Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance

Patricia .E de Almeida, Everett H. Meyer, Nigel G. Kooreman, Sebastian Diecke, Devaveena Dey, Veronica Sanchez-Freire, Shijun Hu, Antje Ebert, Justin Odegaard, Nicholas M. Mordwinkin, Thomas P. Brouwer, David Lo, Daniel T. Montoro, Michael T. Longaker, Robert S. Negrin and Joseph C. Wu ()
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Patricia .E de Almeida: Stanford University School of Medicine
Everett H. Meyer: Stanford University School of Medicine
Nigel G. Kooreman: Stanford University School of Medicine
Sebastian Diecke: Stanford University School of Medicine
Devaveena Dey: Stanford University School of Medicine
Veronica Sanchez-Freire: Stanford University School of Medicine
Shijun Hu: Stanford University School of Medicine
Antje Ebert: Stanford University School of Medicine
Justin Odegaard: Stanford University School of Medicine
Nicholas M. Mordwinkin: Stanford University School of Medicine
Thomas P. Brouwer: Stanford University School of Medicine
David Lo: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Daniel T. Montoro: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Michael T. Longaker: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Robert S. Negrin: Stanford University School of Medicine
Joseph C. Wu: Stanford University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract The exact nature of the immune response elicited by autologous-induced pluripotent stem cell (iPSC) progeny is still not well understood. Here we show in murine models that autologous iPSC-derived endothelial cells (iECs) elicit an immune response that resembles the one against a comparable somatic cell, the aortic endothelial cell (AEC). These cells exhibit long-term survival in vivo and prompt a tolerogenic immune response characterized by elevated IL-10 expression. In contrast, undifferentiated iPSCs elicit a very different immune response with high lymphocytic infiltration and elevated IFN-γ, granzyme-B and perforin intragraft. Furthermore, the clonal structure of infiltrating T cells from iEC grafts is statistically indistinguishable from that of AECs, but is different from that of undifferentiated iPSC grafts. Taken together, our results indicate that the differentiation of iPSCs results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC-derived versus original somatic cells.

Date: 2014
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DOI: 10.1038/ncomms4903

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