**4. MSCs as immunomodulatory, anti-Inflammatory, anti-fibrotic, and anti-rejection therapy**

MSCs exhibit immune-privileged properties in vitro and in vivo [165] likely due to the absence of MHC II, B-7 costimulatory molecule, and CD40 ligand [90–92, 166] (**Figure 8**). The lack of costimulatory molecules prevents T-cell responses and also induces an immunosuppressive local microenvironment through the production of prostaglandins and other soluble mediators including nitric oxide, indoleamine 2,3-dioxygenase, and heme oxygenase-1 [92, 167–170]. MSCs reduce the respiratory burst that follows neutrophilic responses by releasing interleukin (IL)-6 [171]. They also inhibit the differentiation of immature monocytes into dendritic cells hence the antigen presentation to naïve T cells is greatly impaired [172]. In addition, MSCs release soluble factors, such as hepatocyte growth factor and transforming growth factor (TGF)-β1 [173], that suppress the proliferation of cytotoxic and helper T-(Th) cells. MSCs also stimulate Foxp3+ regulatory T cells with concurrent suppression of Th1, Th2, or Th17 responses [174]. These findings suggest that MSCs are an effective therapeutic strategy to induce tolerance in solid organ transplantation [175].

#### **4.1. Transplantation**

Le Blanc *et al.* first reported the clinical immunoregulatory response to MSCs in a case of severe, treatment-resistant grade IV acute graft-vs-host disease (GVHD) [13]. A multicenter phase 2 trials for steroid-resistant, severe acute GVHD confirmed this observation [12] and MSCs obtained from HLA-identical siblings, haploidentical third-party donors, or HLAmismatched third-party donors were similarly effective. Recently, infusion of MSCs the day of hematopoietic cell transplantation (HCT) promotes engraftment and improves outcomes. A pilot study of allogeneic MSC infusion before nonmyeloablative HCT from HLA-mismatched donors showed sustained engraftment in 19 out of 20 patients, and the 1 year incidence of nonrelapse mortality, relapse, overall survival, progression-free survival, and death from GVHD was favorable compared to a historic control group [176]. In another pilot study evaluated the effect of infusion of MSCs at the time of dual transplant of cord blood and third-party donor mobilized hematopoietic stem cells regarding tolerance, cord blood engraftment, and effects on acute GVHD, both preventive and therapeutic [177]. MSC infusions were effective for treating severe acute GVHD, but no significant differences in cord blood engraftment and incidence of severe acute GVHD were observed. Although there is accumulating evidence of safety from these small pilot studies [96], randomized trials are necessary to establish efficacy.

A single-site, open-label, randomized controlled clinical trial in 159 patients undergoing living-related donor kidney transplantation showed that induction therapy with autologous MSCs resulted in lower incidence of acute rejection, decreased the risk of opportunistic infection, and better estimated renal graft function at 6 months compared with anti-IL-2 receptor antibody induction therapy [16]. However, graft function and rejection rates were similar after 1 year [178]. Therefore, MSC therapy can safely replace induction immunotherapy, reducing opportunistic infections, without compromising graft function and survival [179].

Mesenchymal Stromal Cells as a Therapeutic Intervention

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Despite these encouraging results, the long-term safety of MSC transplants needs to be further investigated in chronically immunosuppressed patients that are at increased risk for opportunistic infections and tumors [132, 180]. In this regard, a clinical trial evaluated the safety and tolerability of third party MSC administration after liver transplantation. Patients enrolled in the experimental arm were infused with a single dose of 1.5 million MSCs/kg, 3(±2) days after the liver transplantation [181]. There was no impairment in liver transplant function and no increased rate of opportunistic infection or new cancer detected following MSC infusion. In addition, there was no difference in overall rates of rejection or graft survival. Weaning of

Issues needing further investigation include dose, timing and site of administration, interaction with immunosuppressive drugs, and whether MSCs are effective at preventing acute rejection and/or inducing tolerance. In a murine kidney transplant model, it was shown that MSC administration before (day -1) but not a few days after kidney transplantation avoided the acute deterioration of graft function while maintaining the immunomodulatory effect of MSCs [182]. Moreover, a clinical study found that autologous bone marrow-derived MSC infusion at day 7 post-kidney transplant induced acute kidney graft dysfunction, attributed to engraftment syndrome [183], although MSC infusion was associated with lower memory/ effector CD8+ T cells, expansion of CD4+ regulatory T cells, and reduction of donor-specific CD8+ T-cell cytotoxicity compared with control kidney transplant recipients given the same

