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01-05-2019 | Insulins | Original Article

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

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

Published in: Acta Diabetologica | Issue 5/2019

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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Title: Combination therapy of an iNKT cell ligand and CD40–CD154 blockade establishes islet allograft acceptance in nonmyeloablative bone marrow transplant recipients
Authors: Taichi Kanzawa
Toshihito Hirai
Hironori Fukuda
Haruki Katsumata
Rumi Ishii
Masako Ikemiyagi
Yasuyuki Ishii
Kan Saiga
Masayoshi Okumi
Kazunari Tanabe
Publication date: 01-05-2019
Publisher: Springer Milan
Keywords: Insulins
Hyperglycemia
Insulins
Type 1 Diabetes
Published in: Acta Diabetologica / Issue 5/2019
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-019-01289-7

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