Lymph Node Extracellular Matrix in Antigen Presentation and Immune Regulation

淋巴结细胞外基质在抗原呈递和免疫调节中的作用

• 批准号: 10248335
• 负责人: Paul L Bollky
• 金额: $ 50.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248335
• 关键词: 4-methylumbelliferone; Adult; Affinity; Antigen Presentation; Appearance; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Beta Cell; Binding; Blocking Antibodies; CD44 gene; Cadaver; Cells; Characteristics; Child; Data; Dendritic Cells; Development; Extracellular Matrix; FOXP3 gene; HAS3 gene; Human; Hyaluronan; Hyaluronidase; ITGAX gene; Immune Tolerance; Immune system; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Lymph Node Tissue; MHC Interaction; Mediating; Modeling; Molecular; Mus; Operative Surgical Procedures; Oral; Pancreas; Peripheral; Pharmaceutical Preparations; Play; Polymers; Prediabetes syndrome; Regulatory T-Lymphocyte; Reporting; Risk; Role; Signal Transduction; Site; Specimen; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Therapeutic; Tissues; autoreactive T cell; experimental study; immunological synapse; immunological synapse formation; immunoregulation; in vivo; inhibitor/antagonist; insight; insulitis; islet; lymph nodes; mouse model; novel; overexpression; prevent; response; two photon microscopy

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease associated with T-cell mediated destruction of insulin- producing β-cells. Prediabetic individuals typically lose tolerance first to insulin followed by other islet auto- antigens. This repeated, sequential loss of tolerance suggests that local antigenic responses may be skewed in T1D in ways that contribute to the loss of tolerance. We recently identified characteristic changes in the pancreatic lymph nodes (PLN) of individuals with T1D. Specifically, hyaluronan (HA), an extracellular matrix polymer, is abundant within the inter-follicular regions of PLN – the tissue sites where T-cell responses to self-antigens are primed – of cadaveric donors with T1D. Intrigued by these exciting results, we investigated the possibility that HA may play a role in loss of immune tolerance by potentiating the immune synapse between dendritic cells (DC) and T-cells. We find that activated, mature DC generate a “coat” of HA in association with hyaluronan synthase 3 (HAS3) that modulates antigen presentation, enhancing T-cell activation and proliferation in response to otherwise weak antigenic signals. Conversely, treatments that clear HA or disrupt its binding to CD44 (hyaluronidase, CD44 blocking antibodies, or 4-methylumbelliferone (4-MU), an HA synthesis inhibitor), reduce the efficiency of antigen presentation and promote peripheral FoxP3+ regulatory T-cells (Treg) induction. These data suggest a model whereby interactions between HA surrounding the DC and CD44 on T-cells stabilize the immune synapse. This stabilization, in turn, increases the effective affinity of TCR-MHC interactions, increasing positive selection of otherwise low affinity, autoreactive T-cells. This hypothesis, if true, represents a novel mechanism of co-stimulation of T-cells that contributes to the loss of immune tolerance in T1D. It may be possible to target HA therapeutically to promote tolerance. We recently reported that treatment with oral 4-MU prevented T1D and promoted Foxp3+ Treg expansion in multiple mouse models of T1D. These results are particularly exciting because 4-MU is already an approved drug, currently used for a different indication in children and adults. It may be possible to repurpose 4-MU to prevent T1D in at-risk subjects. However, it is essential that we first establish how HA promotes autoimmunity. We hypothesize that pericellular HA surrounding DC contributes to priming of autoreactive T-cells in T1D. To test this hypothesis, in Aim 1, we will determine how pericellular HA on DC impacts immune synapse formation with T-cells. In Aim 2, we will elucidate how pericellular HA on DC contributes to the loss of tolerance in autoimmune diabetes. Finally, in Aim 3, we will determine whether the appearance of HA within PLN coincides with the loss of tolerance in human prediabetes and the role of DC pericellular HA in mediating T-cell responses. Together, these studies will yield novel insights into the fundamental mechanisms underlying antigen presentation and the development of autoimmunity as well as a potentially transformative therapy for T1D.

