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Prolonged residence of an albumin–IL-4 fusion protein in secondary lymphoid organs ameliorates experimental autoimmune encephalomyelitis

Nature Biomedical Engineering volume 5, pages 387–398 (2021)Cite this article

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Abstract

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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Fig. 1: IL-4 retains activity following fusion to SA.
Fig. 2: Fusion of SA to IL-4 increases the amount of IL-4 in SLOs after i.v. injection.
Fig. 3: SA–IL-4 prevents EAE disease progression and development in the acute phase.
Fig. 4: SA–IL-4 treatment inhibits leukocyte infiltration to the spinal cord and induces immunosuppressive cells in dLNs.
Fig. 5: SA–IL-4 treatment activates the PD-1–PD-L1 axis and decreases integrin and cytokine expression in T cells.
Fig. 6: SA–IL-4 treatment in the chronic phase of EAE decreases the clinical score and prevents immune-cell infiltration to the spinal cord.

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Data availability

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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Acknowledgements

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.

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  1. These authors contributed equally: Jun Ishihara, Elyse A. Watkins.

Authors and Affiliations

  1. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA

    Ako Ishihara, Jun Ishihara, Elyse A. Watkins, Andrew C. Tremain, Mindy Nguyen, Kiyomitsu Katsumata, Aslan Mansurov, Erica Budina, Aaron T. Alpar, Peyman Hosseinchi, Lea Maillat, Joseph W. Reda, Melody A. Swartz, Eiji Yuba & Jeffrey A. Hubbell

  2. Department of Bioengineering, Imperial College London, London, UK

    Jun Ishihara

  3. Committee on Immunology, University of Chicago, Chicago, IL, USA

    Andrew C. Tremain, Melody A. Swartz & Jeffrey A. Hubbell

  4. Animal Resource Center, University of Chicago, Chicago, IL, USA

    Ani Solanki

  5. College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Takahiro Kageyama

  6. Ben May Department of Cancer Research, University of Chicago, Chicago, IL, USA

    Melody A. Swartz

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Contributions

A.I., J.I. and J.A.H. designed the project. A.I., J.I., E.Y., E.A.W., A.C.T., K.K., M.N., A.S., A.M., E.B., A.T.A., P.H., L.M. and J.W.R. performed the experiments. M.N. and A.S. performed the blinded EAE clinical score measurements. A.I. read the blinded histology. A.I., J.I., E.A.W., A.M., E.B., P.H., M.A.S. and J.A.H. analysed the data. J.I., A.I. and J.A.H. wrote the paper.

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Correspondence to Jun Ishihara or Jeffrey A. Hubbell.

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Competing interests

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

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