MSCs enjoy a degree of immune privilege in that allogeneic MSCs may be infused into patients without any preconditioning and seem to survive long enough to exert positive clinical effects without acute toxicity.
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November 2008The mechanisms underlying the immunosuppressive effect of MSCs remain to be fully clarified, with sometimes-conflicting data probably reflecting the variable definitions and experimental conditions. Certainly, mechanisms may be multiple and involve both cell contact and the production of soluble factors including interleukin (IL)-10, transforming growth factor-beta, hepatocyte growth factor, IL-1 receptor antagonist, and soluble HLA-G.
Animal Models
It may be impossible to try to separate the anti-inflammatory, immunomodulatory, and tissue protective “trophic” effects of MSC. An immunosuppressive effect of MSC in vivo was first suggested in a baboon model, where infusion of ex vivo expanded donor or third-party MSCs delayed the time to rejection of histoincompatible skin grafts. In murine models, MSCs can also down-regulate bleomycin-induced lung inflammation and fibrosis, if given early (but not late) after the induction. A similar effect was observed in a murine hepatic fibrosis model (carbon tetrachloride-induced) using an MSC line. Tissue protective effects were also seen in a rat kidney model of ischemia/reperfusion injury in which syngeneic MSCs were used.
In the two murine models of experimental autoimmune encephalomyelitis, both clinical and histological improvement occurred. However, in a murine model of arthritis, collagen induced arthritis was not improved by the addition of MSCs and the in vitro immunosuppressive effects were reversed by the addition of tumor necrosis factor-α. MSCs were not found in the joints. A second murine arthritis model showed, however, a positive outcome.
Recently, a murine model of streptozocin-induced diabetes mellitus was reported to improve clinically following transplantation with a combination of bone marrow derived cells and syngeneic and allogeneic MSCs following sublethal irradiation. The proposed mechanism was regeneration of recipient derived islet cells plus immunosuppression of autoreactive T cells. Neither cell product alone was effective.
MSCs and Human Experience
Ex vivo–expanded allogeneic MSCs have been infused in several phase I studies. No adverse events during or after MSC infusion have been observed, and no ectopic tissue formation has been noted. After infusion, MSCs remain in the circulation for no more than an hour. In another study, infusion of haploidentical MSCs to a patient with steroid-resistant severe acute GvHD of the gut and liver promptly improved liver values and intestinal function.
The EBMT is currently running protocols for prevention and treatment of acute GvHD through its developmental committee, and interim results of the treatment trial have recently been published. Thirty out of 55 steroid-resistant acute-GvHD patients had a complete response with no immediate toxicity.13