Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

• Published in: Cell reports (Cambridge) Vol. 20; no. 8; pp. 1978 - 1990
• Main Authors: Kooreman, Nigel G., de Almeida, Patricia E., Stack, Jonathan P., Nelakanti, Raman V., Diecke, Sebastian, Shao, Ning-Yi, Swijnenburg, Rutger-Jan, Sanchez-Freire, Veronica, Matsa, Elena, Liu, Chun, Connolly, Andrew J., Hamming, Jaap F., Quax, Paul H.A., Brehm, Michael A., Greiner, Dale L., Shultz, Leonard D., Wu, Joseph C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2017; Cell Press; Elsevier
• Subjects: allograft; humanized mice; immunogenicity; pluripotent stem cells; Resource; stem cell therapeutics; T cell exhaustion; wasting disease; pluripotent stem cells; stem cell therapeutics; humanized mice; T cell exhaustion; allograft; immunogenicity; wasting disease
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.08.003

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. [Display omitted] •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 Kooreman et al. use various types of humanized mice for the modeling of pluripotent stem cell alloimmunity. They report the development of a wasting disease-like syndrome within these mice over time, limiting their functionality, and provide ways to address this by using an immune reconstituted “allogenized” mouse model.