PT  - JOURNAL ARTICLE
AU  - Jeffrey Harding
AU  - Kristina Vintersten-Nagy
AU  - Maria Shutova
AU  - Huijuan Yang
AU  - Jean Kit Tang
AU  - Mohammad Massumi
AU  - Mohammad Izaidfar
AU  - Zohreh Izadifar
AU  - Puzheng Zhang
AU  - ChengJin Li
AU  - Andras Nagy
TI  - Induction of long-term allogeneic cell acceptance and formation of immune privileged tissue in immunocompetent hosts
AID  - 10.1101/716571
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 716571
4099  - http://biorxiv.org/content/early/2019/07/30/716571.short
4100  - http://biorxiv.org/content/early/2019/07/30/716571.full
AB  - A vast number of diseases could be treated with therapeutic cells derived from pluripotent stem cells (PSCs). However, cell products that come from non-autologous sources can be immune rejected by the recipient’s immune system. Here, we show that forced expression of eight immunomodulatory transgenes, including Ccl21, Pdl1, Fasl, Serpinb9, H2-M3, Cd47, Cd200, and Mfge8, allows mouse embryonic stem cells (mESCs) and their derivatives to escape immune rejection in fully immunocompetent, allogeneic recipients. Despite no genetic alterations to major histocompatibility complex (MHC) genes, immune-modified C57BL/6 mESCs could generate long-term, allogeneic tissues in inbred FVB/N, C3H, and BALB/c, as well as outbred CD-1 recipients. Due to the tandem incorporation of our safe-cell suicide system, which allows tight and drug-inducible control over proliferation in vivo, these allotolerated cells can generate safe and dormant ectopic tissues in the host. We show that these ectopic tissues maintain high expression of all eight immunomodulatory transgenes and are immune-privileged sites that can host and protect unmodified mouse and human cells from rejection in allogeneic and xenogeneic settings, respectively. If translated to human clinical settings, we envision the development of a single pluripotent cell line that can be used to generate allo-tolerated, off-the-shelf cell products to serve all humankind, as well as immune-privileged ectopic tissues to host and immune-protect any kind of therapeutic cell product.