MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates

Romina Aron Badin,Susannah Williams,Caroline Jan,Aurore Bugi,Marie Michael,Philippe Hantraye,Alberto Nassi,Antoine Blancher,Anselme L Perrier,Sophie Lecourtois,Marta Vadori,Emanuele Cozzi

doi:10.1038/s41467-019-12324-0

Abstract

Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington’s disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain.

Highlights

Cell therapy products (CTP) derived from pluripotent stem cells may constitute a renewable, differentiated source of cells to potentially cure patients with neurodegenerative disorders
Availability of inducedhPSCs derived from the patient himself or from selected donors with some degree of HLA matching opens up opportunities to secure scalable sources of cell therapy products (CTP) with enhanced
We identified two major histocompatibility complex (MHC) homozygous individuals (M1/M1 and M3/ M3, respectively) and derived two iPSC lines from peripheral blood mononuclear cells (PBMCs) (Fig. 1a)

Summary

Introduction

Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, differentiated source of cells to potentially cure patients with neurodegenerative disorders. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain. Clinical trials using fetal cells in Parkinson’s and Huntington’s diseases (HD) have paved the way for the development of human pluripotent stem cell (hPSC)-based replacement strategies in the brain These pioneering trials have demonstrated frequent allo-immunisation to fetal donor antigens, sometimes associated with neuro-inflammation and rejection[1]. The more economically sustainable “MHC-paradigm”, i.e., matching the major histocompatibility complex (MHC) of both donor and recipient[10], was tested in NHPs using retinal[11] or dopaminergic transplants[12] Both studies showed no overt sign of humoral or cellular immune response directed against MHC-matched (MA) grafts and demonstrated improved engraftment of such transplants.

Methods

Results

Conclusion