Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis

Abstract

Objective: Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.

Design: The patient received a single infusion of 1×10⁶ autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer.

Results: The patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3⁺/FoxP3⁺ and CD3⁺/IL-10⁺ T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again.

Conclusion: These findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC.

Trial registration number: NCT04691232.

Keywords: PRIMARY SCLEROSING CHOLANGITIS; ULCERATIVE COLITIS.

Figure 1

Regression of mucosal ulcerations, reduction of fCalprotectin levels and transient improvement of PSC after adoptive Treg transfer. (A) Endoscopic examination showing a regression of mucosal ulcerations 4 and 12 weeks after adoptive Treg transfer accompanied by a reduction in the endoscopic Mayo score. (B) Representative 20× H&E stainings showing an improvement in Nancy Score 4 and 12 weeks after adoptive Treg transfer. (C) Reduced fCalprotectin levels after adoptive Treg transfer. (D) Transient improvement in serum ALP and GGT levels after adoptive Treg transfer. (E) Transient improvement in serum AST and ALT levels after adoptive Treg transfer. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; fCalprotectin, faecal calprotectin; GGT, gamma-glutamyl transferase; Treg, regulatory T cell.

Figure 2

Enrichment of CD3⁺FoxP3⁺ and CD3⁺IL-10⁺ cell populations in the gut. (A) Images of immunohistochemistry staining demonstrating the enrichment of CD3⁺FoxP3⁺ cells and CD3⁺IL-10⁺ cells 4 and 12 weeks after adoptive Treg transfer. Samples were analysed using ×40 objective magnification. Green cells represent CD3⁺ T cells, and red cells are Foxp3⁺ or IL-10⁺ cells, as indicated. (B) Quantification of CD3⁺FoxP3⁺ cells and (C) CD3⁺IL-10⁺ cells in relation to total CD3⁺ cells 4 and 12 weeks after adoptive Treg transfer. IL, interleukin; Treg, regulatory T cell.