Antibody-Mediated Depletion of Autoreactive T Lymphocytes through PD-1 Improves Disease Outcomes and Visualizes T Cell Activation in Experimental Autoimmune Encephalomyelitis

• Published in: The Journal of immunology (1950) Vol. 212; no. 11; pp. 1647 - 1657
• Main Authors: Frank, Connor, Salapa, Hannah E, Allen, Kevin J H, Levin, Michael C, Dawicki, Wojciech, Dadachova, Ekaterina
• Format: Journal Article
• Language: English
• Published: United States 01.06.2024
• Subjects: Animals; Antibodies, Monoclonal; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - immunology; Female; Humans; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Multiple Sclerosis - diagnostic imaging; Multiple Sclerosis - immunology; Positron Emission Tomography Computed Tomography - methods; Programmed Cell Death 1 Receptor - immunology; T-Lymphocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2300751

Long-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice. We also investigated the upregulation of PD-1 on infiltrating lymphocytes in an animal model of MS. Finally, we demonstrate the (to our knowledge) first reported positron-emission tomography/computed tomography imaging of activated PD-1+ cells in the EAE animal model of MS. We found that the 177Lu radioisotope-labeled anti-PD-1 mAb demonstrated significant in vitro cytotoxicity toward activated CD4+PD-1+ T lymphocytes and led to significant reduction in overall disease progression in the EAE animal model. Our results show high expression of PD-1 on infiltrating lymphocytes in the spinal cords of EAE diseased animals. Positron-emission tomography/computed tomography imaging of the anti-PD-1 mAb demonstrated significant uptake in the cervical draining lymph nodes highlighting accumulation of activated lymphocytes. Targeted depletion of T lymphocytes using T cell activation markers such as PD-1 may present a novel method to reduce autoimmune attack and inflammation in autoimmune diseases such as MS. Development of multimodal nuclear theranostic agents may present the opportunity to monitor T cell activation via imaging radioisotopes and simultaneously treat MS using therapeutic radioisotopes.