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Andrew Stewart L`Huillier
B.S., Saint Joseph’s University - 2006
Thesis Advisors: Yufang Shi, D.V.M., Ph.D.
Graduate Program in Microbiology & Molecular Genetics
Child Health Institute of New Jersey
Wednesday, June 25, 2014
It has been previously reported that Mesenchymal Stem Cells (MSCs) have immunosuppressive effects both in vitro and in vivo. Conflicting results exist concerning the mechanisms of this immunosuppression, and it is likely that it is not solely mediated by a single mechanism. It has been reported that some of these mechanisms differ among species. Immunosuppression of lymphocytes by human MSCs can be almost completely reversed using the tryptophan analog 1-MT, a competitive inhibitor of indoleamine 2,3-dioxygenase (IDO). The activity of IDO is thought to play a role in both immune regulation as well as immune escape by tumors. This suggests that IDO, a tryptophan catabolizing enzyme which human MSCs can be induced to express high levels of, is a major mediator of their suppression. To better understand the immuno-biology of MSCs, as well as to better be able to predict and modulate their function for clinical trials, the mechanisms of how MSCs achieve their suppressive effects, including the mechanisms of MSC expressed IDO needs to be better understood. Traditionally the immunosuppressive effect of IDO has been attributed to tryptophan depletion. In this thesis, I tested the role of IDO derived tryptophan metabolites in the regulation of immune responses. We have found that inflammatory cytokine stimulated hMSCs convert tryptophan almost completely to these metabolites. The metabolites were able to substitute for hMSC coculture for suppressing T cell proliferation, which was found to be mediated by interfering with an IL-2 – CD25 positive feedback loop in effector T cells (Teff). Further, they selectively increased CD25 expression in regulatory T cells (Tregs), which are not regulated by the same IL-2 – CD25 feedback loop, and synergized with TGFβ1 to induce CD4+ CD25+ Foxp3+ Treg differentiation from naïve CD4+ T cells. While IDO metabolites held Teff in G1 arrest, Tregs were resistant to this effect and continued to proliferate. These results help to shed light on the mechanisms of hMSC and IDO mediated immunosuppression.