The promise and challenges of cell therapy for psoriasis*

British Journal of DermatologyVolume 185, Issue 5 p. 887-898 Review ArticleOpen Access The promise and challenges of cell therapy for psoriasis* S.M. Lwin, S.M. Lwin orcid.org/0000-0002-3325-3675 St John's Institute of Dermatology, King's College London, Guy's Hospital, London, UKSearch for more papers by this authorJ.A. Snowden, J.A. Snowden orcid.org/0000-0001-6819-3476 Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UKSearch for more papers by this authorC.E.M. Griffiths, Corresponding Author C.E.M. Griffiths christopher.griffiths@manchester.ac.uk orcid.org/0000-0001-5371-4427 Dermatology Centre, Salford Royal Hospital, NIHR Manchester Biomedical Research Centre Manchester Academic Health Science Centre, University of Manchester, Manchester, UK Correspondence C.E.M. Griffiths. Email: christopher.griffiths@manchester.ac.ukSearch for more papers by this author S.M. Lwin, S.M. Lwin orcid.org/0000-0002-3325-3675 St John's Institute of Dermatology, King's College London, Guy's Hospital, London, UKSearch for more papers by this authorJ.A. Snowden, J.A. Snowden orcid.org/0000-0001-6819-3476 Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UKSearch for more papers by this authorC.E.M. Griffiths, Corresponding Author C.E.M. Griffiths christopher.griffiths@manchester.ac.uk orcid.org/0000-0001-5371-4427 Dermatology Centre, Salford Royal Hospital, NIHR Manchester Biomedical Research Centre Manchester Academic Health Science Centre, University of Manchester, Manchester, UK Correspondence C.E.M. Griffiths. Email: christopher.griffiths@manchester.ac.ukSearch for more papers by this author First published: 26 May 2021 https://doi.org/10.1111/bjd.20517 †Funding sources C.E.M.G. is supported in part by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre and by Medical Research Council grant MR/101 1808/1 and is an NIHR Emeritus Senior Investigator. S.M.L. receives funding from Dystrophic Epidermolysis Bullosa Research Association UK. ‡Conflicts of interest C.E.M.G. has received honoraria and/or research funds from AbbVie, Almirall, Amgen, Boehringer Ingelheim, BMS, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi and UCB. J.A.S. has received honoraria for speaking at educational events from Janssen, Jazz, Gilead, Mallinckrodt and Actelion, and for advisory board work from MEDAC, and is a member of a trial IDMC for Kiadis. * Plain language summary available online AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary The management of moderate-to-severe psoriasis has been transformed by the introduction of biological therapies. These medicines, particularly those targeting interleukin (IL)-17 and IL-23p19, can offer clear or nearly clear skin for the majority of patients with psoriasis, with good long-term drug survival. However, as currently used, none of these therapies is curative and disconcertingly there is a small but increasing number of patients with severe psoriasis who have failed all currently available therapeutic modalities. A similar scenario has occurred in other immune-mediated inflammatory diseases (IMIDs) where treatment options are limited in severely affected patients. In these cases, cell therapy, including haematopoietic stem cell transplantation (HSCT) and mesenchymal stromal cells (MSC), has been utilized. This review discusses the various forms of cell therapy currently available, their utility in the management of IMIDs and emerging evidence for efficacy in severe psoriasis that is unresponsive to biological therapy. Balancing the risks and benefits of treatment vs. the underlying disease is key; cell therapy carries significant risks, costs, regulation and other complexities, which must be justified by outcomes. Although HSCT has anecdotally been reported to benefit severe psoriasis, sometimes with apparent cure, this has mainly been in the setting of other coincidental 'routine' indications. In psoriasis, cell therapies, such as MSC and regulatory T cells, with a lower risk of complications are likely to be more appropriate. Well-designed controlled trials coupled with