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

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 progression sometimes developing end stage organ failure.

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 ablation therapies.

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 injury conditions.

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