Immunogenetics/Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh 15224, USA.
Immunol Res. 2011 Aug;50(2-3):213-20. doi: 10.1007/s12026-011-8215-0.
Previous studies by our group, using an experimental autoimmune thyroiditis (EAT) model in Strain 13 inbred guinea pigs, resulted in T cell-mediated delayed hypersensitivity; however, autoantibodies proved not to be cytotoxic to thyroid epithelial cells in the presence or absence of complement proteins. Albeit, T cell-mediated lymphocyte cytotoxicity began to diminish sharply concomitantly with increasing titers of circulating autoantibodies, indicating a skewing of the self-reactive response and amelioration of the EAT. Furthermore, immunization of guinea pigs with thyroglobulin in incomplete Freund's adjuvant (IFA) generated a high titer of antithyroglobulin antibodies and proved to inhibit thyroiditis. These observations indicated that the shift in the immune response from Th1 to Th2 and the production of antibodies were likely responsible for ameliorating EAT. Based upon these results, we extrapolated our studies to design a multivalent vaccine, which shows promise in preventing/reversing T1D in NOD mice. A small pilot study was conducted in which a total of 34 mice, 20 non-immunized controls and 14 immunized with syngeneic islet lysate, were monitored for mean day to diabetes for a total of 28 weeks. Immunization of NOD animals with syngeneic islet lysates resulted in a significant delay in diabetes onset (P < 0.001) as compared to non-immunized controls. To further assess the vaccine's efficacy, robustness, and delay of disease, a large-scale experiment was conducted and monitored for 32 weeks using 106 mice, 64 non-immunized controls and 42 immunized with syngeneic islet lysate. At the end of the study, 90% of the non-immunized group developed diabetes, while less than 25% of the immunized group became diabetic (P < 0.0001). The protective effect, as a result of vaccination, correlated with an increase in the levels of IL-10 and IL-4 cytokines as well as a skewing to Th2-dependent isotype antibodies in serum. Strikingly, adoptive transfer of spleen cells from immunized animals into NOD.scid recipients provided protection against transfer of diabetes by diabetogenic spleen cells. The results of this study provide evidence that vaccination with islet lysate leads to a Th2-dependent skewing of the immune response to islet beta cells as a possible mechanism of protection. This strategy may be implemented as a possible vaccination protocol for arresting and/or preventing T1D in patients.
先前我们小组在近交系 13 号豚鼠的实验性自身免疫性甲状腺炎 (EAT) 模型中进行的研究导致了 T 细胞介导的迟发性超敏反应；然而，在存在或不存在补体蛋白的情况下，自身抗体对甲状腺上皮细胞并没有细胞毒性。尽管如此，T 细胞介导的淋巴细胞细胞毒性随着循环自身抗体滴度的增加而急剧下降，表明自身反应性应答的倾斜和 EAT 的改善。此外，用不完全弗氏佐剂 (IFA) 中的甲状腺球蛋白对豚鼠进行免疫接种会产生高滴度的抗甲状腺球蛋白抗体，并证明可抑制甲状腺炎。这些观察结果表明，从 Th1 到 Th2 的免疫反应转变以及抗体的产生可能是改善 EAT 的原因。基于这些结果，我们推断我们的研究设计了一种多价疫苗，该疫苗有望预防/逆转 NOD 小鼠的 T1D。进行了一项小型试点研究，其中总共监测了 34 只小鼠，20 只未免疫对照和 14 只用同种异体胰岛裂解物免疫的小鼠，以确定糖尿病的平均天数，共 28 周。用同种异体胰岛裂解物免疫 NOD 动物可显著延迟糖尿病发病（P <0.001）与未免疫对照相比。为了进一步评估疫苗的疗效、稳健性和疾病延迟，进行了一项大规模实验，并使用 106 只小鼠、64 只未免疫对照和 42 只用同种异体胰岛裂解物免疫的小鼠进行了 32 周的监测。在研究结束时，90%的未免疫组发生糖尿病，而免疫组中不到 25%的动物发生糖尿病（P <0.0001）。疫苗接种的保护作用与血清中白细胞介素 10 和白细胞介素 4 细胞因子水平的增加以及对 Th2 依赖性同种型抗体的倾斜有关。引人注目的是，将来自免疫动物的脾细胞过继转移到 NOD.scid 受体中，可防止糖尿病脾细胞转移导致糖尿病。这项研究的结果提供了证据，即胰岛裂解物疫苗接种可导致胰岛β细胞的免疫反应向 Th2 依赖性倾斜，这可能是一种保护机制。该策略可作为治疗 T1D 患者的一种可能的疫苗接种方案。
