**4. Immune modulating effects of MSCs that may help suppressing auto inflammatory activity during SLE**

MSCs produce a collection of immune modulating molecules, which can locally (paracrine) or systemically (endocrine) effect inflammation. The actions of MSCs are dependent on the environmental signals they receive and are directed to control the excess inflammatory response. It is well studies that MSCs can switch the T cell

**135**

*expansion and activity are defined on the arrows.*

**Figure 1.**

*Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus*

balance from a pro-inflammatory Th1 phenotype (secreting INF-γ and TNF-α) or Th17 phenotype (secreting IL-17) [47] to an anti-inflammatory to Th2 profile

More relevant MSC activities that may help in SLE treatment are 1) MSCs decrease IFN-γ production *in vitro* by T-cells [50] 2) MSCs are able to modulate the cytokine-production profile of (*in vivo*) differentiated Th17 cells, as well as the production of the IL-17 [51–53], 3) MSCs also influence the development and function of DCs [54, 55], 4) MSCs promote the generation of antigen-specific Tregs either directly or indirectly by modulating dendritic cells (DCs) [56], 5) MSCs modulate macrophages [57–60] 6) down-regulate the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6 and IL-12p70 and increase the production of antiinflammatory cytokine IL-10, 7) enhance the phagocytic activity which in return

MSCs can suppress proliferation of both CD4+ and CD8+ T lymphocytes in vitro

in a dose-dependent, non-apoptotic-induced manner, and the immunosuppressive properties against T cells varies among different MSC sources. Transforming growth factor-β (TGF-β), prostaglandin E2 (PGE2), nitric oxide (NO), and indoleamine 2,3-dioxygenase (IDO) have been reported to be involved in the MSCmediated T cell suppression. CD8+ T cells and their activation axis with Indolamine 2, 3-Dioxygenase (IDO) an important anti-inflammatory factor, is suggested to be required for successful suppression of SLE [64], and there is significant data show-

ing the need to increase the Treg activity in SLE treatment (**Figure 1**) [51].

*Suggested pathways of how anti-inflammatory effects of MSCs that control the loss of tolerance, cellular dysfunction and inflammation. During SLE active disease multiple immune cells that works in both innate and adaptive immune system are dysfunctional leading to loss of tolerance and sever inflammation. MSCs, can sense the inflammatory microenvironment and act on attenuating inflammatory activity by secreting soluble factors, such as IDO, TGF-*β*, PGE-2. VEGF, BMP-7, TNF-*α*, IL-6, IL-7and IL-10, i.e. endocrine effect. MSC exert the immunomodulatory function by promoting a switch from pro-inflammatory to anti-inflammatory phenotype and cytokine secretion by T- cells, dendritic cells and NK cells. MSCs can inhibit the proliferation and activation of B effector cells and CD4 + T lymphocytes, while changing and strengthening the cytotoxic effects of CD8 + T cells and NK cells. MSCs anti-inflammatory effects is also explained by its effect on increase of the Tregs, while its potent effect in decreasing the IL-17 secreting Th17 cells. Red arrows are showing the SLE inflammation activation signaling for pathogenic cellular expansion or decrease, while green arrows and blunted lines are showing the opposing effects of MSCs on the abnormal cellular activation and antiinflammatory effects. MSCs endocrine secreted factors by which they are suggested to act specific cellular* 

One key element of the possible effect of MSCs in SLE is that once MSCs enter the inflammatory environment particularly those SLE affected or injured organs;

*DOI: http://dx.doi.org/10.5772/intechopen.97261*

induce resolution of inflammation [61–63] (**Figure 1**).

(secreting IL-4) (**Figure 1**) [48, 49].

*Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97261*

balance from a pro-inflammatory Th1 phenotype (secreting INF-γ and TNF-α) or Th17 phenotype (secreting IL-17) [47] to an anti-inflammatory to Th2 profile (secreting IL-4) (**Figure 1**) [48, 49].

