**5. MSCs in preclinical and clinical trials**

MSCs delivered alone or with a biomaterial have been used in a variety of regenerative medicine strategies. In vivo evidence supports the hypothesis that MSCs have immunosuppressive properties that include prevention of graft versus

**117**

*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions*

host disease (GvHD), decreased graft rejection, prevention of experimental acute encephalomyelitis, prolonged skin graft survival, etc. [8]. However, in recent years, consistent reports on its immunomodulatory properties have opened up newer avenues for studying MSCs, other than regenerative medicine. As of May 2018, there were over 843 MSC-related clinical trials registered on the NIH Clinical Trial Database (http://clinicaltrial.gov/). Interestingly, half of all registered clinical trials (~45%) are being conducted for immune-mediated diseases. Of these, 69 are based on autoimmune disease, 38 on GVHD, and the rest 290 on other inflammatory diseases. However, in early phase I, phase II, phase III, and phase IV, there were 3, 76, 7, and 6 clinical trials conducted, respectively. Hematopoietic stem cells (HSCs) have been the most successful in providing therapeutic application using stem cells. MSCs represent a lifesaving treatment for patients suffering with hematopoietic malignancies and genetic diseases. HSC transplantation is performed either autologous or with matched allogeneic/third party, depending upon the clinical scenario. Furthermore, in allogenic transplantation, immunosuppression is necessary to reduce the graft rejection in patients. But despite immunosuppressant therapy, immune rejection in the form of GvHD is still a major cause of morbidity and mortality. The clinical application of MSCs for GvHD developed more rapidly than for any other immune-mediated diseases [68]. The probable cause could be case reports in severe GvHD where BMSCs were infused and showed dramatic therapeutic effects. Clearly, MSCs have a strong potential as therapeutic agents for GvHD, but detailed tailoring of patient population and stringent MSC processing criteria are necessary to deliver consistent and

Apart from GvHD condition, multiple sclerosis (MS), joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA), inflammatory bowel diseases (IBD) and inflammatory airway, and pulmonary diseases are few examples of inflammatory diseases in which preclinical studies have established strong therapeutic effect of MSCs [101]. In multiple sclerosis, reports showed that MSC treatment increases accumulation of Th2 cytokines-IL-4 and IL-5 and generation of Treg in vivo both of which help reduce EAE symptomatology. The possible molecular mechanism by which MSCs polarize CD4 T cells in EAE is via IDO. Indeed, both small and large animal studies demonstrate that MSCs decrease inflammation in

The critical part of IBD is the uncontrolled immune response to intestinal microbes, and it is progressively fatal without curative treatment, making MSCs an attractive therapeutic option for these chronic inflammatory diseases. In several experimental models of IBD, MSCs given by intraperitoneal or intravenous routes showed prevention of DSS-induced injury of the intestines. It was observed that MSCs can specifically reduce Th1 and Th17 responses as well as serum level of pro-inflammatory cytokines (IL-1b, IL-6, IL-17, TNF-α, and IFN-γ) while enhancing the numbers of Tregs and splenic (myeloid-derived suppressor cells) MDSCs. A very recent trial using allogeneic placenta-derived MSC-like cells (which were not registered) also showed favorable immune responses. Thus, MSC therapy for IBD—especially CD

Pulmonary diseases like chronic obstructive lung disease (COPD) are driven by alveolar macrophages, cytotoxic T cells, and neutrophils leading to progressive limitations in airflow with small airway fibrosis and alveolar destruction. In in vivo studies documented post-MSC infusion showed downregulation of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and upregulation of VEGF and TGF-β [105, 106]. In addition, MSCs or MSC-conditioned medium improved tissue damage and survival. This involves MSC-derived factors with microvesicles such as

fistula formation—appears to be safe and a viable option [103, 104].

*DOI: http://dx.doi.org/10.5772/intechopen.80772*

reproducible results [97–100].

joint diseases and facilitate cartilage repair [102].

exosomes, which are considered as carriers.

#### *Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions DOI: http://dx.doi.org/10.5772/intechopen.80772*

host disease (GvHD), decreased graft rejection, prevention of experimental acute encephalomyelitis, prolonged skin graft survival, etc. [8]. However, in recent years, consistent reports on its immunomodulatory properties have opened up newer avenues for studying MSCs, other than regenerative medicine. As of May 2018, there were over 843 MSC-related clinical trials registered on the NIH Clinical Trial Database (http://clinicaltrial.gov/). Interestingly, half of all registered clinical trials (~45%) are being conducted for immune-mediated diseases. Of these, 69 are based on autoimmune disease, 38 on GVHD, and the rest 290 on other inflammatory diseases. However, in early phase I, phase II, phase III, and phase IV, there were 3, 76, 7, and 6 clinical trials conducted, respectively. Hematopoietic stem cells (HSCs) have been the most successful in providing therapeutic application using stem cells. MSCs represent a lifesaving treatment for patients suffering with hematopoietic malignancies and genetic diseases. HSC transplantation is performed either autologous or with matched allogeneic/third party, depending upon the clinical scenario. Furthermore, in allogenic transplantation, immunosuppression is necessary to reduce the graft rejection in patients. But despite immunosuppressant therapy, immune rejection in the form of GvHD is still a major cause of morbidity and mortality. The clinical application of MSCs for GvHD developed more rapidly than for any other immune-mediated diseases [68]. The probable cause could be case reports in severe GvHD where BMSCs were infused and showed dramatic therapeutic effects. Clearly, MSCs have a strong potential as therapeutic agents for GvHD, but detailed tailoring of patient population and stringent MSC processing criteria are necessary to deliver consistent and reproducible results [97–100].

