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Exploring Foxp3+ CD4+ Treg cell-stimulating vaccines to inhibit preproinsulin-specific effector CD8+ T cells and autoimmune diabetes

探索 Foxp3 CD4 Treg 细胞刺激疫苗抑制前胰岛素原特异性效应 CD8 T 细胞和自身免疫性糖尿病

基本信息

批准号：
316654766
负责人：
Professor Dr. Reinhold Schirmbeck
金额：
--
依托单位：
Klinik für Innere Medizin I
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/316654766?language=en
关键词：
Exploring Foxp3+CD4+Treg cell

项目摘要

Vaccines that induce or restore peripheral tolerance and inhibit T cell-mediated autoimmune diabetes in a controlled and antigen-specific manner would be a goal in combating type 1 diabetes. We have established a novel diabetes model in PD-L1-/- and PD-1-/- mice to characterize preproinsulin/(ppins)-specific expression requirements that induce (or prevent) autoreactive CD8+ T cells by plasmid-DNA vaccination. A single injection of pCI/ppins-DNA efficiently induced insulin A-chain (Kb/A12-21)-monospecific CD8+ T cells and severe diabetes in PD-L1/PD-1-deficient mice within 3-5 weeks. In contrast, ppins designer antigens targeted to the cytosol and/or the nucleus (and excluded from direct processing in the Endoplasmatic Reticulum) did not induce this autoreactive CD8+ T-cell response, but efficiently induced Foxp3+ CD25+ CD4+ regulatory T cells (Treg) that suppressed inducible diabetes in PD-L1/PD-1-deficient mice by a subsequent injection of pCI/ppins. These antigens also inhibited spontaneous diabetes development in NOD mice expressing the diabetes-susceptible H-2g7 haplotype (Kd; Db; I-Ag7). The proposal aims to elucidate systemic and local (in the pancreas) mechanisms that inhibit CD8+ T cell-mediated destruction of beta-cells in inducible and spontaneous diabetes models. We will establish vaccination protocols that induce and sustain ppins-specific Treg. In particular, we are interested in (i) the characterization of Treg responses in PD1/PD-L1-competent (B6) versus PD-1/PD-L1-deficient animals; (ii) the identification of I-Ab-restricted epitope(s) and the conditions under which CD4+ T and/or Treg cells are stimulated in vitro and/or in vivo; (iii) the characterization of surface marker and cytokine expression profiles of vaccine-induced Treg populations in distinct tissues. To determine the general applicability of ppins designer antigens, we will analyse if (and which specificities of) vaccine-induced Treg inhibit pCI/ppins-inducible diabetes in PD-1/PD-L1-deficient B6.g7 (Kd; Db; I-Ag7) mice and spontaneous diabetes development in B6.g7/RIP-B7.1 tg and diabetes-susceptible NOD mice. These studies may help to design specific immune intervention protocols that attenuate autoreactive immune responses by Treg.

诱导或恢复外周耐受性并以受控和抗原特异性方式抑制T细胞介导的自身免疫性糖尿病的疫苗将是对抗1型糖尿病的目标。我们在PD-L1-/-和PD-1-/-小鼠中建立了一种新的糖尿病模型，以表征通过质粒DNA疫苗接种诱导（或预防）自身反应性CD 8 + T细胞的前胰岛素原/（ppins）特异性表达要求。单次注射pCI/ppins-DNA在3-5周内有效诱导PD-L1/PD-1缺陷小鼠中胰岛素A链（Kb/A12-21）单特异性CD 8 + T细胞和严重糖尿病。相比之下，靶向细胞溶质和/或细胞核的ppins设计者抗原（并且被排除在内质网中的直接加工之外）不诱导这种自身反应性CD 8 + T细胞应答，但是有效地诱导Foxp 3 + CD 25 + CD 4+调节性T细胞（Treg），其通过随后注射pCI/ppins抑制PD-L1/PD-1缺陷小鼠中的诱导型糖尿病。这些抗原还抑制表达糖尿病易感H-2g 7单倍型（Kd; Db; I-Ag 7）的NOD小鼠中自发糖尿病的发展。该提案旨在阐明在诱导型和自发性糖尿病模型中抑制CD 8 + T细胞介导的β细胞破坏的全身和局部（胰腺）机制。我们将建立诱导和维持ppins特异性Treg的疫苗接种方案。我们特别关注的是（i） PD-1/PD-L1活性动物（B6）与PD-1/PD-L1缺陷动物中Treg应答的表征;（ii） I-Ab限制性表位的鉴定和体外和/或体内刺激CD 4 + T和/或Treg细胞的条件;（iii）不同组织中疫苗诱导的Treg群体的表面标志物和细胞因子表达谱的表征。为了确定ppins设计者抗原的普遍适用性，我们将分析疫苗诱导的Treg是否（以及哪些特异性）抑制PD-1/PD-L1缺陷型B6.g7（Kd; Db; I-Ag 7）小鼠中的pCI/ppins诱导型糖尿病以及B6.g7/RIP-B7.1 tg和糖尿病易感NOD小鼠中的自发糖尿病发展。这些研究可能有助于设计特异性免疫干预方案，通过Treg减弱自身反应性免疫反应。