mechanistic studies are warranted if advanced cell therapies are to be developed and delivered as a realistic option for severe psoriasis. Introduction Psoriasis is a common, immune-mediated inflammatory disease (IMID) with significant morbidity and detrimental impact on the affected individual's quality of life. It is associated with important medical conditions, including psoriatic arthritis (PsA), metabolic syndrome, depression and cardiovascular disease; people with psoriasis have a higher mortality than the general population.1 The complex interplay between genetic, epigenetic, immune and environmental factors that underlie the disease pathogenesis is not fully understood.2 However, the emergence of biological therapies targeting key immune pathways in psoriasis pathogenesis, such as tumour necrosis factor (TNF)-α, interleukin (IL)-17 and IL-23, has revolutionized the treatment landscape of severe disease. These therapies can lead to significant improvement in disease burden and quality of life for people with psoriasis. However, targeted therapies are not curative; their limitations include lack of clinical response in certain individuals, diminishing efficacy over time and occasional significant adverse effects.3 Consequently, there is an increasing number of patients with psoriasis who are refractory to multiple lines of biological and nonbiological systemic therapies. This underscores an urgent and increasing need for more advanced, perhaps curative, treatment options including nonpharmaceutical approaches for severe psoriasis. Cell therapy comprises the use of somatic cells (stem, progenitor or primary cells) isolated from either the affected individual (autologous) or a donor (allogeneic) to treat the underlying disease. The various types of somatic cells that are used, or have the potential to be used, as cell therapy in IMIDs include haematopoietic stem cells (HSCs), mesenchymal stem or stromal cells (MSCs), multilineage-differentiating stress-enduring (Muse) cells, fibroblasts, induced pluripotent stem cells (iPSCs), regulatory T cells (Tregs) and chimeric antigen receptor (CAR)-T cells. The last two decades have witnessed rapid advances in clinical trials and commercialization of cell therapy, for which the three most common disease indications in Europe between 2004 and 2014 were cancer, cardiovascular disease and connective tissue diseases.4 Observations of serendipitous 'transfer' and 'cure' of IMIDs after HSC transplantation (HSCT) have raised interest in the potential of cell therapy as an option for these conditions with a number of controlled and open studies mainly in multiple sclerosis (MS), musculoskeletal disease and systemic sclerosis (SS). Similar observations of 'transfer' and 'cure' have been made for psoriasis over the years, but there are few subsequent hypothesis-testing studies. Thus, there appears to be a rationale and an impetus to explore the use of cell therapy in psoriasis, specifically for patients who are refractory to currently available therapies. This review discusses the following three key aspects of cell therapy: (i) types of cell therapy for IMIDs; (ii) accumulated data on the use of cell therapy in the management of psoriasis; and (iii) the future direction of cell therapy for psoriasis. Types of cell therapy The various types of cell therapy that have been used, or have the potential to be used, in IMIDs are detailed in Figure 1. Figure 1Open in figure viewerPowerPoint Types of cell therapy used, or with the potential to be used, in psoriasis. Cell therapy can be either allogeneic (cells from donor to patient) or autologous (the patient's own cells). Different types of somatic cells can be obtained from various tissues, isolated and expanded in laboratories that meet Good Manufacturing Practice standards, and systemically administered to the patient at time of treatment. Fibroblasts and Muse cells are isolated from dermis, whereas MSC can easily be isolated from adipose tissue or bone marrow. CAR-T; chimeric antigen receptor T; iPSC, induced pluripotent stem cell; MSC, mesenchymal stromal or stem