MHC-Matched Induced Pluripotent Stem Cells Can Attenuate Cellular and Humoral Immune Responses but Are Still Susceptible to Innate Immunity in Pigs

Abstract

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.

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

“…However, the degree of immunogenicity of differentiated derivatives of iPS cells upon transplantation back into the individual from whom they were initially derived remains a question (Bjorklund and Kordower, 2013;Morizane et al, 2013;Guha et al, 2013;Araki et al, 2013;Zhao et al, 2011;Mizukami et al, 2014;Lee et al, 2013;Kim, 2011;Lindvall et al, 2012;Parmar and Bjorklund, 2012). For example, previous work in Macaca fasicularis demonstrated that an autologous graft can survive transplantation into a NHP brain (Morizane et al, 2013;Wang et al, 2015), and provided proof-of-concept that patient-specific neurons can be produced for the purposes of autologous transplantation therapy in patients with PD.…”

Induced pluripotent stem cells: Mechanisms, achievements and perspectives in farm animals

“…Furthermore, the methodology for generation of iPS cells is relative simple and and is thought to be easily transferable to other mammalian species. Thus farm animal models may turn out to be ideally suited to determine required cell doses, to assess long-term performance, tumorigenicity, applications methods and fate of transplanted cells [38][39][40][41] . Recent advances in genetic engineering of farm animals allow the generation of precise genetic modifications [42][43][44][45][46][47] , such as the production of immunodeficient pigs [48] which will be instrumental for further advances in preclinical testings of new cell therapies.…”

“…Hence, animal models could be contributed tremendously to a better understanding of disease mechanisms and therapeutic interventions. In addition, iPS cells from monkey [5] , porcine [41,26] , canine [8] and cattle [9] would be useful in animal biotechnology such as making precise genetic engineering for improved production traits and products [137,138] .…”

Impact of Homozygous Conserved Extended HLA Haplotype on Single Cord Blood Transplantation: Lessons for Induced Pluripotent Stem Cell Banking and Transplantation in Allogeneic Settings

“…Concerns remain for allogeneic immunologic events induced due to not only HLA disparity but also natural killer (NK) cell systems. Extensive evaluations of allogeneic responses in this setting have been reported [10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”