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INDOLEAMINE-2,3-DIOXYGENASE IS CRITICAL TO MESENCHYMAL STEM CELL-BASED ALLOGRAFT TOLERIZATION
Presenter: Marc A Soares, MD
Co-Authors: Low YC; Ham MJ; Lalezarzadeh F; Wilson SC; Ojo CO; Lotfi P; Saadeh PB; Ceradini DJ
NYU Medical Center

Background: Acute rejection is characterized by lymphocyte-mediated destruction of donor vasculature. Our previous work demonstrated that mesenchymal stem cells (MSCs) have powerful immunosuppressive functions, yet how they promote allograft tolerance is unclear. Here we characterize the immunomodulatory factor, indoleamine-2,3-dioxygenase (IDO), as a critical regulator of MSC immunosuppression. Further, we investigate novel techniques of allograft-engineering during the ex vivo period to promote peripheral tolerance.

Methods: We characterized expression of pro- & anti- inflammatory markers and IDO using allogenic MSC and endothelial cell (EC) co-culture. CD8+-mediated EC cytotoxicity & CD4+ proliferation assays assessed the functional of MSCs on allorejection. Differential culture conditions were used to enhance IDO expression in MSCs. In vivo, Brown-Norway rat allografts were perfused ex vivo with Lewis rat MSCs prior to transplantation into Lewis recipients and assessed for allograft survival & rejection.

Results: Allogeneic MSC-EC co-culture increased IDO 300% and decreased inflammatory chemokine MCP-1 50%, compared to EC-only culture (p<0.01 for all). Hypoxic and inflammatory cytokine culture increased IDO up to 22-fold, reduced allogenic CD8+ rejection & CD4+ proliferation by 74% and 54%, respectively, when compared to control (p<0.05 for all). In the presence of an IDO inhibitor (1-MT), these effects were abolished. Ex-vivo seeded allografts featured MSCs within immunologically important tissues with pro-tolerance expression profiles (5-fold IDO increase, 4- & 2- fold decreases in MCP1 and CXCL9, respectively) compared to control (p<0.01 for all). Preliminary evidence suggests prolongation in allograft survival via MSC-induced tolerance.

Conclusion: IDO critically-mediates MSC immunosuppression. Moreover, MSC fate can be directed towards immunomodulation, seeded into allografts ex vivo to create a tolerized allograft, and potentially reduce the need for lifelong systemic immunosuppression. This represents technology that is available now with minimal regulatory approval.


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