Apart from GvHD condition, multiple sclerosis (MS), joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA), inflammatory bowel diseases (IBD) and inflammatory airway, and pulmonary diseases are few examples of inflammatory diseases in which preclinical studies have established strong therapeutic effect of MSCs [101]. In multiple sclerosis, reports showed that MSC treatment increases accumulation of Th2 cytokines-IL-4 and IL-5 and generation of Treg in vivo both of which help reduce EAE symptomatology. The possible molecular mechanism by which MSCs polarize CD4 T cells in EAE is via IDO. Indeed, both small and large animal studies demonstrate that MSCs decrease inflammation in joint diseases and facilitate cartilage repair [102].

The critical part of IBD is the uncontrolled immune response to intestinal microbes, and it is progressively fatal without curative treatment, making MSCs an attractive therapeutic option for these chronic inflammatory diseases. In several experimental models of IBD, MSCs given by intraperitoneal or intravenous routes showed prevention of DSS-induced injury of the intestines. It was observed that MSCs can specifically reduce Th1 and Th17 responses as well as serum level of pro-inflammatory cytokines (IL-1b, IL-6, IL-17, TNF-α, and IFN-γ) while enhancing the numbers of Tregs and splenic (myeloid-derived suppressor cells) MDSCs. A very recent trial using allogeneic placenta-derived MSC-like cells (which were not registered) also showed favorable immune responses. Thus, MSC therapy for IBD—especially CD fistula formation—appears to be safe and a viable option [103, 104].

Pulmonary diseases like chronic obstructive lung disease (COPD) are driven by alveolar macrophages, cytotoxic T cells, and neutrophils leading to progressive limitations in airflow with small airway fibrosis and alveolar destruction. In in vivo studies documented post-MSC infusion showed downregulation of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and upregulation of VEGF and TGF-β [105, 106]. In addition, MSCs or MSC-conditioned medium improved tissue damage and survival. This involves MSC-derived factors with microvesicles such as exosomes, which are considered as carriers.

*Immune Response Activation and Immunomodulation*

exerted an inhibitory effect on the differentiation of activated T cells, reduced T-cell proliferation, and IFN-γ secretion in an in vitro stimulatedT-cell model [93]. Favaro et al. has shown the effect of BM-MSC-derived exosomes on PBMNCs isolated from type I diabetic patients. These exosomes were able to inhibit the IFN-γ production and significantly increased the production of immunomodulatory mediators such as PGE-2, TGF-β, IL-10, and IL-6 [94]. The in vitro studies were complemented by the in vivo studies which confirmed the immunosuppressive effect of exosomes in mouse allogeneic skin grafting models [95]. Bai et al 2017 have subcutaneously administered exosomes isolated from human embryonic stem cellderived MSCs and showed that there was delayed occurrence of GvHD for 2days, concomitant with increasing Treg polarization. In continuation, the author has also demonstrated that exosomes released from WJ-MSCs can effectively ameliorate experimental autoimmune uveoretinitis (EAU) in rats by inhibiting the migration of inflammatory cells [95]. Moreover, there is only single case study on humans in which MSC exosomes have been tested in the treatment of resistant grade IV acute GvHD patient which experienced improvement in symptoms for 5 months. There were no side effects reported, and the decrease of pro-inflammatory cytokines such as TNF-α, IL-1β, and IFN-γ was observed. The anti-inflammatory molecules IL-10, TGF-β1, and HLA-G contained in the exosome preparations were believed to

contribute to the immunosuppressive effect of MSC-Exo [96].

therapies provides following key advantages:

e.Off-the-shelf secretome therapies.

efficacy profile of these exosome products.

**5. MSCs in preclinical and clinical trials**

c.Mass production through tailor-made cell lines.

d.Potential to be used as ready-to-go biologic product.

a.Less tumorigenicity.

effects.

Although there are limited studies available using MSC-derived exosomes, future advancements into research and gain in in-depth knowledge of immunomodulatory properties of these MSC exosomes could be seen. These nano-vesicles can be developed as cell-free therapies. The use of these exosomes as cell-free

b.Easy storage without application of potentially toxic cryopreservative agents.

f. The time and cost of expansion and maintenance could be greatly reduced.

g.The biological product obtained could be modified to desired cell-specific

Despite these advantages of MSC-derived exosomes, there has been a lack of manufacturing process that is required to generate exosomes with clinically relevant quantities. Therefore, there is an urgent need for technological advancements. Nevertheless, regulatory requirements will be necessary to establish the safety and

MSCs delivered alone or with a biomaterial have been used in a variety of regenerative medicine strategies. In vivo evidence supports the hypothesis that MSCs have immunosuppressive properties that include prevention of graft versus

**116**
