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Smith-specific regulatory T cells halt the progression of lupus nephritis

Author

Listed:
  • Peter J. Eggenhuizen

    (Monash University)

  • Rachel M. Y. Cheong

    (Monash University)

  • Cecilia Lo

    (Monash University)

  • Janet Chang

    (Monash University)

  • Boaz H. Ng

    (Monash University)

  • Yi Tian Ting

    (Monash University)

  • Julie A. Monk

    (Monash University)

  • Khai L. Loh

    (Monash University)

  • Ashraf Broury

    (Monash University)

  • Elean S. V. Tay

    (Monash University)

  • Chanjuan Shen

    (Central South University)

  • Yong Zhong

    (Monash University
    Central South University)

  • Steven Lim

    (Alfred Research Alliance Flow Cytometry Core Facility)

  • Jia Xi Chung

    (Monash University)

  • Rangi Kandane-Rathnayake

    (Monash University)

  • Rachel Koelmeyer

    (Monash University)

  • Alberta Hoi

    (Monash University
    Monash Health)

  • Ashutosh Chaudhry

    (Former Employee of Amgen)

  • Paolo Manzanillo

    (Amgen Inc)

  • Sarah L. Snelgrove

    (Monash University)

  • Eric F. Morand

    (Monash University
    Monash Health)

  • Joshua D. Ooi

    (Monash University)

Abstract

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Suggested Citation

  • Peter J. Eggenhuizen & Rachel M. Y. Cheong & Cecilia Lo & Janet Chang & Boaz H. Ng & Yi Tian Ting & Julie A. Monk & Khai L. Loh & Ashraf Broury & Elean S. V. Tay & Chanjuan Shen & Yong Zhong & Steven , 2024. "Smith-specific regulatory T cells halt the progression of lupus nephritis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45056-x
    DOI: 10.1038/s41467-024-45056-x
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    References listed on IDEAS

    as
    1. Gouri Shankar Pandey & Chen Yanover & Tom E Howard & Zuben E Sauna, 2013. "Polymorphisms in the F8 Gene and MHC-II Variants as Risk Factors for the Development of Inhibitory Anti-Factor VIII Antibodies during the Treatment of Hemophilia A: A Computational Assessment," PLOS Computational Biology, Public Library of Science, vol. 9(5), pages 1-11, May.
    2. Carl D. Langefeld & Hannah C. Ainsworth & Deborah S. Cunninghame Graham & Jennifer A. Kelly & Mary E. Comeau & Miranda C. Marion & Timothy D. Howard & Paula S. Ramos & Jennifer A. Croker & David L. Mo, 2017. "Transancestral mapping and genetic load in systemic lupus erythematosus," Nature Communications, Nature, vol. 8(1), pages 1-18, December.
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