Development of a Bioconjugate Platform for Modifying the Immune Response of Autoreactive Cytotoxic T Lymphocytes Involved in Type 1 Diabetes.
Development of a Bioconjugate Platform for Modifying the Immune Response of Autoreactive Cytotoxic T Lymphocytes Involved in Type 1 Diabetes.
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开发用于改变 1 型糖尿病相关自身反应性细胞毒性 T 淋巴细胞免疫反应的生物共轭平台。
DOI：
10.1021/acs.bioconjchem.9b00332
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发表时间：
2019
影响因子：
4.7
通讯作者：
McInerney,MarciaF
中科院分区：
文献类型：
--
作者：
Nandedkar-Kulkarni,Neha;Vartak,AbhishekR;Sucheck,StevenJ;Wall,KatherineA;Quinn,Anthony;Morran,MichaelP;McInerney,MarciaF
1型糖尿病（T1D）是一种以自身免疫细胞介导的胰腺细胞破坏为特征的自身免疫性疾病。胰腺细胞是体内胰岛素的唯一来源。因此，T1D患者必须终生依赖胰岛素注射。注射胰岛素可以调节血糖水平，但胰岛素对自身免疫过程影响不大。来自已知T1D自身抗原的改变肽配体（APL）能够在T1D动物模型的自身反应细胞中诱导耐受性，但目前无法在人类中引起这种保护。由于这些短肽很容易被血液中的酶降解，因此需要提高其免疫原性。GAD546-554是非肥胖糖尿病（NOD）小鼠模型中自身反应性T细胞识别的显性表位，可导致β细胞的破坏。GAD546-554肽（APL9）第8位丙氨酸取代诱导GAD546-554特异性细胞毒性T淋巴细胞克隆产生耐受性。为了改善APL9的抗原呈递和内体逃逸，我们开发了一种生物偶联平台，该平台由含有APL9和toll样受体2配体pam3cyssk4生物偶联物的脂质体以及抗巨噬细胞蛋白F4/80的抗体组成。带有F4/80抗体的APL9生物偶联脂质体能够诱导GAD 546-554特异性克隆产生耐受性。用APL9生物偶联物预处理的糖尿病NOD脾细胞也不能将糖尿病转移到糖尿病前期NOD受体小鼠。这项工作有助于预防T1D作为一种免疫治疗策略，使自身反应性免疫细胞对β细胞更具耐受性。
Type 1 diabetes (T1D) is an autoimmune disorder characterized by autoimmune cell mediated destruction of pancreatic beta cells. Pancreatic beta cells are the only source of insulin in the body. T1D patients then have to depend on insulin injections for their lifetime. Insulin injection can modulate the blood sugar levels, but insulin has little effect on the autoimmune process. Altered peptide ligands (APL) derived from known autoantigens in T1D are able to induce tolerance in autoreactive cells in T1D animal models, but are currently unable to elicit this protection in humans. There is a need to improve immunogenicity of the APLs, as these short peptides can be easily degraded by enzymes in the blood. GAD546–554 is a dominant epitope recognized by autoreactive T cells in the nonobese diabetic (NOD) mouse model that can cause destruction of beta cells. Alanine substitution at the eighth position of GAD546–554 peptide (APL9) induced tolerance in a GAD546–554 specific cytotoxic T lymphocyte clone. To improve the antigen presentation and endosomal escape of APL9, we developed a bioconjugate platform that consists of a liposome containing a bioconjugate of APL9 and toll-like receptor 2 ligand Pam3CysSK4as well as an antibody against macrophage protein F4/80. APL9 bioconjugate liposome with F4/80 antibody was able to induce tolerance in a GAD 546–554 specific clone. Diabetic NOD splenocytes pretreated with APL9 bioconjugate were also not able to transfer diabetes into prediabetic NOD recipient mice. This work is beneficial to prevent T1D as an immunotherapy strategy to render autoreactive immune cells more tolerant of beta cells.
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影响因子：
32.4
作者：
NICHOLSON, LB;GREER, JM;KUCHROO, VK
通讯作者：
KUCHROO, VK
影响因子：
3.6
作者：
S. Sévère;A. Gauvrit;A. Vu;J. Bach
通讯作者：
S. Sévère;A. Gauvrit;A. Vu;J. Bach
影响因子：
3.6
作者：
Boehm, Bernhard O.;Rosinger, Silke;Burster, Timo
通讯作者：
Burster, Timo
影响因子：
4.7
作者：
Sarkar, Sourav;Salyer, Alex C. D.;Wall, Katherine A.;Sucheck, Steven J.
通讯作者：
Sucheck, Steven J.
与 GAD 的对话。
影响因子：
12.8
作者：
G. Nepom
通讯作者：
G. Nepom