Abstract 18425: Preventing Allogeneic Immune Rejection by Transplanting MHC-homo Induced Pluripotent Stem Cell-derived Cardiomyocytes to an MHC-matched non-Human Primate
Introduction: Allogeneic, “ready-made” induced pluripotent stem cells (iPSCs) can be efficiently used for treating cardiac disease, although the immune response produced against the allogenicity is still a concern. Major histocompatibility complex (MHC)-matched allogeneic implantation (MMAI) performed with “ready-made” iPSCs that have homozygous MHC haplotypes can be theoretically used for diminishing the immune rejection. We thus explored the efficacy of this MMAI therapy using a non-human primate, Macaca fascicularis model.
Methods: IPSCs constitutively expressing GFP were derived from Macaca fascicularis with homozygous MHC haplotypes (HT1). All alleles constituting MHC genes were homozygous. Cardiomyogenic differentiation was induced in the iPSCs in vitro. More than 80% of iPSCs were positive for troponin T. The derivatives were then subcutaneously transplanted to the Macaca fascicularis with heterozygous HT1, who served as MMAI models. The immunosuppressants included tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisolone (PSL) for Group 1, TAC only for Group 2, and no immunosuppressants for Group 3, and to the Macaca fascicularis with no alleles of HT1 as MHC-mismatched allogeneic transplantation (MmMAI) model with TAC, MMF, and PSL (Group 4).
Results: The relative GFP intensity of the transplanted cell-clusters at 2 weeks assessed by a stereomicroscope was markedly higher in Group 1 (1.41) than in Group 2 (0.97), Group 3 (0.77), Group 4 (0.81), and controls. The GFP intensity was preserved even after 1 (1.26) or 2 months (1.33) for Group 1, whereas it was markedly diminished in Group 3 (0.33) and Group 4 (0.39) after 1 month. Histologically, the CD3- or CD4-positive T cells were abundantly infiltrated into the graft of Groups 3 and 4 after 1 month, whereas these cells were rarely present in Group 1 at 1 and 2 months. Interleukin-2 receptor expression in the grafts of Groups 3 and 4 was 3-fold higher than that in Group 1.
Conclusions: MMAI of cardiomyogenically differentiated MHC-homo-iPSCs was effective for the engraftment of iPSC-derivatives in non-human primates, which was enhanced by the immunosuppressant therapy. MmMAI of iPSC-derivatives were involved in immune rejection despite complete immunosuppressant therapy.
Author Disclosures: T. Kawamura: None. S. Miyagawa: None. S. Fukushima: None. S. Masuda: None. N. Kashiyama: None. A. Kawamura: None. E. Ito: None. A. Saito: None. A. Maeda: None. K. Toda: None. S. Miyagawa: None. Y. Sawa: None.
- © 2014 by American Heart Association, Inc.