Transplantation of Aire-overexpressing bone marrow-derived dendritic cells delays the onset of type 1 diabetes

• Published in: International immunopharmacology 2017-08, Vol.49, p.13-20
• Main Authors: Li, Dongbei, Zhao, Bo, Luo, Yadong, Limbara, Steven, Zhao, Bingjie, Zou, Xueyang, Yang, Wei, Li, Yi
• Format: Article
• Language: English
• Subjects: Aire; AIRE Protein; Anergy; Animals; Antigens; Apoptosis; Autoimmune diseases; BMDCs; Bone marrow; Bone Marrow Cells - physiology; Bone Marrow Transplantation; CD4 antigen; Cell Differentiation; Cells, Cultured; Clonal Anergy; Clonal deletion; Dendritic cells; Dendritic Cells - physiology; Dendritic Cells - transplantation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Ectopic expression; Epithelial cells; Epithelial Cells - immunology; Helper cells; Humans; Immune Tolerance; Immunological tolerance; Immunotherapy; Immunotherapy - methods; Infiltration; Inflammation; Insulin; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Studies; STZ; T-Lymphocytes, Regulatory - immunology; T1D; Th1 Cells - immunology; Th17 Cells - immunology; Thymus; Thymus Gland - immunology; Transcription Factors - genetics; Transcription Factors - metabolism; Transplantation; Transplants & implants
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2017.05.023

Autoimmune regulator (Aire) plays an indispensable role in maintaining central immune tolerance by promoting the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), which lead to the deletion of autoreactive T cells or the induction of Tregs and consequently prevent autoimmune disease development. Curing autoimmune diseases has always been a challenge. DC-based immunotherapy represents a new and effective method to establish tolerance. We attempted to transplant Aire-overexpressing bone marrow-derived DCs (Aire-BMDCs) to treat type 1 diabetes (T1D) and to explore a new strategy for autoimmune disease treatment. We observed that the onset of T1D in recipient mice was delayed; insulin autoantibody (IAA) production was significantly decreased; the structure of islets was protected; and the degree of inflammatory infiltration was lower. Furthermore, we found that Aire-BMDCs can promote apoptosis and induce autoreactive CD4+ T cell clonal anergy, inhibit Th1 and Th17 production, and induce Treg production. These results suggest that transplantation of Aire-BMDCs will be a manipulation and effective method for preventing or treating T1D. [Display omitted] •We explored a new strategy for type 1 diabetes treatment by Aire gene transduction and bone marrow dendritic cells transplantation.•Aire-overexpressing BMDCs regulate the expression of many TRAs and provide advantages to solve the epitope spreading of self-antigens during the course of autoimmune disease.•Aire-overexpressing BMDCs can remove antigen-specific T cells to a great extent and induce Treg, resulting in immune tolerance.•This therapy targeting self-antigens specifically does not affect the normal body response to pathogens.