Immune Regulatory Role of Parasympathetic Nervous System in Murine Corneal Allografts via Inhibition of Dendritic Cell Activation and T Cell Polarization.

Abstract

PURPOSE: This study aimed to investigate the role of the parasympathetic nervous system in the allorecognition and rejection of murine corneal allografts. METHODS: We used 8- to 12-week-old male C57BL/6 (B6 and 1Ab) and BALB/C (IAd) murine models of corneal allografts. Following keratoplasty, graft survival rate and opacity were assessed for 5 weeks with or without the administration of a 0.1 mL scopolamine injection. Transcriptome changes and the presence of infiltrating antigen-presenting cells (APCs) and specific T-cell types were serially determined from the donor corneal button and draining lymph nodes (LNs) until 5 weeks after the keratoplasty procedure. RESULTS: Compared with the syngeneic models, the alloimmune models were observed to have significantly distinct gene expression profiles following keratoplasty. The total number of differentially expressed genes (DEGs; defined as ≥2-fold change) in the alloaccepted (allo-ac) models relative to the syngeneic ones was 1046 (712 upregulated and 334 downregulated), whereas 148 DEGs (136 upregulated and 12 downregulated) were identified when the Allo-ac models were compared to the allo-rejected (allo-rj) ones. Corneal opacity and rejection rates increased significantly after scopolamine injection. Flow analysis revealed significantly increased CD11b+, CD11c+, and F4/80+ cell infiltration in the donor cornea following the scopolamine treatment. Additionally, reduced Foxp3+ regulatory T (Treg) generation and enhanced Th1/Th17 polarization in the draining LNs were found in the scopolamine-treated allograft. CONCLUSIONS: Parasympathetic innervation may play a critical role in regulating corneal allograft survival by modulating APC activation, reducing Foxp3+ Treg generation, and enhancing Th1/Th17 polarization.