PMC:6141714 / 155939-174858 JSONTXT

{"project":"MyTest","denotations":[{"id":"30254638-24561556-35421941","span":{"begin":3772,"end":3774},"obj":"24561556"},{"id":"30254638-25436769-35421942","span":{"begin":4293,"end":4296},"obj":"25436769"},{"id":"30254638-23061813-35421943","span":{"begin":4316,"end":4319},"obj":"23061813"},{"id":"30254638-20921206-35421944","span":{"begin":4528,"end":4531},"obj":"20921206"},{"id":"30254638-23154532-35421945","span":{"begin":4756,"end":4758},"obj":"23154532"},{"id":"30254638-21820393-35421946","span":{"begin":7889,"end":7891},"obj":"21820393"},{"id":"30254638-25090227-35421947","span":{"begin":8123,"end":8126},"obj":"25090227"},{"id":"30254638-26700612-35421948","span":{"begin":8555,"end":8558},"obj":"26700612"},{"id":"30254638-24018793-35421949","span":{"begin":9022,"end":9025},"obj":"24018793"},{"id":"30254638-24551087-35421950","span":{"begin":9461,"end":9463},"obj":"24551087"},{"id":"30254638-26528946-35421951","span":{"begin":9777,"end":9779},"obj":"26528946"},{"id":"30254638-26523849-35421952","span":{"begin":10228,"end":10231},"obj":"26523849"},{"id":"30254638-23057962-35421953","span":{"begin":10563,"end":10566},"obj":"23057962"},{"id":"30254638-23324136-35421954","span":{"begin":11188,"end":11190},"obj":"23324136"},{"id":"30254638-27107963-35421955","span":{"begin":11416,"end":11419},"obj":"27107963"},{"id":"30254638-26497134-35421956","span":{"begin":12084,"end":12086},"obj":"26497134"},{"id":"30254638-26276002-35421957","span":{"begin":12680,"end":12682},"obj":"26276002"},{"id":"30254638-25394850-35421958","span":{"begin":12868,"end":12871},"obj":"25394850"},{"id":"30254638-27697286-35421959","span":{"begin":13396,"end":13399},"obj":"27697286"},{"id":"30254638-23574329-35421960","span":{"begin":14064,"end":14066},"obj":"23574329"},{"id":"30254638-21898680-35421961","span":{"begin":14303,"end":14306},"obj":"21898680"},{"id":"30254638-26481415-35421962","span":{"begin":15285,"end":15287},"obj":"26481415"},{"id":"30254638-28290605-35421963","span":{"begin":15641,"end":15643},"obj":"28290605"},{"id":"30254638-26584349-35421964","span":{"begin":16044,"end":16047},"obj":"26584349"},{"id":"30254638-26087385-35421965","span":{"begin":16541,"end":16543},"obj":"26087385"},{"id":"30254638-28084468-35421966","span":{"begin":17328,"end":17330},"obj":"28084468"},{"id":"30254638-25005115-35421967","span":{"begin":17985,"end":17988},"obj":"25005115"},{"id":"30254638-24804993-35421968","span":{"begin":18526,"end":18528},"obj":"24804993"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Discussion\nThrough a statistical analysis of the data obtained in this systematic review, it was possible to determine which immune-related disease was more commonly treated by hMSCs administration among all articles analyzed. The results obtained have shown that in 29.4% of the articles selected hMSCs were administered for the treatment GvHD while in 19.8% of the articles they were used for the treatment of multiple sclerosis, in 15.4% for the treatment of Cronh's disease and ulcerative colitis and in 12.5% for the treatment of rheumatoid arthritis. Treatment of type I diabetes mellitus and systemic lupus erythematosus through the administration of hMSCs was also relatively common among the articles selected, with each of them accounting for 5.9% of all articles analyzed in this systematic review. Other immune-related diseases for which hMSCs were less commonly administered with therapeutic intentions include myasthenia gravis (2.2% of the articles), autoimmune lung fibrosis (1.5% of the articles), ankylosing spondylitis (0.73% of the articles), autoimmune hearing loss (0.73% of the articles), autoimmune uveitis (2.2% of the articles), hemophagocytic syndrome (1.5% of the articles), neuromyelitisoptica (0.73% of the articles), systemic sclerosis (0.73% of the articles) and type II refractory celiac disease (0.73% of the articles). However, a significantly higher proportion of articles in which hMSCs were administered for the treatment of GvHD were observed among the human studies selected, while the treatment of other immune-related diseases was significantly less common in this group. A total of 65.9% of the human studies selected administered hMSCs for the treatment of GvHD. This result emphasizes the need for the conduction of human clinical trials in which hMSCs are employed for the treatment of other important immune-related diseases.\nIn addition, it was possible to determine which sources were most commonly employed for the isolation of hMSCs that were used in the articles selected. In this context, the bone marrow, the umbilical cord and the adipose tissue represents the most common sources of hMSCs employed by the articles selected, with each of them accounting for 47.6, 20, and 18.6% of all the articles, respectively. Other sources of hMSCs less commonly used include menstrual blood (1.4% of the articles), dental pulp (3.5% of the articles), gingiva (1.4% of the articles), placenta and fetal membrane (3.4% of the articles) and embryonic stem cells differentiation (4.1% of the articles). Finally, statistical analysis of the data obtained though the evaluation of the articles selected allowed us to determine which experimental models were more commonly employed in the studies selected. The results obtained demonstrated that the majority of the studies selected (60.7%) have chosen mice as the experimental model while in 32.5% of the studies selected were conducted in humans. Other experimental models less commonly employed by the articles selected included rats (4.6% of the articles) and pigs (2.2% of the articles).