Department of Molecular and Medical Pharmacology, UCLA School of Medicine, University of California, Los Angeles, CA 90095-1735, USA.
Cells. 2022 Mar 23;11(7):1081. doi: 10.3390/cells11071081.
We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of naïve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPI) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPI-specific splenic naive T cell pool gradually increased from 2-12 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15-16 week old mice, insulin B-chain/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFNγ responses to itself and other autoantigens. In contrast, PPI/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFNγ responses to ß-cell autoantigens. In newly diabetic NOD mice, PPI, but not insulin B-chain administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual's naïve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.
我们提出，针对自身免疫性疾病的抗原特异性免疫疗法（ASIs）可以通过给予靶细胞抗原表位（决定簇）来增强，这些决定簇具有免疫原性，但被自身反应性 T 细胞忽视，因为这些决定簇可能有大量的幼稚同源 T 细胞可用于向调节反应进行初始。在这里，我们鉴定了一种免疫原性的前胰岛素原决定簇（PPI），它在 1 型糖尿病（T1D）易感 NOD 小鼠的自身免疫反应中被忽视。PPI 特异性脾幼稚 T 细胞池的大小从 2-12 周龄逐渐增加，并在此后保持稳定，而主要靶决定簇胰岛素 B 链的大小在 12 周龄后大大减少，推测是由于招募到自身免疫反应中。在 15-16 周龄的小鼠中，胰岛素 B 链/明矾免疫诱导适度低水平的脾 T 细胞 IL-10 和 IL-4 反应，这些反应很少或没有扩散，并且增强了对自身和其他自身抗原的 IFNγ 反应。相比之下，PPI/明矾处理诱导了强烈的 IL-10 和 IL-4 反应，这些反应扩散到其他自身抗原，并增加了脾 IL-10 分泌的 Treg 和 Tr-1 样细胞的频率，而不会增强对ß细胞自身抗原的 IFNγ 反应。在新发生糖尿病的 NOD 小鼠中，PPI 而非胰岛素 B 链（用明矾）腹膜内或皮内（作为可溶性抗原）给予，并辅以口服 GABA，可诱导长期疾病缓解。我们讨论了基于个体幼稚自身抗原反应性 T 细胞池的个性化 ASIs 的潜力，以及使用 HLA 合适的被忽视自身抗原决定簇来安全增强 ASIs 疗效的可能性。
