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Immunosuppression Induced by Inflammatory Cytokines in Mesenchymal Stem Cells and Dendritic Cells

by
Guangwen Ren
MS, 2002
Shandong University
PR, China

Thesis Advisor: Dr. Yufang Shi

Graduate Program of Physiology and Integrative Biology

RWJMS Room V-10

Thursday, April 9, 2009
10:00 am


Abstract

Mesenchymal stem cells (MSCs) have great potential for treating many different diseases, especially those related to immune reactions. It is safe to predict that in addition to hematopoietic stem cells, the first clinical applications of stem cells will likely involve the use of MSCs to correct aberrant immune reactions. Various studies have indicated that MSCs are strongly immunosuppressive in vitro and in vivo, while some others have found they are not. We believe that we have resolved this discrepancy by demonstrating that while un-stimulated MSCs are indeed incapable of immunosuppression, they become potently immunosuppressive upon stimulation with the products of activated lymphocytes, or particular combinations of inflammatory cytokines. This observation reveals that under certain circumstances, inflammatory cytokines can actually have immunosuppressive effects. Furthermore, we indicated the species variation in the mechanisms of MSC-mediated immunosuppression: inflammatory cytokines induce production of abundant nitric oxide (NO) to suppress the immune responses in mouse MSCs, whereas immunosuppression by cytokine-primed human MSCs is effected through indoleamine 2, 3-dioxygenase (IDO). Nevertheless, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into proximity with MSCs, where NO or IDO are predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO. Our results provide critical information that helps to explain the apparently conflicting reports about MSC-mediated immunosuppression in the literatures and allow better application of MSCs in treating immune disorders in clinic.

To further investigate if inflammatory cytokine-induced immunosuppression is extendable to other bio-systems other than MSCs, we examine how apoptotic cells induce immunoregulation by dendritic cells (DC), since apoptotic cells have been shown to effectively evoke immune tolerance. Through the in vivo and in vitro experimental models in mouse, we have found that DC exposed to apoptotic cells (DCap) are affected in at least two ways: reduced ability to prime T cells to produce IFNgamma and increased sensitivity to IFNgamma-induced production of nitric oxide (NO). In the presence of both DCap and normal DC, T cells are activated by normal DC to produce IFNgamma which in turn induces DCap to release nitric oxide and thus suppresses immune responses. Therefore, a similar immunosuppressive mechanism is found in DCap as we have observed in MSCs.


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