\nIt should be notice that some immune-related diseases are more likely to be treated by hMSCs administration in the near future than others. Currently, the great majority of the clinical trials conducted evaluated the use of hMSCs administration for the treatment of GvHD. As a result, a much greater amount of information describing the clinical benefits and possible adverse effects of hMSCs administration for the treatment of GvHD exist. In fact, a formulation of ex vivo cultured hMSCs called Prochymal was recently developed by Osiris Therapeutics. This formulation is now available in a total of nine countries for the treatment of patients with steroid-resistant grade III and IV GvHD (20) and is currently being tested in a phase III clinical trial sponsored by Osiris Therapeutics. Other immune-related diseases that are likely to be treated by hMSCs administration in the near future include Crohn's disease, multiple sclerosis and type I diabetes mellitus. In one hand, the treatment of multiple sclerosis through hMSCs administration was assessed in several animal studies, and in a randomized placebo-controlled phase II clinical trial and in an open-label phase II study conducted by Llufriu et al. (134) and Bonab et al. (125), respectively. The treatment of Crohn's disease through hMSCs administration, on the other hand, was also evaluated in several animal studies and in a clinical phase I study conducted by Duijvestein et al. (116). Finally, the efficacy of hMSCs administration for the treatment of type I diabetes mellitus and the occurrence of side effects was assessed in several animal studies and in a phase I clinical trial conducted by Hu et al. (78). Despite being already tested in humans, administration of hMSCs for the treatment of hemophagocitic syndrome, neuromyelitis optica and celiac disease was conducted only in single case reports. Therefore, it is not likely that the treatment of these immune-related diseases will be conducted through hMSCs administration in the near future. The treatment of systemic sclerosis, ankylosing spondylitis and myasthenia gravis through hMSCs administration, despite already being tested in phase I clinical trials, still needs to be assessed in a higher number of studies before becoming a reality in clinical practice. In addition, other immune-related diseases such as systemic lupus erythematosus, rheumatoid arthritis, idiopathic pulmonary fibrosis, autoimmune uveitis and autoimmune hearing loss were only treated though hMSCs administration in animal models and, as a result, the treatment of these diseases through hMSCs administration is also not likely to become a reality in clinical practice in the near future.\nMost of the studies analyzed in this systematic review reported positive results when hMSCs were administered for the treatment of immune-related diseases. Clinical effects commonly observed include an increase in the survival rates and a reduction in the severity and incidence of the immune-related diseases studied. In conjunction with this improvement of clinical parameters, many of the studies selected reported significant reduction in tissue pathology and inflammation following treatment with hMSCs. As a consequence, a decrease in the levels of several markers of the autoimmune process was also commonly observed. Furthermore, in the majority of the articles analyzed, an inhibition in the proliferation of inflammatory cells and a decrease in the infiltration of these cells into organs classically affected by the diseases studied was also reported. In general, hMSCs administration resulted in an inhibition in the proliferation and activation of cells from both innate and adaptive immunity, especially CD19+ B cells, CD4+ Th1 and Th17 cells, CD8+ T cells, NK cells, macrophages, monocytes and neutrophils. The clonal expansion of both Bregs and Tregs cells, however, was stimulated by the administration of hMSCs, as reported by many of the studies selected. Administration of hMSCs also resulted in a reduction in the levels of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, IL-2, IL-12, and IL-17 and in an increase in the levels of immunoregulatory cytokines such as IL-4, IL-10, and IL-13. Finally, the effects observed after the administration of hMSCs were also commonly attributed to the expression of molecules with immunoregulatory properties such as LIF, PD-L1, COX-2, activin A, TSG-6, HGF, PGE2, TGF-β1, FGF, IDO, VEGF, and HLA-G by these cells. However, as reported by some of the articles selected, some properties of the hMSCs administered such as the age and weight of the donor, the source and the number of passages might also affect significantly the potential of hMSCs for the treatment of immune-related diseases.