. 82 Drugs that target B cells reactive against disease-specific epitopes on autoantigen-antibody immune complexes are under development. 83 Identifying ways to eliminate or suppress only the subsets of B cells and T cells reactive to lupus-associated autoantigens remains a major goal.…”