Islet cell transplantation combined with MSC therapy for type 1 diabetes in a cynomolgus monkey model provides clinical evidence for the anti-rejection effect of MSCs [185]. MSC treatment significantly enhanced islet engraftment and functions one month post-transplant, compared with animals receiving islets without MSCs. In addition, infusions of donor or third-party MSCs resulted in a reversal of rejection episodes and prolongation of islet function. Stable islet allograft function was associated with increased numbers of regulatory T cells in peripheral blood, suggesting that MSCs enhance islet engraftment, thereby decreasing

Autologous MSC transplantation evaluated in clinical trials of amyotrophic lateral sclerosis [18]

regulatory T cells, decreased proliferative responses of lymphocytes, and lower expression of co-

24 hours of transplantation [17]. In a randomized, placebo-controlled, phase 2 trial of multiple

CD25+

), and HLA-DR on myeloid dendritic cells within

and multiple sclerosis [17, 186] is safe and associated with increased proportion of CD4+

, and CD86+

induction therapy (basiliximab/low dose thymoglobulin) but not MSCs [184].

the numbers of islets needed to achieve insulin independence.

, CD83+

**4.2. Autoimmune diseases**

stimulatory molecules (CD40+

immunosuppression in MSC recipients was not successful.

**Figure 8.** Immunomodulatory effects of mesenchymal stem cells. MSCs are immunoprivileged cells that inhibit both innate (neutrophils, dendritic cells, and natural killer cells) and adaptive (T cells and B cells) immune cells.

A single-site, open-label, randomized controlled clinical trial in 159 patients undergoing living-related donor kidney transplantation showed that induction therapy with autologous MSCs resulted in lower incidence of acute rejection, decreased the risk of opportunistic infection, and better estimated renal graft function at 6 months compared with anti-IL-2 receptor antibody induction therapy [16]. However, graft function and rejection rates were similar after 1 year [178]. Therefore, MSC therapy can safely replace induction immunotherapy, reducing opportunistic infections, without compromising graft function and survival [179].

Despite these encouraging results, the long-term safety of MSC transplants needs to be further investigated in chronically immunosuppressed patients that are at increased risk for opportunistic infections and tumors [132, 180]. In this regard, a clinical trial evaluated the safety and tolerability of third party MSC administration after liver transplantation. Patients enrolled in the experimental arm were infused with a single dose of 1.5 million MSCs/kg, 3(±2) days after the liver transplantation [181]. There was no impairment in liver transplant function and no increased rate of opportunistic infection or new cancer detected following MSC infusion. In addition, there was no difference in overall rates of rejection or graft survival. Weaning of immunosuppression in MSC recipients was not successful.

Issues needing further investigation include dose, timing and site of administration, interaction with immunosuppressive drugs, and whether MSCs are effective at preventing acute rejection and/or inducing tolerance. In a murine kidney transplant model, it was shown that MSC administration before (day -1) but not a few days after kidney transplantation avoided the acute deterioration of graft function while maintaining the immunomodulatory effect of MSCs [182]. Moreover, a clinical study found that autologous bone marrow-derived MSC infusion at day 7 post-kidney transplant induced acute kidney graft dysfunction, attributed to engraftment syndrome [183], although MSC infusion was associated with lower memory/ effector CD8+ T cells, expansion of CD4+ regulatory T cells, and reduction of donor-specific CD8+ T-cell cytotoxicity compared with control kidney transplant recipients given the same induction therapy (basiliximab/low dose thymoglobulin) but not MSCs [184].

Islet cell transplantation combined with MSC therapy for type 1 diabetes in a cynomolgus monkey model provides clinical evidence for the anti-rejection effect of MSCs [185]. MSC treatment significantly enhanced islet engraftment and functions one month post-transplant, compared with animals receiving islets without MSCs. In addition, infusions of donor or third-party MSCs resulted in a reversal of rejection episodes and prolongation of islet function. Stable islet allograft function was associated with increased numbers of regulatory T cells in peripheral blood, suggesting that MSCs enhance islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence.