cell; Muse, multilineage-differentiating stress-enduring cells; Treg, regulatory T cell. Types of cell therapy used for immune-mediated inflammatory diseases Haematopoietic stem cell transplantation HSCT is used to treat a wide range of malignant and nonmalignant conditions.5 It involves intravenous infusion of allogeneic or autologous HSCs following myeloablative and/or lymphoablative cytotoxic therapy. The preparative 'conditioning' regimen may include various combinations of high-dose chemotherapy, total body irradiation and 'serotherapy', such as polyclonal antithymocyte globulin, or therapeutic monoclonal antibodies, e.g. alemtuzumab or rituximab. Sources of HSCs include granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, bone marrow and umbilical cord blood.6 Allogeneic HSCT requires ongoing immunosuppression, usually ciclosporin or tacrolimus, to facilitate engraftment and prevent graft-versus-host disease (GVHD), until tolerization occurs thereby enabling withdrawal. The overall aim of HSCT is to remove the underlying disease process and reconstitute the blood and immune systems, which in allogeneic HSCT may be accompanied by a graft-versus-tumour reaction. Over the last quarter century, autologous HSCT has been increasingly used to treat individuals with IMIDs, including MS, SS and other rheumatological diseases and Crohn disease where, despite modern treatments, some patients have ongoing poor disease control and potentially shortened life expectancy. In these 'difficult-to-treat' patients, HSCT has been explored as an intensive means of disease control, delivered as a 'one-off' treatment with long-term effectiveness. In some IMIDs, such as severe relapsing-remitting MS and SS, randomized controlled trials (RCTs) support sustained benefits of HSCT, whereas in other IMIDs, there appears to be a resetting of disease activity to controllable levels. In highly active resistant relapsing-remitting MS, there has been a single phase III RCT comparing autologous HSCT with various standard-of-care disease-modifying therapies (DMTs).7 Among 110 patients randomized on a 1 : 1 basis, only three patients had disease progression at 1 year as primary endpoint vs. 34 patients in the DMT group. There was also significant improvement of MS at one year and beyond without treatment-related mortality (TRM).7 In severe SS, there has been one small phase I RCT8 and two phase III RCTs, namely 'SCOT'9 and 'ASTIS',10 each using different transplant regimens but with similar control arms. In the North American 'SCOT' trial, Kaplan–Meier estimates at 72 months of event-free survival were 74% vs. 47%, and for overall survival were 86% vs. 51%, for HSCT and control, respectively.9 The TRM was 3% at 54 months and 6% at 72 months.9 These results confirmed similar findings from the earlier European 'ASTIS' trial, which also showed significant improvements in event-free and overall survival, with a TRM of 10%.10 These phase III trial results in MS and SS support the potentially powerful and prolonged effect of autologous HSCT on disease activity in severely affected patients with IMIDs, but also highlight the importance of careful patient selection. Underlying vital organ compromise from the IMID itself manifests in the contrasting TRM between different diseases and requires careful per patient justification of the procedure. Allogeneic HSCT has been applied to IMIDs more rarely because of the higher complication rate (including GVHD) but long-term responses, and probably cures, have been achieved across a variety of diseases.11-14 Although autologous and allogeneic HSCT have been anecdotally reported to benefit severe psoriasis, sometimes with apparent cure, this has mainly been in the setting of other coincidental 'routine' indications (Table 1). Very rare cases involving patients treated specifically for severe PsA have been reported to the European Society for Blood and Marrow Transplantation Registry.14 Table 1. Summary of published reports of cell therapy for psoriasis Cell therapy Auto/Allo Intravenous cell dose Primary target disease Severity of psoriasis at baseline Duration