More relevant MSC activities that may help in SLE treatment are 1) MSCs decrease IFN-γ production *in vitro* by T-cells [50] 2) MSCs are able to modulate the cytokine-production profile of (*in vivo*) differentiated Th17 cells, as well as the production of the IL-17 [51–53], 3) MSCs also influence the development and function of DCs [54, 55], 4) MSCs promote the generation of antigen-specific Tregs either directly or indirectly by modulating dendritic cells (DCs) [56], 5) MSCs modulate macrophages [57–60] 6) down-regulate the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6 and IL-12p70 and increase the production of antiinflammatory cytokine IL-10, 7) enhance the phagocytic activity which in return induce resolution of inflammation [61–63] (**Figure 1**).

MSCs can suppress proliferation of both CD4+ and CD8+ T lymphocytes in vitro in a dose-dependent, non-apoptotic-induced manner, and the immunosuppressive properties against T cells varies among different MSC sources. Transforming growth factor-β (TGF-β), prostaglandin E2 (PGE2), nitric oxide (NO), and indoleamine 2,3-dioxygenase (IDO) have been reported to be involved in the MSCmediated T cell suppression. CD8+ T cells and their activation axis with Indolamine 2, 3-Dioxygenase (IDO) an important anti-inflammatory factor, is suggested to be required for successful suppression of SLE [64], and there is significant data showing the need to increase the Treg activity in SLE treatment (**Figure 1**) [51].

One key element of the possible effect of MSCs in SLE is that once MSCs enter the inflammatory environment particularly those SLE affected or injured organs;

#### **Figure 1.**

*Lupus - Need to Know*

ablation therapies.

injury conditions.

**3. MSC treatment in SLE**

While there is systemic inflammation and autoimmunity ongoing, patients with SLE have less active immune cells that defend against pathogens and tumors [35, 36]. Cytotoxic CD8+ T cells and T regulatory (Treg) cells that play fundamen-

Currently available treatments of SLE (Systemic Lupus Erythematosus) target one cell (CD20+ B cells) or one pathway at a time leaving the others to continue to function abnormally and their immunosuppressant side effects to diminish patients' ability to fight infections. After these treatments, patients become immune compromised and vulnerable to pathogens and develop sepsis and septic shock. In many patients, even combinations of all are not effective in controlling disease

MSCs are multipotent stromal cells than have the potential to differentiate into multiple mesenchymal lineages [38–43]. Core standardized definition of the 'multipotent mesenchymal stromal cell' as a plastic-adherent cell type bearing various stromal surface makers, but lacking hematopoietic markers, capable of at least osteogenic, chondrogenic and adipogenic differentiation was proposed by a consensus group [44]. The name was later modified and was changed to 'mesenchymal stromal cell'. No unique marker exists to define MSCs still and clinical studies will certainly involve different heterogeneous MSCs that can be isolated from different adult and fetal tissues such bone marrow (BM), umbilical cord (UC) and adipose tissue (AT). MSCs are so far defined with the presence of their characteristic cell surface markers such as CD105, CD90, CD73, CD106, CD146, CD166, CD271 and the absence of hematopoietic progenitor cells markers such as CD45, CD34 and CD14. They are uniquely immune privileged and can escape rejection reactions from hosts since they do not express class II MHC, such as HLA-DR and co-stimulatory molecules such as CD80, CD86 and CD40 [43, 45, 46]. Therefore, they are easily used as adoptive transfer cell treatment without any prior immune

Besides their differentiation potentials, MSCs have potent immune regulatory effects. MSCs mediate immune system either by secreting soluble factors or directly interacting with a variety of immune effector cells. MSCs uniquely gain different properties and immunoregulatory effects depending on the inflammatory milieu and disease setting. MSCs secrete numerous cytokines, chemokines, and hormones to exert paracrine effects on adjacent immune cells to modulate their proliferation, differentiation, migration, and adhesion functions under

