Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Abstract

Objective. SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties. The aim of this study was to examine the effects and explore the mechanisms of SM934 to treat autoimmune disease in lupus-prone female MRL/lpr mice.Methods. In vitro, the effects of SM934 on the activation of polyclonal CD4؉ T cells and the differentiation of naive CD4؉ T cells were examined. In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease.Results In female MRL/lpr mice, an autoimmune syndrome develops spontaneously that closely resembles human systemic lupus erythematosus (SLE) and is characterized by the production of various autoantibodies and the development of fatal glomerulonephritis (1,2).Disease begins as early as 8 weeks of age in these mice, with the presence of detectable serum autoantibodies. Pronounced lymphadenopathy is observed at 12 weeks of age, which is largely attributable to the accumulation of a population of B220ϩ and CD3ϩ cells that are mostly CD4Ϫ and CD8Ϫ (double-negative T cells). By 12-16 weeks of age, MRL/lpr mice begin to produce a variety of autoantibodies, including antidouble-stranded DNA (anti-dsDNA) antibodies. Multiple organs are affected, and a steady deterioration of renal function manifesting as severe proteinuria begins at approximately 16 weeks of age. From 16 weeks of age to 24 weeks of age, proliferative immune complex-

Qinghaosu (artemisinin): Chemistry and pharmacology

“…At last, SM 735, SM 905, SM 933, and SM 934 ( Figure 2) were selected and tested in the animal models for 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reaction, sheep red blood cell (SRBC)-induced antibody production, and experimental autoimmune encephalomyelitis (EAE). Up to date, a number of papers related their immuno-suppressive activity and possible mechanisms have been published mainly from this Institute [55][56][57][58][59][60][61][62][63][64] . The preclinical research of SM 934 is in progress.…”

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

“…Surface marker and intracellular transcription factor staining was conducted and analyzed using our previously reported methods [29] . Briefly, for surface marker and intracellular transcription factors, cells were collected and stained with FITC-, PE-, PerCP-Cy5.5-, or APC-conjugated monoclonal antibodies (mAbs) for membrane molecules or intracellular staining after being blocked with anti-mCD16/CD32 (Fc Receptor Block, eBioscience, San Diego, CA, USA).…”

“…Purification of naïve splenic CD4 + T cells CD4 + T cell purification was conducted using our previously reported methods [29] . Briefly, mAb cocktails were added to deplete CD8 + cells, B220 + cells, NK1.1 + cells, and I-A + APCs from splenocytes, and an anti-CD44 mAb (KM201) was added to obtain naïve CD4 + T cells (CD4 + CD44 -CD62L + ).…”

“…In vitro induction of T cell differentiation was conducted as described previously [29] . Briefly, naive CD4 + T cells were activated with an anti-CD3 mAb (5 µg/mL) and an anti-CD28 mAb (2 µg/mL) and were induced to differentiate.…”

“…Serum anti-dsDNA Abs were detected using our previously reported methods [29] . Briefly, 96-well high-binding microplates were coated with calf thymus dsDNA (SigmaAldrich, St Louis, MO, USA) and incubated at 4 °C overnight.…”