of psoriasis (years) Previous treatment for psoriasis PsA Age (years) Sex Adverse events Efficacy Reference HSCT Allo Twice, 1 y apart AML Severe 20 PUVA, MTX, razoxane, etretinate No 36 M NS CR 4y 82 HSCT Allo N/A CML Severe 10 TCS, coal tar, dithranol Yes 35 M NS CR 1y 85 HSCT Allo N/A CML NS NS NS NS 35 M NS CR 4y 86 HSCT Allo N/A AA Severe 25 TCS, PUVA No 36 M cGVHD CR 1.8y 87 HSCT Allo N/A AML BSA 36% 1 TCS, etretinate No 40 M cGVHD CR 2y 88 HSCT Allo N/A CML BSA 19% NS NS Yes 54 M None CR 1y 89 HSCT Allo N/A CML BSA 66% 33 TCS, coal tar, PUVA, MTX NS 55 F aGVHD, cGVHD CR 2.4y 90 HSCT Allo N/A CML BSA 73% 8 PUVA, MTX Yes 38 M Mild GVHD DR 1m 91 HSCT Allo N/A NHL BSA 90% 25 TCS, coal tar, retinoids Yes 50 M None CR 17m 92 HSCT Allo N/A CML NS 20 TCS NS 49 M cGVHD CR 2.5y 93 HSCT Allo N/A AML Mod 21 TCS, TVD, OCS, PUVA NS 67 M GVHD DR 1.3m 94 HSCT Allo N/A AA Severe 16 NS Yes 29 M None DR 1y 82 HSCT Allo 2·1 × 108 per kg AA BSA 45% 2 TCS, TVD No 27 M None CR 10y 83 HSCT Allo N/A DLBCL BSA 10% NS NS No 56 M GVHD CR 2y 84 HSCT Allo N/A AML Mod NS TCS, TVD Yes 55 F aGVHD, cGVHD, death CR from D37 to 1y 95 HSCT Allo N/A AML Mild-Mod NS TCS, TVD No 21 M aGVHD CR from D64 to 5y 7m 95 HSCT Allo N/A DLBCL Severe 15 MTX Yes 59 M None CR from D60 to 5y 95 HSCT Allo N/A AML Severe 20 TCS, TVD Yes 65 M aGVHD CR from D41 to 7y 5m 95 HSCT Allo N/A FL/DLBCL Mod 27 TCS, TVD No 30 F cGVHD CR from D30 to 3y 95 HSCT Allo N/A CNL Mod NS TCS, TVD No 65 M aGVHD, cGVHD, death CR from D71 to 7m 95 HSCT Auto 24 × 106 per kg NHL Mild 15 TCS Yes 35 M NS DR 22m 96 HSCT Auto 2·85 × 108 per kg AML NS NS TCS, coal tar No 53 M NS DR 14m 96 HSCT Auto 4·7 × 106 per kg PCL Severe 13 PUVA No 40 F NS CR 6m; DR 8m 96 HSCT Auto 11·38 × 106 per kg MGUS BSA 36% 16 MTX, CIC, MMF, OCS Yes 34 M None DR 16m 97 HSCT Auto 0·42 × 106 per kg NHL Mod 20 NS No 50 M None DR 21m 83 HSCT Auto N/A MM BSA 50% 15 TCS, TVD, UVB Yes 35 M NS CR 15m 98 HSCT Auto N/A ES Severe (Guttate psoriasis) NS NS No 9 M NS CR from D20 to 15m 99 HSCT Auto N/A MM Mod-severe 20 MTX No 48 F None CR 13y; mild DR thereafter 100 HSCT Auto Twice; M0, M7 MM Severe 25 TCS, PUVA, CIC, MTX, USTE No 54 M NS CR for 3y 101 HSCT Auto N/A AL BSA > 50% 30 TCS No 58 M None CR for 7y 102 HSCT/UC-MSC Auto/Allo Twice/1 × 106 per kg (D0) DLBCL NS 12 NS No 35 M Infections after first HSCT Psoriasis improved but DR 6w after first HSCT; CR 5y after UC-MSC 103 UC-MSC Allo 1 × 106 per kg (W0, 1, 2, 5, 7) Psoriasis NS 18 TCS No 26 F None CR 4y 103 ADSC Auto 0·5–3·1 × 106 per kg (D0, 40) PSA PASI 21·6 29 TCS, MTX, ETA Yes 58 M None 58% reduction in PASI (9·0); no improvement in joint pain for 2y 104 ADSC Auto 0·5–3·1 × 106 per kg (D0, 30, 71) Psoriasis PASI 24·0 5 TCS, TVD, MTX No 28 F None 65% reduction in PASI (8·3) for 9.7m; transient improvement in onycholysis/pitting; reduction in TNF-α; 5 × decrease in ROS 104 G-MSC Allo 3 × 106 per kg (W0, 1, 6, 7, 8) Psoriasis Severe 5 MTX, ACI, CIC, ETA No 19 M None CR from W1 to 3y 105 ACI, acitretin; ADSC, adipose-derived mesenchymal stromal cells; aGVHD, acute graft-versus-host disease; AL, immunoglobulin light chain amyloidosis; Allo, allogeneic; AML, acute myeloid leukaemia; Auto, autologous; BSA, body surface area; cGVHD, chronic graft-versus-host disease; CIC, ciclosporin; CML, chronic myeloid leukaemia; CNL, chronic neutrophilic leukaemia; CR, complete remission; D, day; DLBCL, diffuse large B-cell lymphoma; DR, disease recurrence; ES, Ewing sarcoma; ETA, etanercept; FL, follicular lymphoma; G-MSC, gingival-derived mesenchymal stromal cells; HSCT, haematopoietic stem cell transplantation; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MMF, mycophenolate mofetil; MTX, methotrexate; NHL, non-Hodgkin lymphoma; OCS, oral corticosteroids; PASI, Psoriasis Area and Severity Index; PCL, plasma cell leukaemia; PUVA, psoralen and ultraviolet A; PSA, psoriatic arthritis; ROS, reactive oxygen species; TCS, topical corticosteroids; TNF, tumour necrosis factor; TVD, topical vitamin-D analogue; UC-MSC, umbilical cord-derived mesenchymal stromal cells; USTE, ustekinumab; UVB, ultraviolet B; W, week. Mesenchymal stromal