It has been suggested that with their potent immune regulatory effects MSCs are future of cell therapy in refractory lupus. However, the studies thus far published do not agree on the kind, amount and frequency of MSC treatments or showed consistent efficacy. MSCs have not been FDA approved for any disease indication, mostly due to challenges in potency. MSCs have been used as therapeutics in hundreds of

**4. Immune modulating effects of MSCs that may help suppressing auto** 

MSCs produce a collection of immune modulating molecules, which can locally (paracrine) or systemically (endocrine) effect inflammation. The actions of MSCs are dependent on the environmental signals they receive and are directed to control the excess inflammatory response. It is well studies that MSCs can switch the T cell

clinical trials, including SLE, with no adverse reactions reported.

**inflammatory activity during SLE**

tal role in immune defense are depleted during SLE activity [37].

progression sometimes developing end stage organ failure.

**134**

*Suggested pathways of how anti-inflammatory effects of MSCs that control the loss of tolerance, cellular dysfunction and inflammation. During SLE active disease multiple immune cells that works in both innate and adaptive immune system are dysfunctional leading to loss of tolerance and sever inflammation. MSCs, can sense the inflammatory microenvironment and act on attenuating inflammatory activity by secreting soluble factors, such as IDO, TGF-*β*, PGE-2. VEGF, BMP-7, TNF-*α*, IL-6, IL-7and IL-10, i.e. endocrine effect. MSC exert the immunomodulatory function by promoting a switch from pro-inflammatory to anti-inflammatory phenotype and cytokine secretion by T- cells, dendritic cells and NK cells. MSCs can inhibit the proliferation and activation of B effector cells and CD4 + T lymphocytes, while changing and strengthening the cytotoxic effects of CD8 + T cells and NK cells. MSCs anti-inflammatory effects is also explained by its effect on increase of the Tregs, while its potent effect in decreasing the IL-17 secreting Th17 cells. Red arrows are showing the SLE inflammation activation signaling for pathogenic cellular expansion or decrease, while green arrows and blunted lines are showing the opposing effects of MSCs on the abnormal cellular activation and antiinflammatory effects. MSCs endocrine secreted factors by which they are suggested to act specific cellular expansion and activity are defined on the arrows.*

their immune-modulatory phenotype could become activated by IFN-γ, TNF-α and IL-1β in the microenvironment [65]. Furthermore, it has been shown that MSCs are chemotactically drawn toward a variety of wound healing cytokines in vitro, including IL-1 and TNF-α. These data suggest that MSCs or endogenous cells resembling MSCs, such as pericytes, are likely to migrate to and participate in the response to tissue injury [66–69].

When MSCs are exposed to the microenvironment of diseased tissue, they control/suppress inflammation inducing regeneration [56]. With their potent immune regulatory and regenerative effects in response to their microenvironment, and as no adverse reactions in clinical trials have been reported, MSCs are an attractive treatment in SLE. By increasing the potency of MSCs in SLE, it is anticipated that primed MSCs will lower the overall cost of care for SLE patients that are refractory for the current standard of care.

Effects of human MSCs on interferon regulated mediators, and the connections of these mediators with clinical outcomes in SLE have been suggested, but MSC treatments have not been efficacious across heterogeneous organ involvement of SLE to date.

MSCs have been used as therapeutics in hundreds of clinical trials, as of July 2020, there were a total of 1,138 registered clinical trials to clinicaltrials.gov including SLE. In the 18 published clinical trials with outcomes there were no serious adverse events reported [70]. However, MSCs have not been FDA approved for any disease indication yet, mostly due to challenges in potency. MSC treatment has been shown to be successful for a short time and there were relapses in SLE patients in 6–12 months [71, 72].

MSC sources used in clinical trials have different donor pools and are isolated from different tissues with variable immune regulatory function. Furthermore, large-scale MSC-based cell therapy remains restricted due to the cells' ability to expand, and then efficiently respond to inflammatory environment after several number of passages.
