Chimerism through the activation of invariant natural killer T cells prolongs graft survival after transplantation of induced pluripotent stem cell-derived allogeneic cardiomyocytes.

Shohei Yoshida,Yasuyuki Ishii,Shigeru Miyagawa,Ai Kawamura,Takuji Kawamura,Yuki Nakamura,Emi Fukuda-Kawaguchi,Yoshiki Sawa,Koichi Toda,Takashi Matsuzaki,Stanislaw Stepkowski

doi:10.1371/journal.pone.0264317

Abstract

The loss of functional cells through immunological rejection after transplantation reduces the efficacy of regenerative therapies for cardiac failure that use allogeneic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Recently, mixed-chimera mice with donor-specific immunotolerance have been established using the RGI-2001 (liposomal formulation of α-galactosyl ceramide) ligand, which activates invariant natural killer T (iNKT) cells. The present study aimed to investigate whether mixed chimerism, established using RGI-2001, prolongs graft survival in allogeneic iPSC-CM transplantation. Mixed-chimera mice were established via combinatorial treatment with RGI-2001 and anti-CD154 antibodies in an irradiated murine bone marrow transplant model. Luciferase-expressing allogeneic iPSC-CMs were transplanted into mixed-chimera and untreated mice, followed by in vivo imaging. RGI-2001 enhanced iNKT cell activation in mice, and mixed chimerism was successfully established. In vivo imaging revealed that while the allografts were completely obliterated within 2 weeks when transplanted to untreated mice, their survivals were not affected in the mixed-chimera mice. Furthermore, numerous CD3+ cells infiltrated allografts in untreated mice, but fewer CD3+ cells were present in mixed-chimera mice. We conclude that mixed-chimera mice established using RGI-2001 showed prolonged graft survival after allogeneic iPSC-CM transplantation. This donor-specific immunotolerance might increase the efficacy of regenerative therapies for heart failure with allogeneic iPSC-CMs.

Highlights

Combinatorial treatment with RGI-2001, the ligand activating invariant natural killer T cells, and an anti-CD154 antibody in a sub-lethally irradiated murine bone marrow transplant model reportedly facilitates the establishment of mixed hematopoietic chimerism through the expansion of in vivo regulatory T cells (Tregs) [8–10]
The present study aimed to investigate whether mixed chimerism, established through the method described, reduces immune rejection after allogeneic induced pluripotent stem cell (iPSC)-CM transplantation in mice
RGI-2001 was intravenously administered at 10 μg/kg to BALB/c (H-2Kd) mice, and flow cytometry of murine splenocytes was performed to examine invariant natural killer T (iNKT) cell activation

Summary

Introduction

Despite the development of therapeutic options, including left ventricular assist devices and heart transplantation, severe heart failure afflicts many people because of its inherent. Chimerism through activation of iNKT cells prolongs graft survival after iPSC-CM transplantation these authors are articulated in the author contributions’ section. Combinatorial treatment with RGI-2001 (liposomal formulation of α-galactosyl ceramide), the ligand activating invariant natural killer T (iNKT) cells, and an anti-CD154 antibody in a sub-lethally irradiated murine bone marrow transplant model reportedly facilitates the establishment of mixed hematopoietic chimerism through the expansion of in vivo regulatory T cells (Tregs) [8–10]. Cardiac allografts were subsequently accepted by mixed-chimera mice in a donor-specific manner without immunosuppressive agents [11, 12]. We hypothesized that allogeneic iPSC-CM transplants could be engrafted in mixed-chimera mice without the need for immunosuppressive agents. The present study aimed to investigate whether mixed chimerism, established through the method described, reduces immune rejection after allogeneic iPSC-CM transplantation in mice

Materials and methods

Results

Discussion

Conclusions