Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can be cultured from various adult and fetal tissues and that are capable of diff erentiating into multiple mesenchymal lineages including bone, cartilage, tendon, marrow stroma and adipose tissue [1]. Because of their unique regenerative potential, MSCs are considered a promising therapeutic modality for tissue regeneration and repair. Moreover, MSCs are thought to be critically involved in the formation of survival niches for memory T cells and B cells in the bone marrow, thereby regulating the size, stability and plasticity of immunological memory.
Awareness has additionally been raised by the fi nding that MSCs display immunomodulatory properties in vitro, as evidenced by their ability to inhibit T-cell prolifera tion. Th is inhibition aff ects the proliferation of T cells induced by alloantigens, mitogens and CD3-ligation. More over, MSCs have also been shown to inhibit the proliferation of B cells, and possibly the activity of natural killer cells. Th e molecular interactions responsible for these inhibitory eff ects observed in vitro are the subject of intense investigations and include the action of prostaglandin E 2 , nitric oxide, indoleamine 2,3-dioxygenase and programmed death ligand-1 [2].
Because of their potent inhibitory eff ects in vitro, MSCs have been used in several preclinical disease models, most often aiming to inhibit alloreactive immunity such as is observed in graft-versus-host disease (GVHD), and in transplantation models. Several studies have now shown that infusions of MSCs can be eff ective in controlling GVHD or in promoting engraftment and survival of allogeneic bone marrow cells. Opposing obser vations have also been reported, however, as injection of allogeneic MSCs has been shown to trigger allospecifi c immune responses in vivo resulting in graft rejection [3]. Th erefore it is conceivable that the modulatory eff ects observed in in vivo transplantation models are not all mediated by immune suppression, but possibly also through other mechanisms. Th e latter are presently not known, but could include production of MSCderived cytokines capable of expanding alloreactive natural killer cells. Such natural killer cells can effi ciently kill donor/host-derived professional antigen-presenting cells and thereby inhibit the induction of allo-specifi c T-cell responses [4,5].
Th e observation that MSCs themselves can induce alloreactive T-cell responses indicates a discrepancy between in vivo fi ndings and the immunosuppressive in vitro fi ndings as also observed by Schurgers and colleagues. Although this is poorly understood, MSC-based interventions are already pioneered in the clinical setting and the fi rst promising results have been reported in the context of human GVHD [6] and Crohn's disease [7].

Mesenchymal stem cells in autoimmune rheumatic diseases
Despite these promising results from transplantation settings, eff ects in preclinical autoimmune disease models are less coherent. Some studies report amelioration of arthritic symptoms in preclinical arthritis models, whereas other studies -such as that by Schurgers and colleagues -could not report benefi cial eff ects or even describe a worsening of the disease course [1,8]. Th e latter could in part be related to the use of allogeneic MSCs, as it has been reported that the use of allogeneic cells -presumably through additional cytokine release as a consequence of the underlying allo response -leads to the exacerbation of arthritis [9]. Furthermore, direct comparison of these studies is hampered by the use of diff erent MSC culture conditions in vitro, diff erent tissues from which the MSCs are derived, and a variety of diff erent administration schedules currently used in vivo. Moreover, studies on the phenotype of MSCs in bone marrow indicate that MSCs are a heterogeneous population comprised of subpopulations that diff eren tially express a number of receptors to interact with immunecompetent eff ector cells. Th e ability of MSCs to modulate immune responses therefore probably depends, in part, on the composition of the starting population.
Despite our incomplete understanding of the mechanisms underlying these divergent results, and inspired by positive reports on the use of bone marrow-derived MSCs in the outcome of GVHD and transplantation engraft ment without the observation of severe side eff ects associated with the infusion of MSC, the fi rst studies in human autoimmune disease are already appear ing [10,11]. Not unexpectedly, however, the clinical eff ects are not coherent.

Concluding remarks
Th e mechanisms underlying the possible in vivo immuno modulatory eff ects of MSCs remain a critical and unresolved question. By comparing side by side the eff ects of MSCs in vitro and in vivo, the study by Schurgers and colleagues brings fresh encouragement to the endeavors to elucidate the immunomodulatory eff ects of MSCs in rheumatic diseases [1]. Given the apparent diffi culties in recapitulating the in vitro eff ects in vivo, however, researchers should be cautioned and should remain critical concerning the use of MSCs for the treatment of human autoimmune disease. It is likely that the endeavors will eventually pay off , but more experience with the use of MSCs in the setting of GVHD can help guide their use for rheumatic diseases, thereby certifying or revoking their therapeutic use for the control of autoimmunity.