\nFor instance, a study conducted by von Bahr et al. (49) demonstrated that GvHD patients who received early-passage MSCs had greater survival rates (75%) in comparison with patients who received late-passage MSCs (21%), 1 year after the beginning of the treatment. A study by Yu et al. (101) also demonstrated that the administration of late-passage hMSCs had a significantly compromised protective effect against mouse experimental colitis and that the production PGE2 and COX-2 by these cells was markedly reduced when compared to early-passage hMSCs. The influence of the weight of the donor in the immunoregulatory properties of adipose tissue-derived hMSCs was also analyzed in a study conducted by Strong et al. (136). This study showed that the administration of adipose tissue-derived hMSCs isolated from obese donors failed to alleviate clinical symptoms and inhibit inflammation in the central nervous system of murine experimental autoimmune encephalomyelitis, in contrast with the administration of adipose tissue-derived hMSCs isolated from lean subjects, which exhibited strong anti-inflammatory and therapeutic activities. Similarly, a study conducted by Scruggs et al. (121) demonstrated that experimental autoimmune encephalomyelitis mice treated with adipose tissue-derived hMSCs isolated from older donor cells had increased central nervous system inflammation and demyelination, when compared with the administration of adipose tissue-derived hMSCs isolated from younger donors.\nRegarding the influence of the cell source in the immunomodulatory properties of hMSCs, a study conducted by Yamahara et al. (34) demonstrated that, in contrast to chorion-derived hMSCs administration, amnion-derived hMSCs administration markedly reduced T-lymphocyte proliferation and improved the pathological situation of GvHD mice though the production of PGE2 in higher quantities. In addition, a study conducted by Luz-Crawford et al. (72) demonstrated that, while the administration of menstrual blood-derived hMSCs was able to increase the survival of GvHD mice, bone marrow-derived hMSCs administration did not. In contrast, this study has also shown that only the administration of bone marrow-derived hMSCs resulted in a potent therapeutic effect in mice with collagen induced arthritis, while menstrual blood-derived hMSCs administration did not. A study conducted by Wang et al. (102), however, demonstrated that the administration of hMSCs obtained from the differentiation of embryonic stem cells exerted both preventive and therapeutic effects on experimental autoimmune encephalomyelitis, while bone marrow-derived hMSCs exhibited significantly lower therapeutic efficacy. Furthermore, a study by Payne et al. (128) compared the therapeutic potential of the administration hMSCs isolated from bone marrow, umbilical cord and adipose tissue for the treatment of experimental autoimmune encephalomyelitis. This study demonstrated that the administration of adipose tissue-derived hMSCs had the most significant impact on clinical and pathological disease outcomes, while bone marrow-derived hMSCs administration resulted in a negligible effect on the disease course. Administration of umbilical cord-derived hMSCs had also a positive and significant impact in the progression of the disease. Moreover, a study conducted by Santos et al. (95) demonstrated that the administration umbilical cord-derived hMSCs can reduce paw edema in vivo more efficiently than bone marrow-derived hMSCs in an acute carrageenan-induced arthritis model. Finally, a study by Liu et al. (119) showed that the administration of the supernatant from a bone marrow-derived hMSC culture, which expressed higher level of TGF-β1, has a better therapeutic efficacy in improving the survival rate and reducing pulmonary inflammation and fibrosis in a bleomycin-induced pulmonary fibrosis mouse model when compared to umbilical cord-derived hMSCs, which secrete a lower level of TGF-β1.\nStimulation of hMSCs with immunosuppressive drugs prior to administration had also a significant effect in the efficacy of these stem cells in the treatment of immune-related diseases, as reported by some of the articles selected. For instance, a study conducted by Kim et al. (40) demonstrated that the administration of adipose tissue-derived hMSCs previously treated with rapamycin resulted in a greater reduction in the severity of aGvHD, when compared with the administration of untreated adipose tissue-derived hMSCs. It was also demonstrated by this study that this improvement in the therapeutic potential observed after the administration of adipose tissue-derived hMSCs previously treated with rapamycin was associated with a reduction in the number of Th17 cells and an increase in the number of Tregs cells. Furthermore, a study conducted by Girdlestone et al. (61) demonstrated that rapamycin-treated but not untreated umbilical cord-derived hMSCs significantly inhibit the onset of GvHD in mice. On the other hand, a study conducted by Liu et al. (114) demonstrated that the stimulation of dental pulp stem cells with acetylsalicylic acid upregulates TERT/FASL signaling in these cells, resulting in an increase in T-cell apoptosis and in the improvement in the clinical parameters of dextran sodium sulfate induced colitis in mice.