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Abstract: SA-OR041

Tolerogenic Dendritic Cells Attenuate Autoimmune Vasculitis by Inducing Interleukin 10-Expressing Regulatory T Cells

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Holdsworth, Stephen R., Monash University, Clayton, Victoria, Australia
  • Kitching, A. Richard, Monash University, Clayton, Victoria, Australia
  • Odobasic, Dragana, Monash University, Clayton, Victoria, Australia
Background

Tolerogenic dendritic cells (DCs) are an attractive immunoregulatory tool for the treatment of inflammatory diseases, but their therapeutic efficacy has not been tested in autoimmune renal vasculitis. These studies sought to determine whether tolerogenic DCs can suppress experimental anti-myeloperoxidase (MPO)-associated vasculitis.

Methods

Tolerogenic DCs (BAY-DCs) were generated by culturing bone-marrow cells with an NFkB inhibitor BAY-11-7082. MPO-pulsed BAY-DCs or vehicle were administered to mice with established anti-MPO or anti-methylated bovine serum albumin (mBSA) immunity, after which immune responses and vasculitis were assessed. BAY-DCs were also transferred to DREG mice (expressing diphtheria toxin [DT] receptor under the Foxp3 promotor) in which foxp3+ regulatory T cells (Tregs) were depleted using DT. BAY-DC-induced Tregs or vehicle were administered, with or without a neutralizing anti-IL-10 receptor antibody, to mice with established anti-MPO immunity, and immune responses and vasculitis assessed.

Results

MPO-pulsed BAY-DCs attenuated established anti-MPO T cell autoimmunity (proliferation, IL-17A/IFNg production) and, after glomerulonephritis was triggered by anti-basement membrane globulin, vasculitis (glomerular injury and leukocyte accumulation), in association with an induction of IL-10-producing Tregs in lymph nodes. MPO-pulsed BAY-DCs did not affect immune responses against mBSA. They also failed to inhibit anti-MPO responses in Treg-depleted DREG mice, showing that Tregs are required for BAY-DC-mediated effects on MPO-specific immunity. Furthermore, Treg transfer/IL-10 receptor blocking experiments showed that BAY-DC-induced Tregs suppressed established anti-MPO immunity and glomerulonephritis via IL-10.

Conclusion

Tolerogenic BAY-DCs attenuate established anti-MPO autoimmunity and consequently vasculitis in an antigen-specific manner by inducing IL-10-expressing Tregs. This suggests that tolerogenic DCs may represent a novel therapeutic option for the treatment of autoimmune renal vasculitis.

Funding

  • Government Support - Non-U.S.