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Regulatory T-Cell Therapy in Crohn's Disease: Challenges and Advances

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Regulatory T-Cell Therapy in Crohn's Disease: Challenges and Advances Recent advances in basic science Regulatory T- cell therapy in Crohn’s disease: Gut: first published as 10.1136/gutjnl-2019-319850 on 24 January 2020. Downloaded from challenges and advances Jennie N Clough ,1,2 Omer S Omer,1,3 Scott Tasker ,4 Graham M Lord,1,5 Peter M Irving 1,3 1School of Immunology and ABStract pathological process increasingly recognised as Microbial Sciences, King’s The prevalence of IBD is rising in the Western world. driving intestinal inflammation and autoimmunity College London, London, UK 2NIHR Biomedical Research Despite an increasing repertoire of therapeutic targets, a is the loss of immune homeostasis secondary to Centre at Guy’s and Saint significant proportion of patients suffer chronic morbidity. qualitative or quantitative defects in the regulatory Thomas’ NHS Foundation Trust Studies in mice and humans have highlighted the critical T- cell (Treg) pool. and King’s College, London, UK + 3 role of regulatory T cells in immune homeostasis, with Tregs are CD4 T cells that characteristically Department of defects in number and suppressive function of regulatory Gastroenterology, Guy’s and express the high- affinity IL-2 receptor α-chain Saint Thomas’ Hospitals NHS T cells seen in patients with Crohn’s disease. We review (CD25) and master transcription factor Forkhead Trust, London, UK the function of regulatory T cells and the pathways by box P-3 (Foxp3) which is essential for their suppres- 4 Division of Transplantation which they exert immune tolerance in the intestinal sive phenotype and stability.4–6 As activated CD4+ Immunology and Mucosal mucosa. We explore the principles and challenges of Biology, King’s College London, T cells can upregulate CD25 expression, an addi- London, UK manufacturing a cell therapy, and discuss clinical trial tional defining feature of Tregs is the absence of 5 Faculty of Biology, Medicine evidence to date for their safety and efficacy in human IL-7 receptor α-chain (CD127).7 Their primary and Health, The University of disease, with particular focus on the development of a function is as dominant controllers of self- tolerance, Manchester, Manchester, UK regulatory T- cell therapy for Crohn’s disease. tissue inflammation and long- term immune homeo- Correspondence to stasis. Despite making up only 5%–10% of the + Dr Peter M Irving, Department peripheral CD4 T- cell pool, Tregs exert powerful of Gastroenterology, Guy’s and INTRODUCTION inhibitory effects on effector cells through a variety Saint Thomas’ NHS Foundation of mechanisms including cytokine secretion, meta- Trust, London SE1 9RT, UK; IBD, chiefly comprising Crohn’s disease (CD) and peter. irving@ kcl. ac. uk ulcerative colitis (UC), is a chronic inflammatory bolic disruption, inhibition of dendritic cells (DCs) group of disorders of the GI tract arising from over- and cytolysis. These mechanisms have been rigor- JNC and OSO contributed exuberant innate and adaptive immune responses ously examined using animal models and shown equally. to environmental factors in genetically susceptible to protect against the development of intestinal Received 12 September 2019 individuals. IBD affects at least 0.5% of the popu- inflammation. Studies in patients with IBD have http://gut.bmj.com/ Revised 21 November 2019 lation in the Western world with 1 million sufferers identified defects in the number and distribution of 1 Accepted 19 December 2019 in USA and 2.5 million in Europe. Global preva- Tregs, and their ability to traffic to the GI tract.8 lence continues to increase, largely driven by rising Additionally, resistance to Treg- mediated suppres- numbers of patients in newly industrialised regions sion has been noted in lamina propria T effector 1 including India and Asia. The burden of disease is cells (Teffs).9 These factors are likely to be pivotal significant with 20%–25% of patients experiencing in driving intestinal inflammation. on September 25, 2021 by guest. Protected copyright. chronic continuous symptoms which contributes There is growing interest in the therapeutic poten- to higher rates of unemployment, sick leave and 2 tial of adoptively transferring healthy Tregs into permanent work disability. Even with an aggres- patients with a wide range of conditions, including sive top-down approach to therapy, the majority IBD and autoimmune disease, in an attempt to shift of patients fail to achieve prolonged, steroid- free the balance in areas of active inflammation toward remission and are at particular risk of requiring a more tolerogenic microenvironment. Early surgical intervention. Cumulative surgery rates in phase clinical trials have already reported in the CD are high in Europe