\nSome of the studies selected also reported positive results when hMSCs were stimulated with inflammatory cytokines prior to their administration for the treatment of immune-related diseases. For instance, a study conducted by Torkaman et al. (144) demonstrated that the administration of umbilical cord-derived hMSCs previously treated with IFN-γ resulted in a higher inhibition in leukocyte infiltration into the central nervous system and in the reduction in the symptoms of experimental autoimmune encephalomyelitis in mice, compared to the administration of untreated umbilical cord-derived hMSCs. Furthermore, administration of umbilical cord-derived hMSCs previously treated with IFN-γ stimulated the clonal expansion of Treg cells and decreased the secretion and gene expression of inflammatory cytokines in experimental autoimmune encephalomyelitis mice. In addition, a study conducted by Tobin et al. (35) demonstrated that bone marrow-derived hMSCs, when stimulated by IFN-γ, reduced aGVHD-related weight loss and pathology, while greatly increasing the survival time of mice with aGVHD. Similarly, a study conducted by Duijvestein et al. (109) demonstrated that the administration of bone marrow-derived hMSCs pretreated with IFN-γ resulted in an increase in the survival rates and in the attenuation in the development and in the symptoms of dextran sodium sulfate and trinitrobenzene sulfonate induced colitis in mice, in contrast with the administration of non-stimulated bone marrow-derived hMSCs. Administration of bone marrow-derived hMSCs pretreated with IFN-γ also resulted in a significant reduction in serum amyloid A protein levels and local proinflammatory cytokine levels (especially Th1 cytokines) in colonic tissues. Finally, hMSCs pretreated with IFN-γ showed higher migration potential than unstimulated MSCs to sites within the inflamed intestine.\nWith the intention of enhancing the immunomodulatory properties of hMSCs, in some of the studies selected, hDSCs were transduced with several distinct genes and applied for the treatment of immune-related diseases. In a study conducted by Sadeghi et al. (33), for example, dental pulp stem cells were transduced with immunosuppressive genes encoding IL-10, PGE2 receptor, IDO, IFN-γ, and PDL-1 proteins. However, no difference was observed between transduced and untransduced dental pulp stem cells in both in vitro experiments and for the treatment of GvHD mice. Additionally, a study conducted by Sun et al. (74) demonstrated that the transplantation of adipose tissue-derived hMSCs overexpressing betatrophin into mice with streptozotocin-induced diabetes ameliorated the hyperglycemia and weight loss associated with the disease and also significantly enhanced the ratio of β-cells per islet compared to the transplantation of adipose tissue-derived hMSCs alone. Furthermore, a study conducted by Liao et al. (138) demonstrated that the transfection of bone marrow-derived hMSCs with PSGL-1/SLeX mRNA enhanced the homing of these stem cells to the inflamed spinal cord and, as a consequence, resulted in superior therapeutic function over native bone marrow-derived hMSCs, as evidenced by significantly improved myelination and decreased lymphocytes infiltration into the white matter of the spinal cord of mice with experimental autoimmune encephalomyelitis. In addition, a study conducted by Choi et al. (86) showed that the administration of adipose tissue-derived hMSCs overexpressing the anti-CTLA4 gene protected against the destruction of cartilage in mice with collagen-induced arthritis. This protective effect was more effective when adipose tissue-derived hMSCs overexpressing the anti-CTLA4 gene were administered, compared to the administration of adipose tissue-derived hMSCs alone. As expected, the serum levels of type II collagen autoantibodies and C-telopeptideof type II collagen were also significantly lower in the group transplanted with adipose tissue-derived hMSCs overexpressing the anti-CTLA4 gene, while the ratio of Treg/Th17 cells was increased, compared with the group treated with adipose tissue-derived hMSCs alone. Finally, in a study conducted by Park et al. (92), bone marrow-derived hMSCs were transfected with recombinant minicircles encoding etanercept and applied for the treatment of collagen-induced arthritis in mice. This study demonstrated that arthritis subsided more efficiently in collagen-induced mice injected with bone marrow-derived hMSCs transfected with recombinant minicircles encoding etanercept than in those injected with conventional bone marrow-derived hMSCs or etanercept only.\nLastly, in some of the studies selected, other types of therapies were applied in conjunction with hMSCs administration for the treatment of immune-related diseases. For instance, a study conducted by Hou et al. (126) demonstrated that the administration of bone marrow-derived hMSCs combined with minocycline resulted in a greater reduction in clinical scores, along with the attenuation of inflammation, demyelination, and neurodegeneration in experimental autoimmune encephalomyelitis mice, compared to the use of minocycline or bone marrow-derived hMSCs alone. In addition, the combined treatment also resulted in a significant decrease of the number of apoptotic cells, compared with either treatment alone. Finally, a study conducted by Im et al. (59) demonstrated that, compared with single cell therapy, the administration of adipose tissue-derived hMSCs combined with Tregs cells resulted in a higher reduction in the mortality rates and increased the engraftment rate and the donor-specific tolerance to skin allografts across full major histocompatibility complex barriers in GvHD mice, through reciprocal regulation of Treg/Th17 cells."}

