Extracellular matrix and the regulation of adaptive immune responses

细胞外基质和适应性免疫反应的调节

• 批准号: 8091447
• 负责人: Paul L Bollky
• 金额: $ 7.72万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091447
• 关键词: Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Binding; CD3 Antigens; Cells; Charge; Clinical; Complex; Cues; Data; Diabetic mouse; Extracellular Matrix; Funding; Gel; Generations; Goals; Heparin; Hyaluronan; Hydrogels; Immune Tolerance; Immune response; Immunosuppression; Immunosuppressive Agents; In Situ; In Vitro; Inbred NOD Mice; Infection; Inorganic Sulfates; Insulin-Dependent Diabetes Mellitus; Interleukin-2; MADH3 gene; Mediator of activation protein; Mus; Organ Transplantation; Ovalbumin; Peripheral; Property; Protocols documentation; Reagent; Regulation; Regulatory T-Lymphocyte; Relative (related person); Reporting; Research; Resources; Role; STAT5A gene; Signal Transduction; Staging; Streptavidin; Structure; System; T-Lymphocyte; Testing; Tissue Transplantation; Toxic effect; Transgenic Mice; Transplanted tissue; Unspecified or Sulfate Ion Sulfates; Work; clinical application; crosslink; design; in vivo; lead sulfate; public health relevance; sulfation; uptake

DESCRIPTION (provided by applicant): FoxP3+ regulatory T-cells (T-reg) are thought to be crucial arbiters of immune tolerance. Unfortunately, protocols that have successfully induced FoxP3+ regulatory T-cells (T-reg) in vitro involve levels of TGFb and IL-2 that would be toxic if administered systemically in vivo. Our preliminary data, however, suggests that it is possible to deliver this same set of T-reg induction cues in a local manner by inculcating TGFb, IL-2 and anti-CD3 Ab into a hydrogel platform made of hyaluronan (HA) and heparin sulfate (HS). This approach roughly doubles the number FoxP3+ cells seen with soluble agents. My hypothesis is that antigen specific Treg can be induced from CD4+FoxP3- precursors using similar HA/HS hydrogels. I propose to investigate this hypothesis in three aims: 1) I will elucidate the mechanisms by which HA and HS in crosslinked form promote Treg induction. 2) I will optimize polyclonal Treg induction using HA/HS hydrogels. 3) I will develop HA/HS hydrogels to induce antigen specific Treg. This work is a culmination of my K08 funded research on HA and the promotion of immune tolerance. This R03 will potentially set the stage for studies on the in vivo and in situ induction of antigen specific tolerance in mouse models of diabetes that I hope to pursue in an R01 application. The significance of the planned work lies in the potential to induce antigen specific tolerance without systemic immune suppression in tissue transplantation and in the treatment of autoimmune diseases. PUBLIC HEALTH RELEVANCE: The treatment of autoimmune disease and organ transplantation frequently involves the administration of systemic immunosuppressants, often leading to infection or unacceptable toxicities. Recent efforts at inducing FoxP3+ regulatory T-cells (T-reg), the body's own mediators of immune tolerance, have faced the same limitations. Our preliminary data, however, suggests that it is potentially possible to locally deliver a set of costimulatory cues previously reported to induce T-reg by using hydrogel constructs made of hyaluronan and heparin sulfate as a platform. In this application I propose to develop hydrogels that are capable of inducing tolerance in an antigen specific manner. The significance of this planned work lies in the potential to induce tolerance to specific autoantigens or transplanted tissues without the need for systemic immunosupression.

描述（由申请方提供）：FoxP 3+调节性T细胞（T-reg）被认为是免疫耐受的关键仲裁者。不幸的是，已经成功地在体外诱导FoxP 3+调节性T细胞（T-reg）的方案涉及如果在体内全身施用则将是有毒的TGF β和IL-2的水平。然而，我们的初步数据表明，有可能通过将TGF β、IL-2和抗CD 3 Ab灌输到由透明质酸（HA）和硫酸肝素（HS）制成的水凝胶平台中，以局部方式递送这组相同的T-reg诱导线索。这种方法使可溶性试剂中观察到的FoxP 3+细胞数量大致加倍。 我的假设是，抗原特异性Treg可以使用类似的HA/HS水凝胶从CD 4 + FoxP 3-前体诱导。我建议从三个方面研究这一假说：1）我将阐明交联形式的HA和HS促进Treg诱导的机制。2)我将使用HA/HS水凝胶优化多克隆Treg诱导。3)我将开发HA/HS水凝胶来诱导抗原特异性Treg。 这项工作是我的K 08资助的关于HA和促进免疫耐受的研究的高潮。该R 03将潜在地为在糖尿病小鼠模型中体内和原位诱导抗原特异性耐受的研究奠定基础，我希望在R 01应用中继续进行该研究。 计划工作的意义在于在组织移植和自身免疫性疾病的治疗中诱导抗原特异性耐受而没有全身免疫抑制的潜力。 公共卫生关系：自身免疫性疾病和器官移植的治疗经常涉及全身性免疫抑制剂的施用，经常导致感染或不可接受的毒性。最近在诱导FoxP 3+调节性T细胞（T-reg）（身体自身的免疫耐受介质）方面的努力也面临着同样的局限性。然而，我们的初步数据表明，有可能通过使用由透明质酸和硫酸肝素制成的水凝胶结构作为平台，局部递送先前报道的诱导T-reg的一组共刺激线索。在本申请中，我提出开发能够以抗原特异性方式诱导耐受性的水凝胶。这项计划工作的意义在于诱导对特异性自身抗原或移植组织耐受的潜力，而不需要全身免疫抑制。