Immunosuppressive effect of arsenic trioxide on islet xenotransplantation prolongs xenograft survival in mice

Bin Zhao,Zhong-Quan Qi,Chen Dai,Chang Gao,Qi-Jun Cheng,Lu-Min Wang,Jun-Jie Xia,Jia-Li Li,Qi-Lin Ma,Jia-Yin Liu,Ben-Hua Zhao

doi:10.1038/s41419-018-0446-8

Abstract

The role of arsenic trioxide (As2O3) in inhibiting immune rejection and prolonging islet allograft survival has been identified in islet allotransplantation. This study aims to explore the role of As2O3 in islet xenotransplantation and the action mechanism. The streptozotocin (STZ) was used in C57BL/6 mice to induce the type 1 diabetes mellitus (T1DM) for xenotransplantation models establishment. Donor islets were isolated by digesting. The flow cytometry (FCM) was used to analyze lymphocyte types. The blood sugar level was detected by using intraperitoneal glucose tolerance test (IPGTT). The serum level of cytokines was determined by the enzyme-linked immunosorbent assay (ELIZA). The cell proliferation was measured by MTT assay. The mRNA levels were quantified with qRT-PCR. As2O3 prolonged the survival of the recipient mice but had no influence on body weight. As2O3 protected the function of xenograft in insulin secretion and suppressed immune rejection of recipient. As2O3 inhibited proliferation of T lymphocyte and increased the proportion of Foxp3+ regulatory T cells in recipient mice. As2O3 inhibited activation and promoted clonal anergy of T lymphocyte. As2O3 decreased total number of B cells and reduced partial antibody levels in recipient mice. As2O3 and leflunomide showed a synergistic effect in suppressing islet xenotransplant rejection. As2O3 prolongs islet xenograft survival by inhibiting cellular immune response, and increasing Foxp3+ regulatory T cells, while decreasing partial antibody levels in serum.

Highlights

Introduction The type1 diabetes mellitus (T1DM), called insulin-dependent or juvenile diabetes, begins with insulin-producing beta cells attacked by autoimmune and subsequent deficiency of insulin, leading to increased glucose content in blood and urine[1]
The insulin secretion condition was measured by the immunohistochemistry assay, and the insulin secretion in As and Lef + As group was better than control group, and Lef + As group showed the best insulin secretion condition (Fig. 1b)
It showed that the body weight of mice increased when the blood sugar maintained at the normal levels, while it declined with increased blood sugar; but no difference was found in increase trend of body weight among four groups (Fig. 1c), suggesting that body weight was little influenced by different drug treatments

Summary

Introduction

1 diabetes mellitus (T1DM), called insulin-dependent or juvenile diabetes, begins with insulin-producing beta cells attacked by autoimmune and subsequent deficiency of insulin, leading to increased glucose content in blood and urine[1]. Hyperglycemia caused by deficiency of insulin causes many complications in various tissues and organs, such as eyes, heart, blood vessels, and nerves[2]. The main clinical treatment of diabetes mellitus includes insulin injection, oral hypoglycemic agents, combined with healthy life style, but these therapies often result in increased risk of disorder of glucose metabolism. Islet transplantation is a promising therapy for T1DM through regulating glycometabolism by blood glucose level of the organism[5]. Clinical islet transplantation for diabetes has been focused on and it has achieved success as insulin independence rates up to five years after transplant, with minimal complications[6]. Islet transplantation shows lots of advantages on simple operation, low immunosuppression, and less complication[7], exhibiting great potential in Official journal of the Cell Death Differentiation Association

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