DataSheet_1_Oral Salmonella msbB Mutant as a Carrier for a Salmonella-Based Vaccine for Prevention and Reversal of Type 1 Diabetes.pdf

A therapy that includes an oral vaccine for type 1 diabetes (T1D) using live attenuated Salmonella MvP728 (ΔhtrA/ΔpurD), cytokines (IL10 and TGFβ) and preproinsulin (PPI) antigen in combination with a sub-therapeutic dose of anti-CD3 mAb was developed by our team. The vaccine combination therapy reduced insulitis and prevented and reversed diabetes in non-obese diabetic (NOD) mice. Here, we show the effectiveness of an alternative Salmonella mutant (ΔmsbB) as a carrier strain, which is anticipated to have lower risks of an inflammatory response and septicemia as a result of modification in the lipopolysaccharide (LPS) via detoxification of lipid A. This mutant strain proved to have highly reduced pathogenic side effects. Salmonella strain ΔmsbB expressed autoantigens and in combination with cytokines and anti-CD3 mAb, successfully prevented and reversed T1D to levels comparable to the previously used carrier strain ΔhtrA/ΔpurD. Additionally, the Salmonella msbB mutant resulted in higher rates of host cell infection. These results further demonstrate the potential of an oral Salmonella-based combined therapy in the treatment of early T1D.

本团队开发了一种针对1型糖尿病（type 1 diabetes, T1D）的口服疫苗联合疗法，该疗法采用减毒活沙门氏菌MvP728（ΔhtrA/ΔpurD）、细胞因子（cytokines，包括白细胞介素10（IL10）与转化生长因子β（TGFβ））及前胰岛素原（preproinsulin, PPI）抗原，并联合亚治疗剂量（sub-therapeutic dose）的抗CD3单克隆抗体（anti-CD3 mAb）。该疫苗联合疗法可减轻非肥胖糖尿病（non-obese diabetic, NOD）小鼠的胰岛炎，并预防和逆转糖尿病病程。本研究展示了一种替代沙门氏菌突变株（ΔmsbB）作为载体菌株（carrier strain）的有效性：该菌株通过对脂质A（lipid A）进行脱毒以修饰脂多糖（lipopolysaccharide, LPS）结构，有望降低炎症反应与败血症（septicemia）的发生风险。实验证实该突变株的致病性副作用已大幅降低。沙门氏菌ΔmsbB菌株可表达自身抗原（autoantigens），当其与细胞因子及抗CD3单克隆抗体联合使用时，可成功预防并逆转1型糖尿病，其效果与此前使用的ΔhtrA/ΔpurD载体菌株相当。此外，沙门氏菌msbB突变株还可提高宿主细胞感染率。上述结果进一步证实了基于沙门氏菌的口服联合疗法在早期1型糖尿病治疗中的应用潜力。