Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the brain. Cell replacement therapy using iPS cell-derived dopaminergic neural progenitors (iPSC-DANs) represents a promising strategy to restore motor functions. However, immune rejection remains a major concern, especially in allogeneic transplantation settings.

In the open-label, phase I/II clinical trial, seven patients received bilateral transplants of iPSC-DANs derived from a clinical-grade iPS cell line with a homozygous HLA haplotype common in the Japanese population. Three recipients were fully HLA-matched, while four were mismatched. All patients were administered tacrolimus, a commonly used immunosuppressant, for up to 15 months following surgery.

No clinically significant immune reactions were observed throughout the trial. PET imaging using the TSPO ligand [¹⁸F]GE180 revealed no signs of neuroinflammation at 3, 6, 12, or 16 months after transplantation. Serum analyses showed no elevation of inflammatory cytokines or emergence of donor-specific antibodies, even after the discontinuation of tacrolimus. Renal function remained stable, and no adverse events related to immunosuppression were reported.

To investigate subclinical immune responses in detail, the researchers conducted mixed lymphocyte reaction (MLR) assays using iPS cell-derived dendritic cells (iPSC-DCs) and iPSC-DANs as stimulators. While iPSC-DANs elicited minimal T cell activation, iPSC-DCs triggered significant responses in peripheral blood mononuclear cells from HLA-mismatched recipients, particularly at three months post-transplantation. These findings suggest that the low expression of HLA molecules in iPSC-DANs contributes to immune tolerance in the central nervous system (CNS).

The study highlights the unique immunological environment of the CNS, where reduced immunogenicity of iPS cell-derived grafts and the immune-privileged nature of the brain may allow for less intensive immunosuppressive regimens compared to typical organ transplantations. Importantly, the trial demonstrated that HLA-mismatched iPSC-DANs can survive and function without triggering overt immune rejection under tacrolimus monotherapy.

This work also underscores the advantages of iPS cell-based therapies over fetal tissue transplantation, including donor consistency, scalability, and reduced ethical concerns. As the field advances, the development of hypoimmunogenic or "universal" iPS cells through gene editing may further minimize the need for immunosuppression, expanding access to regenerative treatments for neurodegenerative diseases.

The researchers emphasize the importance of individualized immune monitoring and highlight the need to develop cost-effective tools to detect early immune responses. Altogether, these insights pave the way for safer and more accessible stem cell therapies for Parkinson's disease and other CNS disorders.

Graphical abstract

• doi: 10.1016/j.stem.2025.07.012