Valproic Acid Suppresses Autoimmune Recurrence and Allograft Rejection in Islet Transplantation through Induction of the Differentiation of Regulatory T Cells and Can Be Used in Cell Therapy for Type 1 Diabetes.

Jeng-Rong Lin,Chia-Pi Cheng,Huey-Kang Sytwu,Yuan-Wu Chen,Chih-Hsiung Wu,Gu-Jiun Lin,Shing-Hwa Huang,Zhi-Jie Hong

doi:10.3390/ph14050475

Abstract

Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing β cells in the islet of the pancreas by lymphocytes. Non-obese diabetic (NOD) mouse is an animal model frequently used for this disease. It has been considered that T1D is a T cell-mediated autoimmune disease. Both CD4+ and CD8+ T cells are highly responsible for the destruction of β cells within the pancreatic islets of Langerhans. Previous studies have revealed that regulatory T (Treg) cells play a critical role in the homeostasis of the immune system as well as immune tolerance to autoantigens, thereby preventing autoimmunity. Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Previous reports have demonstrated that VPA treatment decreases the incidence and severity of collagen-induced arthritis and experimental autoimmune neuritis by increasing the population of Treg cells in these mouse disease models. Given the effect of VPA in the induction of Treg cells’ population, we evaluated the therapeutic potential and the protective mechanism of VPA treatment in the suppression of graft autoimmune rejection and immune recurrence in syngeneic or allogenic islet transplantation mouse models. In our study, we found that the treatment of VPA increased the expression of forkhead box P3 (FOXP3), which is a critical transcription factor that controls Treg cells’ development and function. Our data revealed that 400 mg/kg VPA treatment in recipients effectively prolonged the survival of syngeneic and allogenic islet grafts. The percentage of Treg cells in splenocytes increased in VPA-treated recipients. We also proved that adoptive transfer of VPA-induced Tregs to the transplanted recipients effectively prolonged the survival of islet grafts. The results of this study provide evidence of the therapeutic potential and the underlying mechanism of VPA treatment in syngeneic islet transplantation for T1D. It also provides experimental evidence for cell therapy by adoptive transferring of in vitro VPA-induced Tregs for the suppression of autoimmune recurrence.

Highlights

Type 1 diabetes (T1D), known juvenile-onset diabetes or childhood-onset diabetes, is a T cell-mediated autoimmune disease resulting in insulin-producing beta cell destruction in the islet [1,2]
To evaluate the protective effect of Valproic acid (VPA) in islet transplantation, we performed syngeneic and allogenic islet transplantations to monitor islet graft survival in recipients treated with 400 mg/kg VPA (Figure 1A,B)
These results indicated that adoptive transfer of VPA-induced Treg cells to non-obese diabetic (NOD) recipients exhibited a protective effect for islet grafts

Summary

Introduction

Type 1 diabetes (T1D), known juvenile-onset diabetes or childhood-onset diabetes, is a T cell-mediated autoimmune disease resulting in insulin-producing beta cell destruction in the islet [1,2]. The non-obese diabetic (NOD) mouse is a frequently used mouse model for autoimmune type 1 diabetes [6,7] This mouse model spontaneously develops autoimmune diabetes and elicits immune response in various organs, including salivary, lacrimal, thyroid, parathyroid, adrenal, testis, large bowel, and red blood cells [6,8]. Regulatory T cells (Tregs) have been demonstrated to possesses an immunomodulatory effect on the immunomodulation of autoimmune diabetes in NOD mice [9]. They were described as a population of CD4+ CD25+ T cells that could suppress autoimmunity by inducing immune tolerance [10].

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