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Xenotransplantation. 2018 Jan;25(1). doi: 10.1111/xen.12356. Epub 2017 Oct 22.

Pre-clinical results in pig-to-non-human primate islet xenotransplantation using anti-CD40 antibody (2C10R4)-based immunosuppression.

Shin JS1,2,3,4, Kim JM1,3,4, Min BH1,3,4, Yoon IH1,2,4, Kim HJ1,2,4,5, Kim JS1,2,3,4, Kim YH1,2, Kang SJ1,2,4,5, Kim J1,2, Kang HJ6, Lim DG7, Hwang ES1,2, Ha J8, Kim SJ1,9, Park WB10, Park CG1,2,3,4,5,11.

Author information

1
Xenotransplantation Research Center, Seoul National University, College of Medicine, Seoul, Korea.
2
Department of Microbiology and Immunology, Seoul National University, College of Medicine, Seoul, Korea.
3
Institute of Endemic Diseases, Seoul National University, College of Medicine, Seoul, Korea.
4
Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea.
5
Department of Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
6
Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea.
7
National Medical Centre, Seoul, Korea.
8
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
9
Myong-Ji Hospital, Koyang-si, Kyeonggi-do, Korea.
10
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
11
Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

Abstract

BACKGROUND:

Islet transplantation is an effective therapy for selected patients with type 1 diabetes with labile glycemic control and hypoglycemic unawareness, but donor organs are limited. Islet xenotransplantation using porcine islets will potentially solve this problem. Although successful proof of concept studies using clinically inapplicable anti-CD154 monoclonal antibody (mAb) in pig-to-non-human primate (NHP) islet xenotransplantation has been demonstrated by several groups worldwide, potentially clinically applicable anti-CD40 (2C10R4) mAb-based studies have not been reported.

METHODS:

Nine streptozotocin (STZ)-induced diabetic rhesus monkeys were transplanted with adult porcine islets isolated from designated pathogen-free (DPF) miniature pigs. They were treated with anti-CD40 mAb-based immunosuppressive regimen and were divided into 3 groups: anti-CD40 only group (n = 2), belatacept group (anti-CD40 mAb+belatacept, n = 2), and tacrolimus group (anti-CD40 mAb+tacrolimus, n = 5). All monkeys received anti-thymocyte globulin (ATG), cobra venom factor (CVF), adalimumab, and sirolimus. Blood glucose levels (BGL) and serum porcine C-peptide concentrations were measured. Humoral and cellular immune responses were assessed by ELISA and ELISPOT, respectively. Liver biopsy and subsequent immunohistochemistry were conducted.

RESULTS:

All animals restored normoglycemia immediately after porcine islet transplantation and finished the follow-up without any severe adverse effects except for one animal (R092). Most animals maintained their body weight. Median survival, as defined by a serum porcine C-peptide concentration of >0.15 ng/mL, was 31, 27, and 60 days for anti-CD40 only, belatacept, and tacrolimus groups, respectively. Anti-αGal IgG levels in serum and the number of interferon-γ secreting T cells in peripheral blood mononuclear cells did not increase in most animals.

CONCLUSION:

These results showed that anti-CD40 mAb combined with tacrolimus was effective in prolonging porcine islet graft survival, but anti-CD40 mAb was not as effective as anti-CD154 mAb in terms of preventing early islet loss.

KEYWORDS:

anti-CD40 mAb; islet; xenotransplantation

PMID:
29057561
PMCID:
PMC5809197
DOI:
10.1111/xen.12356
[Indexed for MEDLINE]
Free PMC Article

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