Human mesenchymal stem cells exhibit dual immunosuppressive and antimicrobial effector functions – Implications for their clinical use

In addition to their multilineage differentiation potential mesenchymal stem cells (MSC) support hematopoiesis and modulate the adaptive immune system. Based on these properties human MSC are currently under intensive clinical investigation in different therapeutic applications including tissue repair and immune-mediated disorders such as graft rejection and graft-versus-host disease after haematopoietic stem cell transplantation. With regard to the clinical use in immune-mediated disorders, it is a matter of concern that application of MSC might inadvertently inhibit antimicrobial immune responses with an increased risk of infection. We recently demonstrated, that IFNγ-induced expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) acts as a T cell inhibitory effector mechanism in MSC (Meisel et al, Blood, 2004). Now we show, that the growth of various bacteria (Staph. aureus, KNS, Enterococci), intracellular parasites (T. gondii) and viruses (HSV, CMV) is up to 10,000-fold reduced when these pathogens are cultured in the presence of MSC stimulated with inflammatory cytokines (p<.05). Addition of the IDO-specific inhibitor 1-MT or excess amounts of tryptophan restored microbial growth thus identifying IDO-mediated tryptophan starvation as the underlying mechanism. Collectively, our data identify human MSC as the first cellular immunosuppressant that at the same time exhibit an antimicrobial effector function. This observation may have profound implications for the clinical use of MSCs in immune-mediated disorders and tissue engineering approaches.