Interleukin-4 (IL-4) suppresses the development of multiple sclerosis in a murine model of experimental autoimmune encephalomyelitis (EAE). Here, we show that, in mice with EAE, the accumulation and persistence in the lymph nodes and spleen of a systemically administered serum albumin (SA)–IL-4 fusion protein leads to higher efficacy in preventing disease development than the administration of wild-type IL-4 or of the clinically approved drug fingolimod. We also show that the SA–IL-4 fusion protein prevents immune-cell infiltration in the spinal cord, decreases integrin expression in antigen-specific CD4+ T cells, increases the number of granulocyte-like myeloid-derived suppressor cells (and their expression of programmed-death-ligand-1) in spinal cord-draining lymph nodes and decreases the number of T helper 17 cells, a pathogenic cell population in EAE. In mice with chronic EAE, SA–IL-4 inhibits immune-cell infiltration into the spinal cord and completely abrogates immune responses to myelin antigen in the spleen. The SA–IL-4 fusion protein may be prophylactically and therapeutically advantageous in the treatment of multiple sclerosis.
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The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding authors on reasonable request.
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We thank the Human Tissue Resource Center of the University of Chicago for histological analysis. We thank the Integrated Light microscopy Core facility and Cytometry and Antibody Technology core facility. We thank S. Gomes for experimental support. We thank T. Sano (University of Illinois at Chicago) for experimental advice and helpful discussions. This work was supported by the University of Chicago.
J.I., A.I, K.K., A.M. and J.A.H. are inventors on International Patent application PCT/US20/19668. The remaining authors declare no competing interests.
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Ishihara, A., Ishihara, J., Watkins, E.A. et al. Prolonged residence of an albumin–IL-4 fusion protein in secondary lymphoid organs ameliorates experimental autoimmune encephalomyelitis. Nat Biomed Eng 5, 387–398 (2021). https://doi.org/10.1038/s41551-020-00627-3