Paired pre- and post-transplant human immunoprofiling identifies an IFN-γ-JAK1 axis limiting stem-cell-derived RPE...

Area of Science:

• Ophthalmology
• Immunology
• Regenerative Medicine

Background:

• Neovascular age-related macular degeneration (AMD) causes irreversible blindness.
• Current AMD treatments fail to restore damaged retinal cells.
• Human embryonic stem cell-derived RPE (hESC-RPE) transplantation offers regenerative potential but faces immune rejection challenges.

Purpose of the Study:

• To define immune factors contributing to hESC-RPE graft vulnerability.
• To assess a graft-directed intervention to mitigate immune rejection.
• To improve the efficacy and durability of RPE cell therapy for AMD.

Main Methods:

• Immune profiling of blood, aqueous humor, and retinal tissue.
• Allogeneic co-culture and humanized retinal degeneration models.
• Ex vivo conditioning of hESC-RPE with ruxolitinib (JAK inhibitor).

Main Results:

• A Th1-skewed, IFN-γ-rich immune environment was identified in the eye.
• IFN-γ-JAK1 signaling promotes an immunogenic state in hESC-RPE.
• Ex vivo ruxolitinib treatment reduced hESC-RPE immunogenicity without compromising epithelial properties.

Conclusions:

• Ex vivo JAK inhibition attenuates immune responses against hESC-RPE grafts.
• Conditioned grafts demonstrated reduced immune cell infiltration and prolonged survival in models.
• This approach supports ex vivo JAK inhibition as a viable adjunct to RPE cell therapy for AMD, potentially avoiding systemic immunosuppression.