项目总结 1型糖尿病(T1D)是一种与T细胞介导的胰岛素破坏相关的自身免疫性疾病。 产生β细胞。糖尿病前期患者通常首先失去对胰岛素的耐受性，然后是其他胰岛自身- 抗原。这种反复的、顺序的耐受性丧失表明局部抗原反应可能在 T1D会导致容忍度的丧失。 我们最近发现了T1D患者胰腺淋巴结(PLN)的特征性变化。 特别是，透明质酸(HA)是一种细胞外基质聚合物，在PLN的滤泡间区中含量丰富。 -T细胞对自身抗原的反应被启动的组织部位-来自患有T1D的身体捐赠者。对……感兴趣 这些令人兴奋的结果，我们研究了HA可能通过以下途径在免疫耐受丧失中发挥作用的可能性 增强树突状细胞(DC)和T细胞之间的免疫突触。 我们发现，激活的、成熟的树突状细胞与透明质酸合成酶3(HAS3)相关地产生一层透明质酸。 它调节抗原提呈，增强T细胞的激活和增殖，以应对其他方面的疲软 抗原信号。相反，清除HA或破坏其与CD44(透明质酸酶，CD44)结合的处理 阻断抗体或4-甲基伞形酮(4-MU，一种HA合成抑制剂)会降低抗原的效率 提出并促进外周FoxP3+调节性T细胞(Treg)的诱导。 这些数据表明，DC周围的HA和T细胞上的CD44之间的相互作用 稳定免疫突触。这种稳定反过来增加了TCR-MHC相互作用的有效亲和力， 增加对低亲和力、自身反应性T细胞的阳性选择。如果这一假设为真，则代表一种 T细胞共刺激导致T1D免疫耐受丧失的新机制。 通过治疗靶向HA来促进耐受性是可能的。我们最近报告说，使用 口服4-MU可预防T1D，促进Foxp3+Treg在多种T1D小鼠模型中的扩增。这些结果 特别令人兴奋，因为4-MU已经是一种批准的药物，目前用于 无论是孩子还是成年人。有可能改变4-MU的用途，以预防高危受试者的T1D。然而，它是 我们首先要确定HA是如何促进自身免疫的。 我们假设DC周围的细胞周围HA参与了T1D中自身反应性T细胞的启动。至 验证这一假设，在目标1中，我们将确定DC上的细胞周围HA如何影响免疫突触的形成 与T细胞有关。在目标2中，我们将阐明DC上的细胞周围HA是如何导致 自身免疫性糖尿病。最后，在目标3中，我们将确定在PLN内HA的出现是否一致 随着人类糖尿病前期耐受性的丧失以及DC细胞周围HA在介导T细胞反应中的作用。 总之，这些研究将对抗原潜在的基本机制产生新的见解。 自身免疫的介绍和发展，以及治疗T1D的潜在变革性疗法。

项目成果

Weekly injection of IL-2 using an injectable hydrogel reduces autoimmune diabetes incidence in NOD mice.

• DOI: 10.1007/s00125-020-05314-1
• 发表时间: 2021-01
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Nagy N;Kaber G;Kratochvil MJ;Kuipers HF;Ruppert SM;Yadava K;Yang J;Heilshorn SC;Long SA;Pugliese A;Bollyky PL
• 通讯作者: Bollyky PL

Evaluation of in vivo T cell kinetics: use of heavy isotope labelling in type 1 diabetes.

体内 T 细胞动力学评估：重同位素标记在 1 型糖尿病中的应用。

• DOI: 10.1111/cei.12064
• 发表时间: 2013
• 期刊: Clinical and experimental immunology
• 影响因子: 4.6
• 作者: Bollyky,JB;Long,SA;Fitch,M;Bollyky,PL;Rieck,M;Rogers,R;Samuels,PL;Sanda,S;Buckner,JH;Hellerstein,MK;Greenbaum,CJ
• 通讯作者: Greenbaum,CJ

Natural Tr1-like cells do not confer long-term tolerogenic memory.

天然 Tr1 样细胞不会赋予长期耐受性记忆。

• DOI: 10.7554/elife.44821
• 发表时间: 2019
• 期刊: eLife
• 影响因子: 7.7
• 作者: Yadava,Koshika;Medina,CarlosObed;Ishak,Heather;Gurevich,Irina;Kuipers,Hedwich;Shamskhou,ElyaAli;Koliesnik,IevgenO;Moon,JamesJ;Weaver,Casey;Nadeau,KariChristine;Bollyky,PaulL
• 通讯作者: Bollyky,PaulL

Hyaluronan in immune dysregulation and autoimmune diseases.

• DOI: 10.1016/j.matbio.2018.03.022
• 发表时间: 2019-05
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Nagy N;Kuipers HF;Marshall PL;Wang E;Kaber G;Bollyky PL
• 通讯作者: Bollyky PL

Reversal of diabetes in mice with a bioengineered islet implant incorporating a type I collagen hydrogel and sustained release of vascular endothelial growth factor.

• DOI: 10.3727/096368912x636786
• 发表时间: 2012
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Vernon RB;Preisinger A;Gooden MD;D'Amico LA;Yue BB;Bollyky PL;Kuhr CS;Hefty TR;Nepom GT;Gebe JA
• 通讯作者: Gebe JA