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Modular complement assemblies for mitigating inflammatory conditions.

Publication ,  Journal Article
Hainline, KM; Shores, LS; Votaw, NL; Bernstein, ZJ; Kelly, SH; Fries, CN; Madhira, MS; Gilroy, CA; Chilkoti, A; Collier, JH
Published in: Proceedings of the National Academy of Sciences of the United States of America
April 2021

Complement protein C3dg, a key linkage between innate and adaptive immunity, is capable of stimulating both humoral and cell-mediated immune responses, leading to considerable interest in its use as a molecular adjuvant. However, the potential of C3dg as an adjuvant is limited without ways of controllably assembling multiple copies of it into vaccine platforms. Here, we report a strategy to assemble C3dg into supramolecular nanofibers with excellent compositional control, using β-tail fusion tags. These assemblies were investigated as therapeutic active immunotherapies, which may offer advantages over existing biologics, particularly toward chronic inflammatory diseases. Supramolecular assemblies based on the Q11 peptide system containing β-tail-tagged C3dg, B cell epitopes from TNF, and the universal T cell epitope PADRE raised strong antibody responses against both TNF and C3dg, and prophylactic immunization with these materials significantly improved protection in a lethal TNF-mediated inflammation model. Additionally, in a murine model of psoriasis induced by imiquimod, the C3dg-adjuvanted nanofiber vaccine performed as well as anti-TNF monoclonal antibodies. Nanofibers containing only β-tail-C3dg and lacking the TNF B cell epitope also showed improvements in both models, suggesting that supramolecular C3dg, by itself, played an important therapeutic role. We observed that immunization with β-tail-C3dg caused the expansion of an autoreactive C3dg-specific T cell population, which may act to dampen the immune response, preventing excessive inflammation. These findings indicate that molecular assemblies displaying C3dg warrant further development as active immunotherapies.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

April 2021

Volume

118

Issue

15

Start / End Page

e2018627118

Related Subject Headings

  • Vaccines
  • Tumor Necrosis Factor-alpha
  • T-Lymphocytes
  • Psoriasis
  • Nanofibers
  • Mice, Inbred C57BL
  • Mice
  • Epitopes
  • Complement C3d
  • Cells, Cultured
 

Citation

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Hainline, K. M., Shores, L. S., Votaw, N. L., Bernstein, Z. J., Kelly, S. H., Fries, C. N., … Collier, J. H. (2021). Modular complement assemblies for mitigating inflammatory conditions. Proceedings of the National Academy of Sciences of the United States of America, 118(15), e2018627118. https://doi.org/10.1073/pnas.2018627118
Hainline, Kelly M., Lucas S. Shores, Nicole L. Votaw, Zachary J. Bernstein, Sean H. Kelly, Chelsea N. Fries, Marisha S. Madhira, Caslin A. Gilroy, Ashutosh Chilkoti, and Joel H. Collier. “Modular complement assemblies for mitigating inflammatory conditions.Proceedings of the National Academy of Sciences of the United States of America 118, no. 15 (April 2021): e2018627118. https://doi.org/10.1073/pnas.2018627118.
Hainline KM, Shores LS, Votaw NL, Bernstein ZJ, Kelly SH, Fries CN, et al. Modular complement assemblies for mitigating inflammatory conditions. Proceedings of the National Academy of Sciences of the United States of America. 2021 Apr;118(15):e2018627118.
Hainline, Kelly M., et al. “Modular complement assemblies for mitigating inflammatory conditions.Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 15, Apr. 2021, p. e2018627118. Epmc, doi:10.1073/pnas.2018627118.
Hainline KM, Shores LS, Votaw NL, Bernstein ZJ, Kelly SH, Fries CN, Madhira MS, Gilroy CA, Chilkoti A, Collier JH. Modular complement assemblies for mitigating inflammatory conditions. Proceedings of the National Academy of Sciences of the United States of America. 2021 Apr;118(15):e2018627118.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

April 2021

Volume

118

Issue

15

Start / End Page

e2018627118

Related Subject Headings

  • Vaccines
  • Tumor Necrosis Factor-alpha
  • T-Lymphocytes
  • Psoriasis
  • Nanofibers
  • Mice, Inbred C57BL
  • Mice
  • Epitopes
  • Complement C3d
  • Cells, Cultured