PNAS：开发出潜在疫苗来帮助预防人类患1型糖尿病

  近日，来自芭芭拉·戴维斯儿童糖尿病中心等处的研究人员通过研究发现，一种抑制小鼠患1型糖尿病的分子或许会诱发人类细胞的免疫反应，相关研究刊登于国际杂志PNAS上，该研究表明，突变的胰岛素碎片或许可以被用于抑制人类患1型糖尿病。

  John Kappler博士表示，近年来1型糖尿病的发病率明显增加，我们的研究发现或为开发潜在的疫苗来抑制人类患1型糖尿病提供帮助。1型糖尿病是一种自身免疫疾病，即机体免疫系统会破坏制造胰岛素的能力，而胰岛素则是一种糖类代谢的必要激素，研究者尝试着将胰岛素应用于风险患者中来作为治疗类似于治疗过敏症的免疫疗法，但目前并没有试验证明存在有效的反应。

  然而最新的研究发现，单一氨基酸发生改变的胰岛素片段或许可以刺激特定的免疫反应，而研究者指出，胰岛素中单一氨基酸的突变或许会刺激机体免疫系统使其更好地进行识别；早在2011年时来自哈佛大学的研究人员就报道了研究者Kappler的策略的确可以抑制小鼠患糖尿病，然而小鼠和人类在很多方面并不相同，因此在小鼠机体中有效的策略或许经常在人类机体中失效。

  而当前研究中，研究者将天然的胰岛素片段和来自不同人类细胞的突变胰岛素片段进行混合，结果发现人类T细胞对天然发生的胰岛素片段反应最小，但却对突变的胰岛素片段反应最为强烈，人类T细胞可以产生促炎性和抗炎性的化学物，名为细胞因子类。研究者认为，健康的免疫反应可以平衡促炎性因子和抗炎性因子，而当促炎性因子占据主导地位时就会引发自身免疫疾病。

  当前的研究结果并不能证明突变的胰岛素片段可以作为人类的疫苗来发挥作用，而其在人类中的反应和在小鼠中的接种反应是相一致的，人类细胞中的某些信号和T细胞调节细胞直接相关，这或许可以帮助减缓机体的免疫反应。最后研究者Kappler指出，这项研究证实了我们辛苦工作的价值，也可以帮助我们理解胰岛素和人类免疫系统之间的非常规相互作用，为后期开发新型疫苗和疗法来治疗糖尿病提供了一定的帮助和希望。（转化医学网360zhyx.com）

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转化医学网推荐的原文摘要：

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects
PNAS doi: 10.1073/pnas.1502967112
Maki Nakayamaa,b, Kristen McDaniela, Lisa Fitzgerald-Millera, Carol Kiekhaefera, Janet K. Snell-Bergeona, Howard W. Davidsona,b, Marian Rewersa, Liping Yua, Peter Gottlieba, John W. Kapplerb,c,d,1, and Aaron Michelsa,1
Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9–23) mimotopes engineered to bind the mouse MHCII molecule, IAg7, in an unfavorable position or register. Because of the similarities between IAg7 and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9–23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9–23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset.