Tregs regulate or suppress other immunocytes by modulating their responses to the endogenous environment and antigens, thereby helping to avoid autoimmunity and chronic inflammation. These functions are accomplished via inhibitory cytokines, such as IL-10, metabolism interference, modification of the maturation or functioning of dendritic cells, binding of lymphocyte-activation gene 3 to MHC class II molecules, and cytolysis (through granzyme A/B and perforin).4

Many treatments for psoriasis appear to boost the numbers of Tregs and their performance in patients with psoriasis. Anti-TNF therapy (particularly etanercept) increases Tregs and decreases the expression of IL-6 and IL-22.5 Increased numbers of Tregs may be associated with improved clinical outcomes, and infliximab stimulates a more divergent TCR repertoire.6 In one study, TNF blockade was found to increase the release of pro-inflammatory cytokines and Th17 activity and decrease numbers of Tregs and expression of Foxp3, resulting in worsening of the disease.7

Several biologics, including anti-IL-23 (p40-specific ustekinumab and p19-specific guselkumab) and anti-IL-17A (secukinumab), has been approved to treat psoriasis. There is other anti-IL 23 (risankizumab, guselkumab, briakinumab, tildrakizumab) and anti-IL17 (ixekizumab and brodalumab) approved and in the market.8 Anti-IL-17A and anti-IL-23 have been shown to enhance Foxp3+ cells. Therefore, anti-IL-17 treatment in psoriasis may restore a healthy Th17/Treg balance and thus reduce inflammation and ameliorate disease. In a recent Phase I–IIa trial, low-dose IL-2 was administered to patients with various autoimmune diseases. Patients with psoriasis showed increased Treg frequencies and improved body surface area and PASI scores.9 Therefore, a combination of low-dose IL-2 medication with a regimen that restores the functions of Tregs, e.g., phototherapy or sotrastaurin, is a promising therapeutic approach in psoriasis.

The stability and functionality of the Treg lineage depend on epigenetic programming. Histone Deacetylase (HDAC-1) is expressed in the tissues of people with psoriasis. Trichostatin-A, which inhibits the HDAC protein, has been found to shift Tregs towards an IL-17 phenotype.10 This finding suggests that HDAC inhibitors may also be beneficial in the treatment of psoriasis. By resetting the Th17/Treg ratio and decreasing the number of subsets of inflammatory T-cells, Treg-based cell therapies may have the ability to interfere with the pathogenesis of psoriasis despite their high cost and hazards.11

MSCs are a type of pluripotent cell found in tissues of mesenchymal origin and are responsible for tissue regeneration. The role of MSCs in the pathogenesis of psoriasis is shown in Fig. 2. MSCs are distinguished by specific surface indicators and their ability to adhere to plastic substrates and develop into adipocytes, osteocytes, and chondrocytes in vitro. MSCs consist of various types of cells, and the most well-known are bone marrow-derived stromal stem cells. Other MSCs include umbilical cord MSCs, adipose-derived stem cells, and amniotic fluid stem cells, which are found in the stromal vascular fraction of adipose tissue. MSCs are being studied not only for their ability to regenerate cells but also for their immunomodulatory properties, given that they appear to modulate the release of lymphocyte-derived cytokines directly.12 According to a recent study, MSCs from the skin of patients with psoriasis show low differentiation capacity, low immunoregulatory function, and high HLA-I expression levels.13 In psoriatic skin, inhibition of lymphocytes appears to be impaired, likely because of the abnormal dermal MSCs, which result in abnormal cytokine secretion through circular RNA.14 Furthermore, MSCs from psoriatic plaques have been shown to stimulate the growth of keratinocytes, leading to epidermal thickening.15

Figure 2.

Role of mesenchymal stem cells in the pathogenesis of psoriasis.

(0.17MB).

Several studies have reported that MSCs play a significant role in determining the pleiotropic effects of biological therapy on keratinocytes and T-cells. According to Campanati et al., TNF-α inhibitors affect cutaneous MSCs, the cells most likely to be implicated in psoriasis.16 Several recent studies have investigated the use of MSCs as a possible therapeutic option for psoriasis (Table 1).17–25

MSCs play a role in innate and adaptive immunity in terms of immunomodulation. Their immune-enhancing activities are performed via synergy with immune cells, including neutrophils, dendritic cells, monocytes, natural killer cells, macrophages, B-cells, and T-cells via cell-to-cell encounters and paracrine activity.26 Several growth factors, chemokines, and cytokines are found in the MSC secretome, enveloped in extracellular vesicles; these include nitric oxide, indoleamine-pyrrole 2.3-dioxygenase, fibroblasts, and hepatocyte growth factors, IFN-ɣ, prostaglandin E2, TNF-α, and transforming growth factor-β1.27

Most of the favorable evidence concerning the use of MSCs in psoriasis comes from Phase I or II studies. To date, there has been no significant toxicity. However, more extensive controlled trials are needed to determine this treatment strategy's efficacy and long-term safety. Despite the growing body of knowledge and experience with MSCs in the clinical setting, cell dose and constancy differ between the trials reported to date, and the best regimen has yet to be identified.

