Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics
Nigel G. Kooreman9, Patricia E. de Almeida9, Jonathan P. Stack9, Raman V. Nelakanti, Sebastian Diecke, Ning-Yi Shao, Rutger-Jan Swijnenburg, Veronica Sanchez-Freire, Elena Matsa, Chun Liu, Andrew J. Connolly, Jaap F. Hamming, Paul H.A. Quax, Michael A. Brehm, Dale L. Greiner, Dale L. Greiner, Leonard D. Shultz, Joseph C. Wu10.
9These authors contributed equally
10Lead Contact
Open access funded by Bloodwise
Article Info
Publication History
Published: August 22, 2017 Accepted: July 26, 2017
Received in revised form: April 23, 2017 Received: July 9, 2015
User License
Creative Commons Attribution (CC BY 4.0)
Highlights
• Innate immunity is crucial in rejection of minor HA mismatched grafts
• Stem cell alloimmune responses modeled with an “allogenized mouse”
• Humanized mice are unable to fully model immune responses to stem cell allografts
• Splenocytes and graft-infiltrating lymphocytes display an exhausted phenotype
Summary
There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an “allogenized” mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.
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