cells MSCs comprise a heterogeneous population of self-renewable, multipotent non-HSCs with immunomodulatory, angiogenic, anti-inflammatory and antiapoptotic properties.15, 16 These properties, combined with ease of isolation from human tissues and ability to evade allogeneic rejection (owing to lack of expression of major histocompatibility complex [MHC] class II and costimulatory molecules CD80 and CD86, and low levels of MHC class I),17, 18 make MSCs an ideal cell therapy for various conditions, including IMIDs, without the need for cytotoxic conditioning regimes.19 MSCs are found in virtually all organs but are predominantly harvested from bone marrow (BM-MSCs), umbilical cord (UC-MSCs), placental tissues, Wharton's jelly, peripheral blood, dental pulp, skin and adipose tissue (ADSCs). Depending on the source of MSCs, their biological characteristics can vary, including differentiation capacity, paracrine potential and immunomodulatory properties. For instance, BM-MSCs and ADSCs express stemness markers Sox2 and Oct4 in␣vitro, which enable them to maintain their differentiation capacity in the long term,20 whereas ADSCs, when compared with BM-MSCs and UC-MSCs, exhibit a stronger inhibitory effect on peripheral blood B cells, T cells and natural killer (NK) cells in␣vitro;21 but all three types can promote Treg and T helper (Th)1 polarization, evidenced by the increased expression of forkhead box (FOX)P3 and T-bet mRNA within purified activated T cells, and a reduction in TNF-α and perforin production by activated NK cells.21 In terms of immunomodulation, MSCs participate in both innate and adaptive immunity; their immune regulatory functions are exerted via interactions with immune cells through cell-to-cell contact and paracrine activity involving T cells, B cells, NK cells, macrophages, monocytes, dendritic cells and neutrophils (reviewed in Gao et␣al.22 and Song et␣al.).23 The MSC secretome, encapsulated in extracellular vesicles, includes several cytokines, growth factors and chemokines, including transforming growth factor (TGF)-β1, TNF-α, prostaglandin-E2, interferon-γ, fibroblast and hepatocyte growth factors, indoleamine-pyrrole 2,3-dioxygenase and nitric oxide, among others.24, 25 One of the translational challenges with MSCs is their scalability. In this regard, ADSCs are often preferred as they can be obtained in large quantities from liposuction,26, 27 with better proliferative capacity, higher yield, slower rate of senescence and better preservation of a normal diploid karyotype than BM-MSCs.28-31 To date, safety and efficacy of MSCs have been demonstrated in early phase trials in IMIDs, including rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SS, GVHD, MS, type I diabetes mellitus, autoimmune hepatitis and inflammatory bowel disease (IBD).32-39 Specifically, a meta-analysis of 477 patients with Crohn disease fistulae showed a significantly increased healing rate and a lower recurrence rate in those with severe disease receiving allogeneic ADSCs compared with those who received dose-adjusted BM-MSCs, with an optimal cell dose of 2–4 × 107 cells mL−1, indicating the considerable potential of MSCs for the treatment of IBD.40 A recent phase II RCT of autologous MSCs in 48 patients with MS demonstrated disease remission, without safety issues, in 58·6% compared with 9·7% in a sham-treatment group.39 However, most of the MSC-based trials for IMIDs are still in early phase I or II clinical trials with some promising results and no toxicity to date, but larger controlled trials are needed to confirm their efficacy and long-term safety.31, 32, 34, 35, 38, 39 However, several MSC products have been approved including Prochymal (Osiris Therapeutics, Columbia, MD, USA) for acute GVHD in Canada and New Zealand.22 One of the theoretical pitfalls of MSCs is risk of carcinogenesis.17, 41, 42 Despite emerging knowledge and experience with clinical application of MSCs, the cell dose and frequency of administration vary between trials and the optimal dosing regimen has yet to be determined. Regulatory T cells Tregs regulate or suppress other immunocytes