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Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system

Gene Therapy volume 22, pages 217–226 (2015)Cite this article

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Abstract

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5′-end of the siRNA sense strand that was stably incorporated into 1,3-β-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4+, CD8+ T cells into the graft was lower, and that the numbers of CD40lowCD11c+ DCs cells and CD4+Foxp3+cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

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Acknowledgements

This study was supported by research grants from the Grant of Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid 20390349, 21659310, 25462535 and 22/00830); Grant of National Center for Child Health and Development (22-10); Japan Science and Technology Agency (A-step, AS2414902Q).

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Author notes

  1. Q Zhang, N Ichimaru and S Higuchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

    Q Zhang, S Cai, J Hou, M Fujino & X-K Li

  2. Huashan Hospital, Fudan University, Shanghai, China

    Q Zhang, J Hou, H Zou & J Xu

  3. Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan

    N Ichimaru, S Cai & S Takahara

  4. NapaJen Pharma, Inc., Tokyo, Japan

    S Higuchi, M Kobayashi, H Ando & A Uno

  5. AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan

    M Fujino

  6. Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan

    N Nonomura

  7. Department of Chemistry and Biochemistry, University of Kitakyushu, Kitakyushu, Japan

    K Sakurai & S Mochizuki

  8. Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan

    Y Adachi & N Ohno

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  1. Q Zhang
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Corresponding author

Correspondence to X-K Li.

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The authors declare no conflict of interest.

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This study was performed in Tokyo, Japan.

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Zhang, Q., Ichimaru, N., Higuchi, S. et al. Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system. Gene Ther 22, 217–226 (2015). https://doi.org/10.1038/gt.2014.119

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  • DOI: https://doi.org/10.1038/gt.2014.119

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