Induced immune tolerance of autoantigen loaded immature dendritic cells in homogenic lupus mice

Xie, Jinmin; Lin, Yuanzhen; Wang, K.; Biao, Che; Li, J.Q.; Xu, Xiaofeng; Han, Fei; Liang, Dan

doi:10.4238/2014.february.27.10

Cited by 6 publications

(4 citation statements)

References 19 publications

(16 reference statements)

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“…SLE is a complex autoimmune disease in which DCs play critical roles in the disease pathogenesis. 7 , 39 Therefore, targeting DC activation and function could have therapeutic potential in the treatment of SLE. Standard treatments involve non-steroidal anti-inflammatory drugs (NSAIDs) and antimalarial and immunosuppressive agents, which are nonspecific and have severe side effects.…”

Section: Discussionmentioning

confidence: 99%

Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

Elshikha

Yuan

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by high levels of pathogenic autoantibodies and tissue damage. Multiple studies showed that dendritic cell (DC) activation plays a critical role in SLE pathogenesis. Human alpha 1 antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory and cytoprotective properties. In this study, we first examined the effects of hAAT on the functions of DCs from lupus-prone mice, and we showed that hAAT treatment efficiently inhibited CpG- (TLR9 agonist) induced activation of bone marrow-derived conventional and plasmacytoid DCs as well as the production of pro-inflammatory cytokines. The hAAT treatment also attenuated DC help for B cell proliferation and immunoglobulin M (IgM) production. We next tested the protective effect of hAAT protein and gene therapy using recombinant adeno-associated virus 8 (rAAV8-CB-hAAT) in a spontaneous lupus mouse model, and we showed that both treatments decreased autoantibody levels. Importantly, rAAV8-CB-hAAT did not induce an immune response to its transgene product (hAAT), but it showed more pronounced therapeutic effects in reducing urine protein levels and extending the lifespan of these mice. These results indicate that AAT has therapeutic potential in the treatment of SLE in humans.

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Section: Discussionmentioning

confidence: 99%

Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

Elshikha

Yuan

et al. 2018

Molecular Therapy - Methods & Clinical Development

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“…Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by dysregulation in multiple arms of the immune system and the production of hallmark autoantibodies [ 1 ]. Increasing evidence indicates that dendritic cells (DCs) play critical roles in the development of SLE [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. DCs are activated by immune complexes and act as a bridge between the innate and adaptive immune responses [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus

Elshikha

Chen

et al. 2016

PLoS ONE

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Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.

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“…Dendritic cells (DCs) are important regulatory cells in the immune system and play a critical role in induction of immune tolerance and autoimmunity [7-9]. There are at least four subpopulations of DCs, including conventional DCs (cDCs), plasmacytoid DCs (pDCs), monocyte-derived DCs and myeloid DCs (mDCs) [10-12].…”

Section: Introductionmentioning

confidence: 99%

Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4+ effector memory T cells

2015

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CD4+ memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4+ memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4+ effector memory T cells in vitro and in vivo. Simultaneously, i.v. transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4+ T cells, not central memory CD4+ T cells, which play a major role in chronic inflammatory responses in mice with EAE. I.V. transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4+ effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo

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Induced immune tolerance of autoantigen loaded immature dendritic cells in homogenic lupus mice

Cited by 6 publications

References 19 publications

Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus

Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4+ effector memory T cells

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