PMID- 24927426 OWN - NLM STAT- MEDLINE DCOM- 20151022 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 6 DP - 2014 TI - MHC-matched induced pluripotent stem cells can attenuate cellular and humoral immune responses but are still susceptible to innate immunity in pigs. PG - e98319 LID - 10.1371/journal.pone.0098319 [doi] LID - e98319 AB - Recent studies have revealed negligible immunogenicity of induced pluripotent stem (iPS) cells in syngeneic mice and in autologous monkeys. Therefore, human iPS cells would not elicit immune responses in the autologous setting. However, given that human leukocyte antigen (HLA)-matched allogeneic iPS cells would likely be used for medical applications, a more faithful model system is needed to reflect HLA-matched allogeneic settings. Here we examined whether iPS cells induce immune responses in the swine leukocyte antigen (SLA)-matched setting. iPS cells were generated from the SLA-defined C1 strain of Clawn miniature swine, which were confirmed to develop teratomas in mice, and transplanted into the testes (n = 4) and ovary (n = 1) of C1 pigs. No teratomas were found in pigs on 47 to 125 days after transplantation. A Mixed lymphocyte reaction revealed that T-cell responses to the transplanted MHC-matched (C1) iPS cells were significantly lower compared to allogeneic cells. The humoral immune responses were also attenuated in the C1-to-C1 setting. More importantly, even MHC-matched iPS cells were susceptible to innate immunity, NK cells and serum complement. iPS cells lacked the expression of SLA class I and sialic acids. The in vitro cytotoxic assay showed that C1 iPS cells were targeted by NK cells and serum complement of C1. In vivo, the C1 iPS cells developed larger teratomas in NK-deficient NOG (T-B-NK-) mice (n = 10) than in NK-competent NOD/SCID (T-B-NK+) mice (n = 8) (p<0.01). In addition, C1 iPS cell failed to form teratomas after incubation with the porcine complement-active serum. Taken together, MHC-matched iPS cells can attenuate cellular and humoral immune responses, but still susceptible to innate immunity in pigs. FAU - Mizukami, Yoshihisa AU - Mizukami Y AD - Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan. FAU - Abe, Tomoyuki AU - Abe T AD - Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan. FAU - Shibata, Hiroaki AU - Shibata H AD - Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan. FAU - Makimura, Yukitoshi AU - Makimura Y AD - Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan. FAU - Fujishiro, Shuh-hei AU - Fujishiro SH AD - Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan. FAU - Yanase, Kimihide AU - Yanase K AD - Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan. FAU - Hishikawa, Shuji AU - Hishikawa S AD - Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan. FAU - Kobayashi, Eiji AU - Kobayashi E AD - Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan. FAU - Hanazono, Yutaka AU - Hanazono Y AD - Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140613 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (swine leukocyte antigen) SB - IM MH - Animals MH - Cells, Cultured MH - Female MH - Histocompatibility Antigens Class I MH - Histocompatibility Antigens Class II MH - Immunity, Humoral MH - Immunity, Innate MH - Induced Pluripotent Stem Cells/immunology/*transplantation MH - Killer Cells, Natural/*immunology MH - *Major Histocompatibility Complex MH - Male MH - Mice MH - Mice, SCID MH - Ovary/immunology MH - Swine/*immunology MH - Swine, Miniature/*immunology MH - Teratoma/*etiology MH - Testis/immunology MH - Transplantation, Autologous PMC - PMC4057111 COIS- Competing Interests: Prof. Eiji Kobayashi is a chief scientific advisor; however, this does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials. EDAT- 2014/06/14 06:00 MHDA- 2015/10/23 06:00 PMCR- 2014/06/13 CRDT- 2014/06/14 06:00 PHST- 2013/10/20 00:00 [received] PHST- 2014/04/30 00:00 [accepted] PHST- 2014/06/14 06:00 [entrez] PHST- 2014/06/14 06:00 [pubmed] PHST- 2015/10/23 06:00 [medline] PHST- 2014/06/13 00:00 [pmc-release] AID - PONE-D-13-42849 [pii] AID - 10.1371/journal.pone.0098319 [doi] PST - epublish SO - PLoS One. 2014 Jun 13;9(6):e98319. doi: 10.1371/journal.pone.0098319. eCollection 2014.