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CpG oligonucleotides are recently described as a class of pharmaco-therapeutic agents that are found in bacterial DNA and some synthetic oligonucleotide sequences. CpG oligonucleotides have immune stimulatory activity due to an unmethylated 5'-CG-3 ' dinucleotide^[1]. CpG oligonucleotides trigger an immunostimulatory cascade inducing the maturation, differentiation and proliferation of multiple immune cells including B and T- lymphocytes, macrophages, natural killer (NK) cells and monocytes/macrophages that produce interleukin (IL)- 1, 6, 12 and 18, interferon-γ (INF-γ) and tumor necrosis factor-α (TNF-α). CpG oligonucleotides can enhance immune capacity through interaction of cytokines and inflammatory cells^[2]. Evidence exists that CpG oligonucleotides can improve peripheral blood mononuclear cells (PBMCs) function in type 2 diabetes mellitus^[3], but no evidence exists that CpG oligonucleotides function in type 1 diabetes mellitus. The present study aimed to evaluate the effects of CpG oligonucleotides on INF-γ, IL-10 and IL-12 levels of PBMC and to investigate whether CpG oligonucleotides can improve the function of PBMCs in patients with type 1 diametes mellitus.

Many studies have confirmed that patients with diabetes mellitus have poorer immune functions than normal population and easily suffer from a variety of infectious diseases. This may be related to high glucose toxicity, increase in advanced glycation end products, cell and humoral immune dysfunction related to sorbitol accumulation^[6]. In this study, we demonstrated that IFN-γ and IL-12 expression levels in PBMCs were significantly lower in patients with type 1 diabetes mellitus than in healthy volunteers. Type 1 diabetes melittus is the organ specific autoimmune disease with the primary feature of β-cell damage under the effects of genetic and environmental factors mediated by T lymphocytes. The underlying mechanism is that CD4⁺ and CD8⁺ T lymphocytes, B lymphocytes, monocytes, macrophages and dendritic cells infiltrate islets, resulting in islet inflammation and damage of pancreatic β-cells and finally leading to absolute reduction of insuliun secretion. Infiltration and destruction of islet cells by T lymphocyte is a key link of pathogenesis of type 1 diabetes mellitus. In addition, B lymphocytes and NK cells also play an important role in the pathogenesis of type 1diabetes mellitus. Under normal physiological conditions, Th1/Th2 type cytokines are in the relative equilibrium, endogenous Th-1type cytokines play a leading role in type 1 diabetes mellitus^[7]. IL-4, IL-10 cytokines secreted by Th2 cell can prevent and treat diabetes mellitus^[8]. IL-10 mediates monocyte infiltration of pancreatic islets and also accelerates the apoptosis of islet β cells^[9]. Both cytotoxic granules and Fas-Fasl pathway play a role in the pathogenesis of type 1 diabetes mellitus^[10]. Blocking Fas-Fasl pathway can protect islet β cells and thereby hamper the occurrence and development of diabetes mellitus^[11]. B lymphocytes infiltrating islet can directly kill islet cells by acting as antigen presenting cells to recurit other inflammatory cells and secrete TNF-α^[12]. IL-4 produced by NKT cells from NOD mice is lower than from mice without diabetes mellitus^[13], indicating that NKT cells also play a key role in the occurrence and development of type 1 diabetes mellitus^[14]. Abnormal genetic regulation of DC function enhances antigen-presenting ability and increases the expression of TNF-α since the neonatal period of NOD mice, and this abnormal expression promotes the pathogenesis of diabetes mellitus in neonatal NOD mice^[15]. It is an important issue regarding how to treat type 1 diabetes mellitus by regulating the immune mechanism. Because containing unmethylated cytosine guanine dinucleotide, CpG oligonucleotides can be recognized by the immune system in mammals. It can active B lymphocytes, macrophages, dendritic cells and other immune cells to induce the production of IL-12 and IFN-γ and strengthen the immune defense functions of host cells against microbial infection, in particular the viral and cellular pathogens^[16]. Results from this study demonstrated that CpG oligonucleotides can increase INF-γ and IL-12 mRNA expression levels in the PBMCs of patients with type 1 diabetes mellitus close to the levels in healthy controls, but not increase IL-10 mRNA expression, to strengthen and immune function of PBMCs and that CpG oligonucleotides exhibit similar effect in healthy controls. Therefore, CpG oligonucleotides, as endogenous INF-γ and IL-12 inductor, is promising to serve as an ideal preparation to improve the immune functions of type 1 diabetes mellitus and healthy population. The present study is an in vitro cell study and sample size is small. Further human and animal studies involving large sample size are needed to investigate the efficacy and safety of CpG oligonucleotides and provide new insights and helps for treatment of type 1 diabetes mellitus.

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