{"project":"2_test","denotations":[{"id":"30254638-24561556-35421941","span":{"begin":3772,"end":3774},"obj":"24561556"},{"id":"30254638-25436769-35421942","span":{"begin":4293,"end":4296},"obj":"25436769"},{"id":"30254638-23061813-35421943","span":{"begin":4316,"end":4319},"obj":"23061813"},{"id":"30254638-20921206-35421944","span":{"begin":4528,"end":4531},"obj":"20921206"},{"id":"30254638-23154532-35421945","span":{"begin":4756,"end":4758},"obj":"23154532"},{"id":"30254638-21820393-35421946","span":{"begin":7889,"end":7891},"obj":"21820393"},{"id":"30254638-25090227-35421947","span":{"begin":8123,"end":8126},"obj":"25090227"},{"id":"30254638-26700612-35421948","span":{"begin":8555,"end":8558},"obj":"26700612"},{"id":"30254638-24018793-35421949","span":{"begin":9022,"end":9025},"obj":"24018793"},{"id":"30254638-24551087-35421950","span":{"begin":9461,"end":9463},"obj":"24551087"},{"id":"30254638-26528946-35421951","span":{"begin":9777,"end":9779},"obj":"26528946"},{"id":"30254638-26523849-35421952","span":{"begin":10228,"end":10231},"obj":"26523849"},{"id":"30254638-23057962-35421953","span":{"begin":10563,"end":10566},"obj":"23057962"},{"id":"30254638-23324136-35421954","span":{"begin":11188,"end":11190},"obj":"23324136"},{"id":"30254638-27107963-35421955","span":{"begin":11416,"end":11419},"obj":"27107963"},{"id":"30254638-26497134-35421956","span":{"begin":12084,"end":12086},"obj":"26497134"},{"id":"30254638-26276002-35421957","span":{"begin":12680,"end":12682},"obj":"26276002"},{"id":"30254638-25394850-35421958","span":{"begin":12868,"end":12871},"obj":"25394850"},{"id":"30254638-27697286-35421959","span":{"begin":13396,"end":13399},"obj":"27697286"},{"id":"30254638-23574329-35421960","span":{"begin":14064,"end":14066},"obj":"23574329"},{"id":"30254638-21898680-35421961","span":{"begin":14303,"end":14306},"obj":"21898680"},{"id":"30254638-26481415-35421962","span":{"begin":15285,"end":15287},"obj":"26481415"},{"id":"30254638-28290605-35421963","span":{"begin":15641,"end":15643},"obj":"28290605"},{"id":"30254638-26584349-35421964","span":{"begin":16044,"end":16047},"obj":"26584349"},{"id":"30254638-26087385-35421965","span":{"begin":16541,"end":16543},"obj":"26087385"},{"id":"30254638-28084468-35421966","span":{"begin":17328,"end":17330},"obj":"28084468"},{"id":"30254638-25005115-35421967","span":{"begin":17985,"end":17988},"obj":"25005115"},{"id":"30254638-24804993-35421968","span":{"begin":18526,"end":18528},"obj":"24804993"}],"text":"Discussion\nThrough a statistical analysis of the data obtained in this systematic review, it was possible to determine which immune-related disease was more commonly treated by hMSCs administration among all articles analyzed. The results obtained have shown that in 29.4% of the articles selected hMSCs were administered for the treatment GvHD while in 19.8% of the articles they were used for the treatment of multiple sclerosis, in 15.4% for the treatment of Cronh's disease and ulcerative colitis and in 12.5% for the treatment of rheumatoid arthritis. Treatment of type I diabetes mellitus and systemic lupus erythematosus through the administration of hMSCs was also relatively common among the articles selected, with each of them accounting for 5.9% of all articles analyzed in this systematic review. Other immune-related diseases for which hMSCs were less commonly administered with therapeutic intentions include myasthenia gravis (2.2% of the articles), autoimmune lung fibrosis (1.5% of the articles), ankylosing spondylitis (0.73% of the articles), autoimmune hearing loss (0.73% of the articles), autoimmune uveitis (2.2% of the articles), hemophagocytic syndrome (1.5% of the articles), neuromyelitisoptica (0.73% of the articles), systemic sclerosis (0.73% of the articles) and type II refractory celiac disease (0.73% of the articles). However, a significantly higher proportion of articles in which hMSCs were administered for the treatment of GvHD were observed among the human studies selected, while the treatment of other immune-related diseases was significantly less common in this group. A total of 65.9% of the human studies selected administered hMSCs for the treatment of GvHD. This result emphasizes the need for the conduction of human clinical trials in which hMSCs are employed for the treatment of other important immune-related diseases.\nIn addition, it was possible to determine which sources were most commonly employed for the isolation of hMSCs that were used in the articles selected. In this context, the bone marrow, the umbilical cord and the adipose tissue represents the most common sources of hMSCs employed by the articles selected, with each of them accounting for 47.6, 20, and 18.6% of all the articles, respectively. Other sources of hMSCs less commonly used include menstrual blood (1.4% of the articles), dental pulp (3.5% of the articles), gingiva (1.4% of the articles), placenta and fetal membrane (3.4% of the articles) and embryonic stem cells differentiation (4.1% of the articles). Finally, statistical analysis of the data obtained though the evaluation of the articles selected allowed us to determine which experimental models were more commonly employed in the studies selected. The results obtained demonstrated that the majority of the studies selected (60.7%) have chosen mice as the experimental model while in 32.5% of the studies selected were conducted in humans. Other experimental models less commonly employed by the articles selected included rats (4.6% of the articles) and pigs (2.2% of the articles).