Systemic administration of agonist peptide blocks the progression of spontaneous CD8-mediated autoimmune diabetes in transgenic mice without bystander damage
Systemic administration of agonist peptide blocks the progression of spontaneous CD8-mediated autoimmune diabetes in transgenic mice without bystander damage
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DOI：
10.4049/jimmunol.165.1.202
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发表时间：
2000-07-01
影响因子：
4.4
通讯作者：
Liblau, R
中科院分区：
文献类型：
--
作者：
Bercovici, N;Heurtier, A;Liblau, R
胰岛素依赖型糖尿病是一种靶向胰岛β细胞的自身免疫性疾病。最近的数据表明，自身反应性CD 8（+）T细胞参与导致胰岛炎的早期事件和导致糖尿病的晚期破坏性阶段。尽管在几种模型中，治疗性注射对应于CD 4（+）T细胞表位的蛋白质和合成肽已被证明可以预防或阻断自身免疫性疾病，但使用这种方法下调正在进行的CD 8（+）T细胞介导的自身免疫应答尚未报道。使用CL 4-TCR单转基因小鼠，其中大多数CD 8（+）T细胞表达对流感病毒血凝素HA（512-520）肽：K-d复合物特异性的TCR，我们首先表明静脉注射可溶性HA（512-520）肽诱导Tc 1样CD 8（+）T细胞的瞬时活化，随后凋亡。我们接下来在（CL 4-TCR x Ins-HA）F-1双转基因小鼠中测试了类似的耐受性诱导策略，所述双转基因小鼠也在β-胰岛细胞中表达HA，并且因此自发地发展幼年发病和致死性糖尿病。当致病性CD 8（+）T细胞已经浸润胰腺时，可溶性HA（512-520）肽处理非常显著地延长了双转基因幼仔的存活。此外，我们发现Ag施用消除了胰腺中的CD 8（+）T细胞浸润，而没有旁观者损伤的组织学证据。我们的数据表明，激动剂肽可以下调体内由CD 8（+）T细胞介导的自身免疫反应，并阻断疾病进展。因此，除了自身反应性CD 4（+）T细胞外，CD 8（+）T细胞可能构成自身免疫性疾病Ag特异性治疗的靶点。
Insulin-dependent diabetes is an autoimmune disease targeting pancreatic beta-islet cells. Recent data suggest that autoreactive CD8(+) T cells are involved in both the early events leading to insulitis and the late destructive phase resulting in diabetes. Although therapeutic injection of protein and synthetic peptides corresponding to CD4(+) T cell epitopes has been shown to prevent or block autoimmune disease in several models, down-regulation of an ongoing CD8(+) T cell-mediated autoimmune response using this approach has not yet been reported. Using CL4-TCR single transgenic mice, in which most CD8(+) T cells express a TCR specific for the influenza virus hemagglutinin HA(512-520) peptide:K-d complex, we first show that i.v. injection of soluble HA(512-520) peptide induces transient activation followed by apoptosis of Tc1-like CD8(+) T cells. We next tested a similar tolerance induction strategy in (CL4-TCR x Ins-HA)F-1 double transgenic mice that also express HA in the beta-islet cells and, as a result, spontaneously develop a juvenile onset and lethal diabetes. Soluble HA(512-520) peptide treatment, at a time when pathogenic CD8(+) T cells have already infiltrated the pancreas, very significantly prolongs survival of the double transgenic pups, In addition, we found that Ag administration eliminates CD8(+) T cell infiltrates from the pancreas without histological evidence of bystander damage. Our data indicate that agonist peptide can down-regulate an autoimmune reaction mediated by CD8(+) T cells in vivo and block disease progression. Thus, in addition to autoreactive CD4(+) T cells, CD8(+) T cells may constitute targets for Ag-specific therapy in autoimmune diseases.