by controlling response to self-antigens and nonself antigens, thus helping to prevent autoimmunity and limit chronic inflammation. They exert these functions through inhibitory cytokines (e.g. IL-10), cytolysis (via granzyme A/B and perforin), metabolic disruption and modulation of dendritic cell maturation or function, and lymphocyte-activation gene-3 binding to MHC class II molecules.43 Rapid progress in the clinical translation of adoptive cell therapy of Tregs is underpinned by various preclinical models of autoimmune diseases demonstrating the therapeutic potential of a unique FOXP3+ immunosuppressive subset of Tregs. To date, there are more than 50 active and completed clinical trials testing the safety and efficacy of Tregs for IMIDs including pemphigus vulgaris, SLE, IBD, autoimmune hepatitis and asthma.44, 45 Published results indicate excellent safety profiles and some efficacy in patients treated with as many as 2·5 billion Tregs. Although psoriasis is believed to represent an imbalance between Th17 cells and Tregs, there are no studies to ascertain whether Treg-based therapy can restore this balance.46 However, there are current challenges with the use of Treg therapy for IMIDs, which include the variability in expansion of Tregs ex␣vivo, the relative paucity of clinical grade reagents required for the manufacture of Tregs for therapy and the observation that tissue antigen-specific Tregs, although more potent than polyclonal Tregs, are expressed in very low numbers and are unstable. It may be that the opportunities offered by synthetic biology, e.g. for CAR-T therapy, could be harnessed for Treg therapy.44 Further investigation of the most suitable Treg subset to use for a particular disease, and controlled trials with larger sample size and a standardized dosing regimen, are required to obtain robust evidence of the clinical benefit of correcting breaks in immune tolerance in IMIDs.47 For further review of this topic please see Roth-Walter et␣al.48 Types of cell therapy with potential for use in immune-mediated inflammatory diseases There are a number of other forms of cell therapy that could potentially be used in the treatment of psoriasis, although these are not currently being tested in IMIDs. These include fibroblasts, Muse cells, iPSCs and CAR-T cells. Fibroblasts Fibroblasts, which exhibit similar characteristics to MSCs with immunomodulatory and regenerative properties through paracrine effects, play a vital role in wound healing through deposition of extracellular matrix and formation of scar tissue.49-53 Thus, fibroblasts can be considered as an alternative to MSCs for immunomodulatory cell therapy.51 Both allogeneic and autologous fibroblasts have been used for treatment of chronic wounds including venous leg ulcers and recessive dystrophic epidermolysis bullosa, with notable anti-inflammatory effect.54-57 The main concern with fibroblast cell therapy is the risk of fibrosis and hypertrophic scars.50 However, fibroblasts from the papillary dermis have a particular therapeutic relevance as they are involved in wound healing with anti-inflammatory effects without fibrosis.58 Although fibroblasts have not been tested in humans with IMIDs, their therapeutic potential has been highlighted through a number of preclinical studies using mouse models of IMIDs including type I diabetes, autoimmune arthritis, alopecia areata and MS.51, 59-61 Multilineage-differentiating stress-enduring cells Muse cells are pluripotent stem cells, occurring naturally in tissues of mesenchymal origin, with regenerative, anti-inflammatory, antiapoptotic, antifibrotic and immunomodulatory properties.62-64 They comprise 1–2% of BM-MSCs, 5% of dermal fibroblasts and a small population in adipose tissue.65 Upon tissue injury, the alerting signal, sphingosine-1-phosphate, induces mobilization of Muse cells to peripheral blood, and subsequently to the site of damage.64 This is followed by spontaneous differentiation into, and replenishment of, tissue-compatible cells for repair.64, 66 Furthermore, Muse cells have immunomodulatory properties, exerted via TGF-β1 and