The favorable effects of HSCT in patients with lymphoma and leukemia and other autoimmune illnesses, including systemic lupus erythematosus, diabetes, rheumatoid arthritis, and multiple sclerosis, prompted investigations of HSCT in patients with psoriasis.28–30 In the last 25-years, extended remission of psoriasis has been documented in more than 30 patients who have undergone Bone Marrow Transplantation (BMT).31,32 However, a small number of patients have developed psoriasis after receiving an allogeneic BMT or a blood transfusion from a donor with psoriasis.31 Details of the studies that have demonstrated remission of psoriasis after autologous HSCT are shown in Table 2.33–41

According to the pathogenesis of psoriasis, T-cells can provoke the development of changes after a blood transfusion, but peripheral T-cells have a relatively short lifetime. Amelioration of psoriasis has been documented in patients who have undergone allogeneic (rather than autologous) HSCT, suggesting that hematopoietic stem cells could be the primary cause of the disease.31,42 Mori et al. described the case of a 54-year-old male patient with a 10-year history of psoriasis who was treated with an allogeneic bone marrow transplant with preceding myeloablation with busulfan and cyclophosphamide because of a myelodysplastic syndrome, who achieved complete remission of psoriasis, which remained throughout the 8-month follow-up.39 The authors of that report stressed the need to eliminate autoreactive cells during allogeneic BMT and treatment with immunosuppressive medication to maintain remission. Similarly, Adkins et al. reported on a 55-year-old woman with refractory psoriasis and chronic myeloid leukemia who received an allogeneic BMT and achieved complete remission of her psoriasis,28 although the drugs used to prepare the patient for transplant (cyclophosphamide and busulfan) could have contributed to the rapid remission of psoriasis in this patient. Zurita et al. presented the findings of a trial that compared the effects of autologous HSCT (n = 30) with UVA photochemotherapy (n = 19) in patients with severe psoriasis. After obtaining bone marrow from the iliac crest and isolating the CD34+ fraction, autologous cells were administered intravenously as a single dose.30 The therapeutic effects were controlled for up to six months and compared with the effects of Photochemotherapy UVA (PUVA). PASI75 reached a statistically significant level in the group treated with stem cells, but no significant difference was observed compared to the effects of PUVA.30

The discovery of stem cell therapy as a feasible alternative treatment for refractory psoriasis has been serendipitous. Eedy et al. described a 35-year-old man who received allogeneic HSCs from his unaffected brother to treat acute myelomonocytic leukemia and was cured of severe, intractable psoriasis. The recipient was still clear of psoriasis five years after the transplant.43 The mechanisms underlying the effectiveness of allogeneic HSCT in psoriasis are still unknown. The immunosuppressive medications and immune ablation required for surgery are thought to decrease the number of autoreactive T-cells. The immune system is rebuilt with potentially non-reactive T-cell populations from donors who do not have psoriasis. A durable remission of psoriasis (for up to 20-years) has been reported in people who have undergone allogeneic HSCT rather than autologous HSCT.32

In a contrasting report, ""transfer"" of psoriasis was documented in a 40-year-old man with acute myeloid leukemia who received a syngeneic HSCT from his phenotypically identical twin brother with a 20-year history of severe psoriasis and psoriatic arthritis.44 The recipient sibling developed intractable psoriasis within ten days of the graft. Even after a second donation from the same donor, his condition continued with the onset of psoriatic arthritis. This case suggests that adoptive transfer can be used to transmit the cellular features of psoriasis. On the other hand, autologous HSCT does not fully alleviate psoriasis; relapses are common and can occur up to 10-years after transplantation. In one study, five of 11 patients with psoriasis who received autologous HSCT relapsed within two years, and one relapsed 13-years later.45 However, even when psoriasis recurs, it follows a more benign course than before the transplant. The myeloablative and lymphoablative effects of preconditioning and delayed immune reconstitution after transplantation are all factors to consider and are thought to be responsible for the remission of psoriasis after autologous HSCT. 37

Chen et al. explored the mechanism of action of umbilical cord-MSCs for psoriasis using the imiquimod mouse model and infusion of human umbilical cord-MSCs; this MSC significantly reduced psoriasis severity.46 Less generation of type I IFN by plasmacytoid dendritic cells was a significant characteristic of the response. Finally, Wang et al. used five infusions of allogeneic gingival MSCs, which have immunomodulatory and anti-inflammatory effects, to treat a 19-year-old man with severe plaque psoriasis that was recalcitrant to systemic regimens. The patient's psoriasis cleared after the sixth infusion, and the patient remained psoriasis-free three years later.24