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Combination therapy of an iNKT cell ligand and CD40–CD154 blockade establishes islet allograft acceptance in nonmyeloablative bone marrow transplant recipients

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Abstract

Aims

Islet transplantation is an effective therapeutic option for type 1 diabetes. Although maintenance immunosuppression therapy is required to prevent allogeneic rejection and recurrence of autoimmunity, long-term allograft survival has not yet been achieved partly because of its adverse effects. The induction of donor-specific immunotolerance is a promising approach for long-term allograft survival without maintenance immunosuppression therapy. We previously reported that combination therapy using a liposomal ligand for invariant natural killer T cells, RGI-2001, and anti-CD154 antibody established mixed hematopoietic chimerism for the induction of donor-specific immunotolerance. This study investigated whether the protocol could promote islet allograft acceptance in experimental diabetes.

Methods

Streptozotocin-induced diabetic BALB/c mice were transplanted with bone marrow cells from C57BL/6 donors and received combination therapy of RGI-2001 and anti-CD154 antibody after 3-Gy total body irradiation. 3 Weeks after bone marrow transplantation, islets isolated from C57BL/6 donors were transplanted under the kidney capsule.

Results

Mixed chimerism was established in diabetic mice receiving the tolerance induction protocol. After islet transplantation, blood glucose levels improved and normoglycemia persisted for over 100 days. Hyperglycemia recurred after islet grafts were removed. Histopathological examinations showed insulin-positive staining and absence of cellular infiltration in the islet grafts. T cells of recipients showed donor-specific hyporesponsiveness, and anti-donor antibodies were not detected.

Conclusions

The tolerance induction protocol with combination therapy of RGI-2001 and anti-CD154 antibody promoted islet allograft acceptance in a mouse diabetic model. This protocol may be clinically applied to islet transplantation for type 1 diabetes mellitus.

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Acknowledgements

During this research, we used instruments from the Medical Research Institute (MRI), Tokyo Women’s Medical University. The authors would like to thank Hideki Nakayama for the staining of pathological samples. This work was supported by JSPS KAKENHI Grant number JP15K19864.

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Authors and Affiliations

  1. Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan

    Taichi Kanzawa, Toshihito Hirai, Hironori Fukuda, Haruki Katsumata, Rumi Ishii, Masako Ikemiyagi, Kan Saiga, Masayoshi Okumi & Kazunari Tanabe

  2. Vaccine Innovation Laboratory, RIKEN Cluster for Science, Technology and Innovation Hub (RCSTI), Yokohama, Japan

    Yasuyuki Ishii

  3. REGiMMUNE Corporation, Tokyo, Japan

    Yasuyuki Ishii

  4. Department of Urology, Jyoban Hospital of Tokiwa Foundation, Fukushima, Japan

    Kan Saiga

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  1. Taichi Kanzawa
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  2. Toshihito Hirai
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  4. Haruki Katsumata
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Corresponding author

Correspondence to Toshihito Hirai.

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Conflict of interest

Y. Ishii is the executive chairman of REGiMMUNE Corp. The other authors declare that they have no conflict of interest.

Human and animal right disclosure

Animal studies were approved by the Tokyo Women’s Medical University internal committee on the use and care of laboratory animals approved all experiments (Reference ID: AE16-105-2). All animals received human care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23, revised 1985) as well as the current version of the Japanese law “Act on Welfare and Management of Animals” (revised 2013).

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Kanzawa, T., Hirai, T., Fukuda, H. et al. Combination therapy of an iNKT cell ligand and CD40–CD154 blockade establishes islet allograft acceptance in nonmyeloablative bone marrow transplant recipients. Acta Diabetol 56, 541–550 (2019). https://doi.org/10.1007/s00592-019-01289-7

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