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

Caroline Voskens, Diane Stoica, Marita Rosenberg, Francesco Vitali, Sebastian Zundler, Marion Ganslmayer, Heike Knott, Manuel Wiesinger, Jutta Wunder, Mirko Kummer, Britta Siegmund, Elisabeth Schnoy, Timo Rath, Arndt Hartmann, Holger Hackstein, Beatrice Schuler-Thurner, Carola Berking, Gerold Schuler, Raja Atreya, Markus F Neurath, Caroline Voskens, Diane Stoica, Marita Rosenberg, Francesco Vitali, Sebastian Zundler, Marion Ganslmayer, Heike Knott, Manuel Wiesinger, Jutta Wunder, Mirko Kummer, Britta Siegmund, Elisabeth Schnoy, Timo Rath, Arndt Hartmann, Holger Hackstein, Beatrice Schuler-Thurner, Carola Berking, Gerold Schuler, Raja Atreya, Markus F Neurath

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.

Conflict of interest statement

Competing interests: GS is the inventor of granted patents related to the manuscript (publication number EP 1379625, CD4+CD25+ regulatory T cells from human blood).

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
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
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.

References

    1. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014;14:329–42. 10.1038/nri3661
    1. Rubtsov YP, Rasmussen JP, Chi EY, et al. . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28:546–58. 10.1016/j.immuni.2008.02.017
    1. Murai M, Turovskaya O, Kim G, et al. . Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor FOXP3 and suppressive function in mice with colitis. Nat Immunol 2009;10:1178–84. 10.1038/ni.1791
    1. Griseri T, Asquith M, Thompson C, et al. . Ox40 is required for regulatory T cell-mediated control of colitis. J Exp Med 2010;207:699–709. 10.1084/jem.20091618
    1. Fantini MC, Becker C, Tubbe I, et al. . Transforming growth factor beta induced Foxp3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 2006;55:671–80. 10.1136/gut.2005.072801
    1. Wiesinger M, Stoica D, Roessner S, et al. . Good manufacturing practice-compliant production and lot-release of Ex Vivo expanded regulatory t cells as basis for treatment of patients with autoimmune and inflammatory disorders. Front Immunol 2017;8:1371. 10.3389/fimmu.2017.01371
    1. Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med 2016;375:1161–70. 10.1056/NEJMra1506330
    1. Sebode M, Peiseler M, Franke B, et al. . Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms. J Hepatol 2014;60:1010–6. 10.1016/j.jhep.2013.12.027
    1. Voskens CJ, Stoica D, Roessner S, et al. . Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial. BMJ Open 2021;11:e049208. 10.1136/bmjopen-2021-049208
    1. Desreumaux P, Foussat A, Allez M, et al. . Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology 2012;143:1207–17. 10.1053/j.gastro.2012.07.116
    1. Eksteen B, Grant AJ, Miles A, et al. . Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med 2004;200:1511–7. 10.1084/jem.20041035
    1. de Krijger M, Visseren T, Wildenberg ME, et al. . Characterization of gut-homing molecules in non-endstage livers of patients with primary sclerosing cholangitis and inflammatory bowel disease. J Transl Autoimmun 2020;3:100054. 10.1016/j.jtauto.2020.100054
    1. Afford SC, Humphreys EH, Reid DT, et al. . Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis. Hepatology 2014;59:1932–43. 10.1002/hep.26965
    1. Henriksen EKK, Jørgensen KK, Kaveh F, et al. . Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease. J Hepatol 2017;66:116–22. 10.1016/j.jhep.2016.09.002
    1. Graham JJ, Mukherjee S, Yuksel M, et al. . Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis. Hepatology 2022;75:518–30. 10.1002/hep.32193
    1. Lynch KD, Chapman RW, Keshav S, et al. . Effects of Vedolizumab in patients with primary sclerosing cholangitis and inflammatory bowel diseases. Clin Gastroenterol Hepatol 2020;18:179–87. 10.1016/j.cgh.2019.05.013
    1. Fickert P, Hirschfield GM, Denk G, et al. . norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 2017;67:549–58. 10.1016/j.jhep.2017.05.009
    1. Bluestone JA, Buckner JH, Fitch M, et al. . Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 2015;7:ra189. 10.1126/scitranslmed.aad4134

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