A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice.
A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice.
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DOI：
10.1007/s12026-011-8215-0
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发表时间：
2011-08
影响因子：
4.4
通讯作者：
Piganelli, Jon D.
中科院分区：
文献类型：
--
作者：
Lin, Ming S.;Tse, Hubert M.;Delmastro, Meghan M.;Bertera, Suzanne;Wong, Caterina T.;Lakomy, Robert;He, Jing;Sklavos, Martha M.;Coudriet, Gina M.;Pietropaolo, Massimo;Trucco, Massimo M.;Piganelli, Jon D.
我们小组之前的研究，在品系 13 近交系豚鼠中使用实验性自身免疫性甲状腺炎 (EAT) 模型，结果导致 T 细胞介导的迟发型超敏反应；然而，在补体蛋白存在或不存在的情况下，自身抗体被证明对甲状腺上皮细胞不具有细胞毒性。尽管如此，随着循环自身抗体滴度的增加，T 细胞介导的淋巴细胞的细胞毒性开始急剧减弱，表明自身反应性反应的倾斜和 EAT 的改善。此外，用不完全弗氏佐剂（IFA）中的甲状腺球蛋白免疫豚鼠可产生高滴度的抗甲状腺球蛋白抗体，并被证明可以抑制甲状腺炎。这些观察结果表明，免疫反应从 Th1 向 Th2 的转变以及抗体的产生可能是改善 EAT 的原因。根据这些结果，我们推断我们的研究设计了一种多价疫苗，该疫苗在预防/逆转 NOD 小鼠中显示出预防/逆转 T1D 的希望。进行了一项小型试点研究，对总共 34 只小鼠（20 只未免疫对照小鼠和 14 只用同基因胰岛裂解物免疫的小鼠）进行了为期 28 周的糖尿病平均日监测。与未免疫对照相比，用同基因胰岛裂解物对 NOD 动物进行免疫导致糖尿病发病显着延迟（P < 0.001）。为了进一步评估疫苗的功效、稳健性和延迟疾病的能力，使用 106 只小鼠、64 只未免疫对照小鼠和 42 只用同基因胰岛裂解物免疫的小鼠进行了为期 32 周的大规模实验。研究结束时，90% 的非免疫组患上糖尿病，而不到 25% 的免疫组患上糖尿病（P < 0.0001）。疫苗接种产生的保护作用与血清中 IL-10 和 IL-4 细胞因子水平的增加以及 Th2 依赖性同种型抗体的偏向相关。引人注目的是，将免疫动物的脾细胞过继转移至 NOD.scid 受体中，可防止由致糖尿病的脾细胞引起的糖尿病转移。这项研究的结果提供了证据，表明接种胰岛裂解物会导致对胰岛β细胞的免疫反应出现Th2依赖性倾斜，这是一种可能的保护机制。该策略可以作为一种可能的疫苗接种方案来实施，以阻止和/或预防患者的 T1D。
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.
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