regulation of macrophages towards the M2-phenotype, which make them an attractive therapeutic option for psoriasis.67, 68 To date, Muse cells have been used clinically in the context of an early phase trial in myocardial infarction, demonstrating safety and efficacy.69 Inducible pluripotent stem cells One of the main limitations of somatic cell-based therapy is that the limited lifespan of differentiated cells after clinical application inevitably leads to a decline in therapeutic efficacy over time. One revolutionary technology provides a solution to this issue – iPSCs can be produced from any somatic cell (e.g. fibroblasts) using reprogramming factors (Oct-4, Sox-2, Klf-4 and c-Myc) and can differentiate into specialized cell types with indefinite expansion, thus resembling embryonic stem cells.70-72 The fundamental concept in the use of iPSCs as cell therapy is that they are differentiated into the desired cell types, such as keratinocytes or Tregs, and then transplanted as tissue constructs or cell suspensions. Owing to their unlimited self-renewal and differentiation potential, patient-specific iPSCs can be genetically corrected and differentiated into required somatic cell lineages and administered as an autograft.72, 73 Viral-mediated gene supplementation or genome editing using tools such as CRISPR/Cas9 can be applied to iPSCs in their undifferentiated state to correct the underlying molecular pathology. Although combined genome editing and iPSC technology is used as cell therapy in various disease models, clinical translation to humans is still limited to a narrow scope of indications. These comprise cardiovascular diseases, neurological disorders, GVHD and ophthalmic diseases such as age-related macular degeneration.74 Caution is needed because if undifferentiated proliferating iPSCs are directly administered, they can form malignant teratomas owing to their highly proliferative nature and broad differentiation potential.75 However, iPSCs hold huge promise as both a regenerative and an immunomodulatory cell therapy for various skin diseases.76 Chimeric antigen receptor-T cell therapy CAR-T cells are derived by transferring genetically engineered CAR fusion proteins via lentiviral or retroviral vectors into autologous T cells. The CAR constructs usually comprise a single-chain variable fragment antigen-recognition domain, a transmembrane CD-3-derived T-cell activation domain and an intracellular costimulatory domain, e.g. CD28. The CAR-T cells recognize and kill antigen-bearing cells via cytokine release. Before infusion, the recipient requires cytotoxic conditioning therapy. CAR-T cell therapy has been used in the management of haematological malignancies, especially B-cell lymphoma, acute lymphoblastic leukaemia and myeloma,77 and is being considered in the management of melanoma resistant to checkpoint inhibitors.78 However, it carries a significant risk of cytokine release syndrome and neurotoxicity in the short term, and long-term immunodeficiency owing to depletion of immune effectors.79 As they have the ability to achieve profound depletion of B cells or other immune targets, genetically engineered T cells have been considered in the context of IMIDs. In a recent preclinical study to treat pemphigus vulgaris in a mouse model of the disease, the results demonstrated selective reduction of serum anti-Desmoglein (Dsg)3 antibody titres and improvement in blistering, hair loss and histological acantholysis.80 These preclinical data have led to an early phase open-label clinical trial of Dsg3-CAR-T therapy for patients with pemphigus vulgaris (NCT04422912).80 Beneficial effects of cell therapy for psoriasis Serendipity played an important role in determining our current consideration of cell therapy as a viable option for patients with refractory psoriasis. Eedy et␣al.81 reported on the 'cure' of severe intractable psoriasis in a 35-year-old man who received an allogeneic HSCT from his unaffected brother for acute myelomonocytic leukaemia. The recipient remained free of psoriasis 5 years post-transplant. Although the mechanisms underlying the effi