OP004 Resetting of the mucosal T cell repertoire after hematopoietic stem cell transplantation in refractory Crohn's disease

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Background: Autologous hematopoietic stem cell transplantation (HSCT) is a therapeutic option for Crohn's disease (CD) patients with severe disease, refractory to immunosuppressants and biologics, after consideration of all therapeutic options including surgery. Several mechanism of action may be involved, including a resetting of the adaptive immune system. The role of T cells in CD physiopathology is well established although no specific antigen nor T cell TCR have been associated with CD.

The aim our study was to analyze the impact of HSCT on the T cell repertoire in the inflamed intestinal mucosa.

Methods: Intestinal mucosal samples (ileal or colonic biopsies) were collected at baseline (pre-mobilization) and after HSCT (6 months and/or 1 year post transplant), in 16 CD patients recruited in the ASTIC trial or in the Barcelona Center. Endoscopic severity was evaluated by segment using SES-CD. T cell repertoire analysis was performed on DNA extracted from biopsies by next generation sequencing of the TCRβ locus (Adaptive Biotechnology Inc., Seattle, Washington, USA). TCR diversity of each sample was studied by quantification of the size taken in the repertoire by significantly expanded clones, and correlated with clinical outcome and endoscopic response (global and by segment) at one year. T cell clones were tracked and the repertoire similarities were quantified between different time points by the Morisita-Horn index (M-H; range 0–1).

Results: Monoclonal expansions in the T cell compartment were present at baseline in the mucosa of CD patients prior to HSCT procedure, expanded clones represented from 5 to 30 per cent of the total repertoire. The T cell repertoire appeared more polyclonal than previously anticipated (from 1000 to 20 000 unique TCR sequences, diversity index 0.02 to 0.1). Importantly, no shared public TCR sequences were found in the mucosa of different patients. After HSCT, TCR clonality was significantly increased in the mucosa of patients. Although around 20 per cent of specific TCR sequences persisted between baseline and after HSCT, the similarity index comparing the TCR repertoire was low (mean M-H=0.17), indicating a profound resetting of the TCR repertoire. In contrast, a high degree of similarity (mean M-H=0.7) was observed between mucosal samples collected at different time points after the procedure in the same patient.

Conclusions: Clonal expansions are present in the mucosa of refractory CD patients. HSCT induces dramatic changes and a significant resetting in the mucosal T cell repertoire.

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