\nIt should be notice that some immune-related diseases are more likely to be treated by hMSCs administration in the near future than others. Currently, the great majority of the clinical trials conducted evaluated the use of hMSCs administration for the treatment of GvHD. As a result, a much greater amount of information describing the clinical benefits and possible adverse effects of hMSCs administration for the treatment of GvHD exist. In fact, a formulation of ex vivo cultured hMSCs called Prochymal was recently developed by Osiris Therapeutics. This formulation is now available in a total of nine countries for the treatment of patients with steroid-resistant grade III and IV GvHD (20) and is currently being tested in a phase III clinical trial sponsored by Osiris Therapeutics. Other immune-related diseases that are likely to be treated by hMSCs administration in the near future include Crohn's disease, multiple sclerosis and type I diabetes mellitus. In one hand, the treatment of multiple sclerosis through hMSCs administration was assessed in several animal studies, and in a randomized placebo-controlled phase II clinical trial and in an open-label phase II study conducted by Llufriu et al. (134) and Bonab et al. (125), respectively. The treatment of Crohn's disease through hMSCs administration, on the other hand, was also evaluated in several animal studies and in a clinical phase I study conducted by Duijvestein et al. (116). Finally, the efficacy of hMSCs administration for the treatment of type I diabetes mellitus and the occurrence of side effects was assessed in several animal studies and in a phase I clinical trial conducted by Hu et al. (78). Despite being already tested in humans, administration of hMSCs for the treatment of hemophagocitic syndrome, neuromyelitis optica and celiac disease was conducted only in single case reports. Therefore, it is not likely that the treatment of these immune-related diseases will be conducted through hMSCs administration in the near future. The treatment of systemic sclerosis, ankylosing spondylitis and myasthenia gravis through hMSCs administration, despite already being tested in phase I clinical trials, still needs to be assessed in a higher number of studies before becoming a reality in clinical practice. In addition, other immune-related diseases such as systemic lupus erythematosus, rheumatoid arthritis, idiopathic pulmonary fibrosis, autoimmune uveitis and autoimmune hearing loss were only treated though hMSCs administration in animal models and, as a result, the treatment of these diseases through hMSCs administration is also not likely to become a reality in clinical practice in the near future.\nMost of the studies analyzed in this systematic review reported positive results when hMSCs were administered for the treatment of immune-related diseases. Clinical effects commonly observed include an increase in the survival rates and a reduction in the severity and incidence of the immune-related diseases studied. In conjunction with this improvement of clinical parameters, many of the studies selected reported significant reduction in tissue pathology and inflammation following treatment with hMSCs. As a consequence, a decrease in the levels of several markers of the autoimmune process was also commonly observed. Furthermore, in the majority of the articles analyzed, an inhibition in the proliferation of inflammatory cells and a decrease in the infiltration of these cells into organs classically affected by the diseases studied was also reported. In general, hMSCs administration resulted in an inhibition in the proliferation and activation of cells from both innate and adaptive immunity, especially CD19+ B cells, CD4+ Th1 and Th17 cells, CD8+ T cells, NK cells, macrophages, monocytes and neutrophils. The clonal expansion of both Bregs and Tregs cells, however, was stimulated by the administration of hMSCs, as reported by many of the studies selected. Administration of hMSCs also resulted in a reduction in the levels of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, IL-2, IL-12, and IL-17 and in an increase in the levels of immunoregulatory cytokines such as IL-4, IL-10, and IL-13. Finally, the effects observed after the administration of hMSCs were also commonly attributed to the expression of molecules with immunoregulatory properties such as LIF, PD-L1, COX-2, activin A, TSG-6, HGF, PGE2, TGF-β1, FGF, IDO, VEGF, and HLA-G by these cells. However, as reported by some of the articles selected, some properties of the hMSCs administered such as the age and weight of the donor, the source and the number of passages might also affect significantly the potential of hMSCs for the treatment of immune-related diseases.