MHC matching improves engraftment of iPSC-derived neurons in non-human primates

Asuka Morizane,Jun Takahashi,Daisuke Doi,Keisuke Okita,Kazumasa Ogasawara,Hirohito Ishigaki,Takashi Shiina,Shinya Yamanaka,Sayuki Takara,Yasushi Itoh,Takuya Hayashi,Aya Mawatari,Tetsuhiro Kikuchi,Hiroshi Mizuma,Matthew F Glasser,Hirotaka Onoe,Emi Yamasaki,Hisashi Doi

doi:10.1038/s41467-017-00926-5

Abstract

The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells (iPSCs) is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection. Here we show the efficacy of major histocompatibility complex (MHC)-matched allogeneic neural cell grafting in the brain, which is considered a less immune-responsive tissue, using iPSCs derived from an MHC homozygous cynomolgus macaque. Positron emission tomography imaging reveals neuroinflammation associated with an immune response against MHC-mismatched grafted cells. Immunohistological analyses reveal that MHC-matching reduces the immune response by suppressing the accumulation of microglia (Iba-1+) and lymphocytes (CD45+) into the grafts. Consequently, MHC-matching increases the survival of grafted dopamine neurons (tyrosine hydroxylase: TH+). The effect of an immunosuppressant, Tacrolimus, is also confirmed in the same experimental setting. Our results demonstrate the rationale for MHC-matching in neural cell grafting to the brain and its feasibility in a clinical setting.

Highlights

The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection
We show Major histocompatibility complex (MHC) matching reduces the immune response with microglia and lymphocytes, and increases the survival of induced pluripotent stem cells (iPSCs)-derived dopamine (DA) neurons in non-human primates (NHPs)
The DA neurons were transplanted to monkeys in which at least one of the alleles was identical to the homozygotes for MHC-matched transplantation

Summary

Introduction

The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells (iPSCs) is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection. We show the efficacy of major histocompatibility complex (MHC)-matched allogeneic neural cell grafting in the brain, which is considered a less immune-responsive tissue, using iPSCs derived from an MHC homozygous cynomolgus macaque. A recent report showed that MHC-matched allogeneic induced pluripotent stem cells (iPSC)-derived cardiomyocytes survived and functioned in monkeys that received immunosuppressive treatment[14]. These facts are consistent with the notion that HLA-matched transplantation using HLA-homozygous iPSCs could reduce immunological rejection[9, 15, 16]. We show MHC matching reduces the immune response with microglia and lymphocytes, and increases the survival of iPSC-derived dopamine (DA) neurons in non-human primates (NHPs)

Methods

Results

Conclusion