with 30%–50% of patients fields of solid organ transplantation, graft- versus- requiring surgical intervention and up to 20% host disease (GvHD) and type 1 diabetes mellitus needing a reoperation 5–10 years from diagnosis.2 (T1DM) with reassuring safety data and potential As our understanding of the pathophysiology of IBD and its socioeconomic impact has evolved, signals of efficacy. there has been great impetus to identify novel This review provides a summary of the suppressive therapeutic targets to add to the existing arsenal mechanisms used by Tregs and highlights seminal © Author(s) (or their of immunomodulators and biologics. These have work linking intestinal inflammation with loss of employer(s)) 2020. Re- use Treg function in both animal models of disease and permitted under CC BY. focused on a variety of areas including targeting Published by BMJ. lymphocyte trafficking (vedolizumab, ozanimod, humans. Additionally, we review ongoing clinical anti-MAdCAM1) and activation (anti-IL (inter- trials with Treg therapy and outline an entirely novel To cite: Clough JN, Omer OS, leukin)-6, anti-IL-12/IL-23), modulating intestinal therapeutic strategy for CD using Tregs expanded Tasker S, et al. Gut Epub under good manufacturing practice (GMP) condi- ahead of print: [please barrier function (phosphatidylcholine), matrix include Day Month Year]. remodelling (STNM-01, matrix metalloproteinase tions that will be adoptively transferred to patients doi:10.1136/ 9 blocker) and manipulation of gut microbiota in an attempt to ameliorate intestinal inflammation gutjnl-2019-319850 (faecal microbiota transplant).3 An important and restore immune homeostasis. Clough JN, et al. Gut 2020;0:1–11. doi:10.1136/gutjnl-2019-319850 1 Recent advances in basic science TREGS IN HEALTH AND DISEASE chronic diarrhoea and malabsorption) a predominant feature, Tregs can be broadly divided into two groups, thymic Tregs attention was focused on the functional role of Tregs within the Gut: first published as 10.1136/gutjnl-2019-319850 on 24 January 2020. Downloaded from (tTregs) or peripherally induced Tregs (pTregs), based on their GI tract. developmental origin. Tregs generated in the thymus (tTregs) in pTregs are found in abundance in the intestinal lamina the early neonatal period migrate to peripheral organs where propria where interactions with environmental antigens can they maintain tolerance. This was discovered in 1969 by shape phenotypic differences and transcription factor expres- 29 Nishizuka and Sakakura who showed that in mice, thymectomy sion. The gut microbiota represents a substantial antigen load 3 days after birth led to the depletion of Foxp3+ Tregs and devel- driving the expansion of colonic pTregs that coexpress the Th17 30 + + opment of autoimmune oophoritis.10 In contrast, mice who had master transcription factor RORγt. These Foxp3 RORγt thymectomy at day 7 remained healthy as the tTregs had already pTregs have a stable regulatory phenotype and provide tolerance 31 32 - migrated to the periphery by this point.11 Over a decade later, towards the gut microbiota. Conversely, RORγt pTregs are Sakaguchi et al demonstrated that day-3 thymectomy autoim- found in the small intestine where they are induced by dietary mune oophoritis could be prevented with CD4+ T- cell inocu- antigens and repress underlying Th1 cell responses to ingested 33 lation from healthy syngeneic donors. Conversely, the adoptive proteins. Finally, an intestinal tTreg population that coexpress transfer of T cells from these sick mice was capable of inducing the Th2 master transcription factor, GATA3, has been shown + autoimmune disease in healthy T-cell- deficient mice.11 Similar to mediate repair of the intestinal mucosa. GATA3 tTregs findings were noted in rats that underwent adult thymectomy express high levels of the IL-33 receptor, ST2, and amphiregulin and irradiation resulting in lymphopenia, autoimmune diabetes (AREG), an epidermal growth factor receptor ligand involved in 34 35 and insulitis. An injection of CD45RC(low) T cells from healthy tissue repair. donors was capable of preventing disease.12 Mottet et al subse- Following on from the fundamental observations linking quently described CD25- expressing CD4+ T cells that were able Treg dysfunction to an array of autoimmune polyendocrine to cure established T-cell transfer colitis.13 By the early 2000s, syndromes, studies began to emerge identifying defects in either it was clear that a thymically derived CD4+CD25+ T- cell popu- number or function of peripheral blood Tregs in autoimmune lation possessed the ability to suppress autoreactive T cells and disorders including IBD, T1DM, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis and rheumatoid eliminate autoimmunity. 8 36–40 + - arthritis. Maul et al observed that in patients with active pTregs were first described in 2003
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