\nFor instance, a study conducted by von Bahr et al. (49) demonstrated that GvHD patients who received early-passage MSCs had greater survival rates (75%) in comparison with patients who received late-passage MSCs (21%), 1 year after the beginning of the treatment. A study by Yu et al. (101) also demonstrated that the administration of late-passage hMSCs had a significantly compromised protective effect against mouse experimental colitis and that the production PGE2 and COX-2 by these cells was markedly reduced when compared to early-passage hMSCs. The influence of the weight of the donor in the immunoregulatory properties of adipose tissue-derived hMSCs was also analyzed in a study conducted by Strong et al. (136). This study showed that the administration of adipose tissue-derived hMSCs isolated from obese donors failed to alleviate clinical symptoms and inhibit inflammation in the central nervous system of murine experimental autoimmune encephalomyelitis, in contrast with the administration of adipose tissue-derived hMSCs isolated from lean subjects, which exhibited strong anti-inflammatory and therapeutic activities. Similarly, a study conducted by Scruggs et al. (121) demonstrated that experimental autoimmune encephalomyelitis mice treated with adipose tissue-derived hMSCs isolated from older donor cells had increased central nervous system inflammation and demyelination, when compared with the administration of adipose tissue-derived hMSCs isolated from younger donors.\nRegarding the influence of the cell source in the immunomodulatory properties of hMSCs, a study conducted by Yamahara et al. (34) demonstrated that, in contrast to chorion-derived hMSCs administration, amnion-derived hMSCs administration markedly reduced T-lymphocyte proliferation and improved the pathological situation of GvHD mice though the production of PGE2 in higher quantities. In addition, a study conducted by Luz-Crawford et al. (72) demonstrated that, while the administration of menstrual blood-derived hMSCs was able to increase the survival of GvHD mice, bone marrow-derived hMSCs administration did not. In contrast, this study has also shown that only the administration of bone marrow-derived hMSCs resulted in a potent therapeutic effect in mice with collagen induced arthritis, while menstrual blood-derived hMSCs administration did not. A study conducted by Wang et al. (102), however, demonstrated that the administration of hMSCs obtained from the differentiation of embryonic stem cells exerted both preventive and therapeutic effects on experimental autoimmune encephalomyelitis, while bone marrow-derived hMSCs exhibited significantly lower therapeutic efficacy. Furthermore, a study by Payne et al. (128) compared the therapeutic potential of the administration hMSCs isolated from bone marrow, umbilical cord and adipose tissue for the treatment of experimental autoimmune encephalomyelitis. This study demonstrated that the administration of adipose tissue-derived hMSCs had the most significant impact on clinical and pathological disease outcomes, while bone marrow-derived hMSCs administration resulted in a negligible effect on the disease course. Administration of umbilical cord-derived hMSCs had also a positive and significant impact in the progression of the disease. Moreover, a study conducted by Santos et al. (95) demonstrated that the administration umbilical cord-derived hMSCs can reduce paw edema in vivo more efficiently than bone marrow-derived hMSCs in an acute carrageenan-induced arthritis model. Finally, a study by Liu et al. (119) showed that the administration of the supernatant from a bone marrow-derived hMSC culture, which expressed higher level of TGF-β1, has a better therapeutic efficacy in improving the survival rate and reducing pulmonary inflammation and fibrosis in a bleomycin-induced pulmonary fibrosis mouse model when compared to umbilical cord-derived hMSCs, which secrete a lower level of TGF-β1.\nStimulation of hMSCs with immunosuppressive drugs prior to administration had also a significant effect in the efficacy of these stem cells in the treatment of immune-related diseases, as reported by some of the articles selected. For instance, a study conducted by Kim et al. (40) demonstrated that the administration of adipose tissue-derived hMSCs previously treated with rapamycin resulted in a greater reduction in the severity of aGvHD, when compared with the administration of untreated adipose tissue-derived hMSCs. It was also demonstrated by this study that this improvement in the therapeutic potential observed after the administration of adipose tissue-derived hMSCs previously treated with rapamycin was associated with a reduction in the number of Th17 cells and an increase in the number of Tregs cells. Furthermore, a study conducted by Girdlestone et al. (61) demonstrated that rapamycin-treated but not untreated umbilical cord-derived hMSCs significantly inhibit the onset of GvHD in mice. On the other hand, a study conducted by Liu et al. (114) demonstrated that the stimulation of dental pulp stem cells with acetylsalicylic acid upregulates TERT/FASL signaling in these cells, resulting in an increase in T-cell apoptosis and in the improvement in the clinical parameters of dextran sodium sulfate induced colitis in mice.