On the edge of autoimmunity: T-cell stimulation by steady-state dendritic cells prevents autoimmune diabetes.
Targeting of antigens to immature dendritic cells has been shown to result in antigen-specific T-cell tolerance in vivo. In the INS-HA/TCR-HA transgenic mouse model for type 1 diabetes, we tested the potential of the dendritic cell-specific monoclonal antibody DEC-205 conjugated to the hemagglutinin (HA) antigen (DEC-HA) to prevent disease onset. Whereas untreated INS-HA/TCR-HA mice all develop insulitis, and approximately 40% of these mice become diabetic, repeated injection of newborn mice with DEC-HA protected almost all mice from disease development. Histological examination of the pancreata revealed significant reduction of peri-islet infiltrations in DEC-HA-treated mice, and the islet structure remained intact. Moreover, HA-specific CD4+ T-cells from anti-DEC-HA-treated INS-HA/TCR-HA mice exhibited increased expression of Foxp3, cytotoxic T-lymphocyte-associated antigen-4, and the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta. The findings indicate that targeting of the HA antigen to immature dendritic cells in vivo leads to a relative increase of antigen-specific Foxp3+ regulatory T-cells that suppress the development of type 1 diabetes. Our results provide a basis for the development of novel strategies focusing on prevention rather than treatment of autoimmune diseases.
Bruder
Dunja
D
Department of Mucosal Immunity, German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany. dbr@gbf.de
Westendorf
Astrid M
AM
Hansen
Wiebke
W
Prettin
Silvia
S
Gruber
Achim D
AD
Qian
Yingjie
Y
von Boehmer
Harald
H
Mahnke
Karsten
K
Buer
Jan
J
D000818:Animals; D015551:Autoimmunity; D001786:Blood Glucose / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
D001786:Blood Glucose