SP0093 Resetting the immune system in autoimmunity

Autologous hematopoietic stem cell transplantation (HSCT) is a last resort treatment for refractory autoimmune patients and the only therapy so far that can induce long-term drug-free remission in these patients. Understanding the mechanisms responsible for this regained immune tolerance may help to develop other, less aggressive immune-mediated interventions with a similar outcome. Although the underlying mechanisms are incompletely understood, extensive immune ablation followed by autologous stem cell infusion seems to be able to rewire a faulty immune system. It is so far unknown which cells need to be removed prior to autologous transplantation and which cells are important in controlling disease after transplantation. We have previously shown that transplantation restores immune tolerance by renewal and modulation of both the CD4 effector T cell (Teff) and FOXP3 Treg compartment in a proteoglycan induced arthritis (PGIA) mouse model. In the human setting we further looked into T cell renewal by TCR CDR3 b chain repertoire sequencing prior to and post HSCT of juvenile idiopathic arthritis and dermatomyositis patients. We found that TCR beta chain diversity of Treg was highly restricted prior to transplantation and that the TCR b chain diversity of Treg increased post-transplantation. The TCR beta chain diversity of the CD4 non-Treg compartment also expanded after aSCT, although not as strikingly as the Treg compartment, indicating that the Treg compartment is more affected. Interestingly, in patients these highly dominant T(reg) cell clones persist over time and (locally) expand with every relapse of disease. The question is now how HSCT or related therapies can efficiently target and stimulate T cell renewal in chronic autoimmune inflammation, with limited toxicity.

Disclosure of Interest

None declared