Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system characterized by loss of immune tolerance to the water channel aquaporin-4 (AQP4). Current therapies do not specifically restore AQP4 tolerance or selectively suppress antigen-specific immune responses. Reprogramming patient's own dendritic cells (DCs) with mRNA to induce tolerance represents a promising therapeutic strategy. A key prerequisite for this approach is generating mRNAs encoding disease-relevant autoantigens recognized by the patient's immune system. Here, we generated recombinant mRNAs encoding human AQP4 and evaluated T cell responses to autologous DCs transfected with AQP4 mRNA in eight NMOSD patients and ten healthy controls. Transfected DCs were co-cultured with autologous T cells and stimulated twice. The assay detected robust AQP4-specific T cell response in a patient with recent disease activity who was not receiving immunosuppressive therapy, demonstrating its ability to identify clinically relevant autoreactive T cell responses. These findings establish the feasibility of an mRNA-based antigen-specific T cell assay for studying NMOSD pathogenesis, stratifying patients by T cell involvement, and supporting development of personalized tolerance-inducing therapies.
Pauly, V., Hastermann, M., Paul, F., Garner, C. C., Cestari, S., Schmitz, D., Klotzsch, E., Strempel, N. U.
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