\nSome of the studies selected also reported positive results when hMSCs were stimulated with inflammatory cytokines prior to their administration for the treatment of immune-related diseases. For instance, a study conducted by Torkaman et al. (144) demonstrated that the administration of umbilical cord-derived hMSCs previously treated with IFN-γ resulted in a higher inhibition in leukocyte infiltration into the central nervous system and in the reduction in the symptoms of experimental autoimmune encephalomyelitis in mice, compared to the administration of untreated umbilical cord-derived hMSCs. Furthermore, administration of umbilical cord-derived hMSCs previously treated with IFN-γ stimulated the clonal expansion of Treg cells and decreased the secretion and gene expression of inflammatory cytokines in experimental autoimmune encephalomyelitis mice. In addition, a study conducted by Tobin et al. (35) demonstrated that bone marrow-derived hMSCs, when stimulated by IFN-γ, reduced aGVHD-related weight loss and pathology, while greatly increasing the survival time of mice with aGVHD. Similarly, a study conducted by Duijvestein et al. (109) demonstrated that the administration of bone marrow-derived hMSCs pretreated with IFN-γ resulted in an increase in the survival rates and in the attenuation in the development and in the symptoms of dextran sodium sulfate and trinitrobenzene sulfonate induced colitis in mice, in contrast with the administration of non-stimulated bone marrow-derived hMSCs. Administration of bone marrow-derived hMSCs pretreated with IFN-γ also resulted in a significant reduction in serum amyloid A protein levels and local proinflammatory cytokine levels (especially Th1 cytokines) in colonic tissues. Finally, hMSCs pretreated with IFN-γ showed higher migration potential than unstimulated MSCs to sites within the inflamed intestine.\nWith the intention of enhancing the immunomodulatory properties of hMSCs, in some of the studies selected, hDSCs were transduced with several distinct genes and applied for the treatment of immune-related diseases. In a study conducted by Sadeghi et al. (33), for example, dental pulp stem cells were transduced with immunosuppressive genes encoding IL-10, PGE2 receptor, IDO, IFN-γ, and PDL-1 proteins. However, no difference was observed between transduced and untransduced dental pulp stem cells in both in vitro experiments and for the treatment of GvHD mice. Additionally, a study conducted by Sun et al. (74) demonstrated that the transplantation of adipose tissue-derived hMSCs overexpressing betatrophin into mice with streptozotocin-induced diabetes ameliorated the hyperglycemia and weight loss associated with the disease and also significantly enhanced the ratio of β-cells per islet compared to the transplantation of adipose tissue-derived hMSCs alone. Furthermore, a study conducted by Liao et al. (138) demonstrated that the transfection of bone marrow-derived hMSCs with PSGL-1/SLeX mRNA enhanced the homing of these stem cells to the inflamed spinal cord and, as a consequence, resulted in superior therapeutic function over native bone marrow-derived hMSCs, as evidenced by significantly improved myelination and decreased lymphocytes infiltration into the white matter of the spinal cord of mice with experimental autoimmune encephalomyelitis. In addition, a study conducted by Choi et al. (86) showed that the administration of adipose tissue-derived hMSCs overexpressing the anti-CTLA4 gene protected against the destruction of cartilage in mice with collagen-induced arthritis. This protective effect was more effective when adipose tissue-derived hMSCs overexpressing the anti-CTLA4 gene were administered, compared to the administration of adipose tissue-derived hMSCs alone. As expected, the serum levels of type II collagen autoantibodies and C-telopeptideof type II collagen were also significantly lower in the group transplanted with adipose tissue-derived hMSCs overexpressing the anti-CTLA4 gene, while the ratio of Treg/Th17 cells was increased, compared with the group treated with adipose tissue-derived hMSCs alone. Finally, in a study conducted by Park et al. (92), bone marrow-derived hMSCs were transfected with recombinant minicircles encoding etanercept and applied for the treatment of collagen-induced arthritis in mice. This study demonstrated that arthritis subsided more efficiently in collagen-induced mice injected with bone marrow-derived hMSCs transfected with recombinant minicircles encoding etanercept than in those injected with conventional bone marrow-derived hMSCs or etanercept only.\nLastly, in some of the studies selected, other types of therapies were applied in conjunction with hMSCs administration for the treatment of immune-related diseases. For instance, a study conducted by Hou et al. (126) demonstrated that the administration of bone marrow-derived hMSCs combined with minocycline resulted in a greater reduction in clinical scores, along with the attenuation of inflammation, demyelination, and neurodegeneration in experimental autoimmune encephalomyelitis mice, compared to the use of minocycline or bone marrow-derived hMSCs alone. In addition, the combined treatment also resulted in a significant decrease of the number of apoptotic cells, compared with either treatment alone. Finally, a study conducted by Im et al. (59) demonstrated that, compared with single cell therapy, the administration of adipose tissue-derived hMSCs combined with Tregs cells resulted in a higher reduction in the mortality rates and increased the engraftment rate and the donor-specific tolerance to skin allografts across full major histocompatibility complex barriers in GvHD mice, through reciprocal regulation of Treg/Th17 cells."}