Disruption of Treg-dependent Tolerance by B lymphocytes in Islet Transplantation

胰岛移植中 B 淋巴细胞对 Treg 依赖性耐受性的破坏

• 批准号: 10347665
• 负责人: Daniel J. Moore
• 金额: $ 17.3万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347665
• 关键词: Address; Allogenic; Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Appearance; Autoimmune; Autoimmune Diseases; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Beta Cell; Biological Models; Cell Compartmentation; Cell physiology; Cells; Cellular Immunity; Child; Clinical; Collaborations; Data; Development; Disease; Effector Cell; Epitope spreading; Equilibrium; Eragrostis; Failure; Functional disorder; Future; Goals; Graft Rejection; Immune; Immune System Diseases; Immune Tolerance; Immune mediated destruction; Immune system; Immunity; Immunosuppression; Immunotherapy; Impairment; Inbred NOD Mice; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans Transplantation; Mediating; Pattern; Process; Protocols documentation; Recovery; Regulatory T-Lymphocyte; Role; Shapes; Signal Transduction; Specificity; System; T-Cell Activation; T-Lymphocyte; Technology; Tissues; Transgenic Model; Transgenic Organisms; Transplantation; Transplantation Tolerance; anergy; autoimmune pathogenesis; autoreactivity; career; cell type; design; effector T cell; humoral immunity deficiency; immune function; immunomodulatory therapies; immunoregulation; innovation; islet; novel; prevent; repaired; response; success; targeted treatment; tissue injury

Project Summary Although clinical approaches directed at T cells, B cells, and immune effector molecules prevent transplant rejection and slow the progression of autoimmune disease, these therapies do not induce durable immune tolerance as immune-mediated destruction recurs when therapy is stopped. This failure is due to an imbalance in regulatory and effector immunity that no current approach has been able to address and is particularly difficult in approaches like islet transplantation for T1D where the induction of durable immune tolerance would be curative alongside islet replacement. Islet loss following transplant and autoimmune attack in T1D are both heralded by the presence of anti-islet antibodies, which are so important in signifying incipient islet injury that they define new onset stage 1 T1D. Traditionally, it has been thought that the production of these antibodies is a sign of T-B collaboration that leads to effector cell activation. This proposal will investigate an alternative hypothesis that B lymphocytes also directly erode immune regulatory cell function. In the absence of B lymphocytes, we find that the T1D-prone NOD immune system becomes susceptible to inducible transplantation tolerance, which is not otherwise achievable in this background, and that tolerance following islet transplantation is also enhanced in healthy, non-autoimmune recipients. This successful transplantation was not due to loss of effector cell specificities in the absence of B cells but instead was associated with an increase in islet-protective Tregs and a recovery in their response to immune therapy. Thus, we have determined that B lymphocytes are the critical barrier to successful immune reprogramming and that they act by disrupting Treg function. We hypothesize that B cells interact with T cells during their development through both antigen-specific (signal 1) and co-stimulatory (signal 2) interactions to shape the balance of Tregs and Teffs in a way that depends on B cell tolerance. In this proposal, we will investigate this new paradigm in two aims. In Aim 1, we will determine the role of antigen presentation, acquisition, and tissue origin on the interaction of B lymphocytes and Tregs using transgenic systems to control and trace their relationships. In Aim 2, we will determine the mechanism of deleterious B cell-Treg contact including the roles of B cell development, B cell tolerance including anergy, and the intercellular interactions between B and T cells that modulate immunity. Together, these aims will reveal how B cells impede tolerance induction and how this barrier may be repaired to permit inducible immune tolerance in islet transplantation.

项目摘要 尽管针对T细胞、B细胞和免疫效应分子的临床方法阻止了移植 但是，尽管这些疗法可以减少排斥反应并减缓自身免疫性疾病的进展，但这些疗法不能诱导持久的免疫应答， 当治疗停止时，免疫介导的破坏耐受性复发。这种失败是由于不平衡 在调节免疫和效应免疫中，目前没有方法能够解决 在T1 D的胰岛移植等方法中， 与胰岛移植同时进行治疗T1 D患者移植后胰岛丢失和自身免疫性发作 都是由抗胰岛抗体的存在预示的，这在标志早期胰岛 他们定义为新发1期T1 D。传统上，人们认为这些产品的生产 抗体是导致效应细胞活化的T-B协作的标志。该提案将调查 另一种假设是B淋巴细胞也直接侵蚀免疫调节细胞的功能。在没有 B淋巴细胞，我们发现，T1 D倾向的NOD免疫系统变得容易受到诱导 移植耐受性，这在这种背景下是不可能实现的， 胰岛移植在健康的非自身免疫受体中也得到增强。这次成功的移植 并不是由于缺乏B细胞时效应细胞特异性的丧失，而是与 增加胰岛保护性T细胞和恢复其对免疫治疗的反应。因此，我们有 确定了B淋巴细胞是成功免疫重编程的关键屏障，并且它们的作用 通过破坏Treg功能我们假设B细胞在发育过程中通过以下途径与T细胞相互作用： 抗原特异性（信号1）和共刺激（信号2）相互作用，以形成T细胞的平衡， Teffs在某种程度上取决于B细胞的耐受性。在本提案中，我们将分两部分研究这一新范式。 目标。在目标1中，我们将确定抗原呈递、获得和组织来源对免疫应答的作用。 使用转基因系统控制和追踪B淋巴细胞和TCLs的相互作用。在 目的2：探讨B细胞与Treg细胞接触的机制，包括B细胞在其中的作用 发育、包括无反应性的B细胞耐受性以及B和T细胞之间的细胞间相互作用， 调节免疫力。总之，这些目标将揭示B细胞如何阻碍耐受性诱导，以及这是如何影响免疫耐受性的。 可以修复屏障以允许胰岛移植中的诱导免疫耐受。

项目成果

A human IgM enriched immunoglobulin preparation, Pentaglobin, reverses autoimmune diabetes without immune suppression in NOD mice.

• DOI: 10.1038/s41598-022-15676-8
• 发表时间: 2022-07-11
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Wilson, Christopher S.;Hoopes, Emilee M.;Falk, Alexander C.;Moore, Daniel J.
• 通讯作者: Moore, Daniel J.