795 - Apoptotic Cells Induce a Population of Regulatory T Cells and Protect Mice from Collagen Induced Arthritis

MOHINI GRAY1, Katherine Miles1, Donald Salter1, David Gray2, John Savill1. 1Queen's Medical Research Institute, Edinburgh university, United Kingdom; 2IIIR, Edinburgh university, United Kingdom
Presentation Number: 795

Purpose: Apoptosis is the programmed and physiological cell death of surplus cells and in vitro studies have shown that the uptake of apoptotic cells by phagocytes is profoundly anti-inflammatory. Immature dendritic cells pulsed with apoptotic cells have been shown to inhibit the proliferation of antigen specific T cells in vitro and in vivo. We wanted to ask if apoptotic cells (AC) given at the time of induction of an aggressive auto-immune disease, collagen induced arthritis (CIA), could protect from clinical disease.
Methods. DBA1 mice were immunized with heterologous collagen emulsified in complete Freund's adjuvant (CFA). Clinically apparent arthritis began between 21 and 35 days later in 100% of the mice. At the time of immunization they were also given an iv injection of apoptotic syngeneic thymocytes on days 0,1 and 2 . Control mice received vehicle alone.
Results. Mice treated with AC at least 18 days prior to the onset of clinical disease showed a significantly reduced severity of arthritis when compared to mice treated with vehicle alone. Histology of the joints showed marked synovial thickening with pannus formation and associated cartilage and bone destruction in the control group. In comparison, AC treated mice had a mild infiltrate in the synovium with minimal bone and cartilage loss. CIA depends for its expression on the generation of pathogenic anti collagen antibodies that bind to joint cartilage and fix complement. Mice given AC on days 0-2 had a significantly reduced titre of both total and pathogenic IgG2a levels up to 56 days later. We postulated that this effect was due to inefficient priming of collagen specific T cells in the AC treated mice. However T cells isolated at various time points following immunization consistently proliferated normally upon re-stimulation with collagen when compared to control mice. However their cytokine profile was markedly different with significantly more IL-10 secreted. We inhibited IL-10 with anti-IL10 antibody injected weekly for 3 weeks and noted a rise in normal levels of pathogenic antibody produced by the AC treated mice.
Conclusion. AC afford protection from an aggressive auto-immune disease despite the presence of dendritic cell maturation stimuli in the form of CFA. The mechanism of protection is dependent on the induction of an antigen specific population of T cells that secretes IL-10 and inhibits the generation of pathogenic auto-antibodies.

 M. Gray, None.