The role of TIGIT in Treg-mediated suppression of C8+ T cells in Transplantation

TIGIT 在移植中 Treg 介导的 C8 T 细胞抑制中的作用

• 批准号: 10668239
• 负责人: Christina Rose Hartigan
• 金额: $ 2.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668239
• 关键词: Acute; Adoption; Affect; Aftercare; Agonist; Allografting; Antibodies; Antigen-Presenting Cells; Apoptosis; B-Lymphocytes; Binding; CD28 gene; CD8-Positive T-Lymphocytes; CD80 gene; CD86 gene; CTLA4 gene; Calcineurin inhibitor; Cell Count; Cell Survival; Cell physiology; Cells; Chimeric Proteins; Clinical; Data; Environment; FDA approved; FOXP3 gene; Frequencies; Graft Rejection; Health; Homeostasis; ITIM; Immune; Immune system; Immunosuppression; In Vitro; Individual; Induction of Apoptosis; Infiltration; Interleukin-10; Knockout Mice; Longevity; Mediating; Mus; Natural Killer Cells; Organ Transplantation; Outcome; Pathway interactions; Patients; Phenotype; Play; Publications; Regulatory T-Lymphocyte; Resistance; Risk; Role; Signal Induction; Signal Transduction; Skin graft; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Studies; Therapeutic immunosuppression; Tissue Grafts; Tissues; Toxic effect; Transplant Recipients; Transplantation; allograft rejection; conditional knockout; cost; curative treatments; cytokine; end-stage organ failure; experimental study; improved; knockout animal; mTOR Inhibitor; novel; pharmacologic; post-transplant; preservation; prevent; receptor; synergism; transcriptome sequencing; transplant centers

Summary/Abstract Transplantation is a curative strategy for end stage organ failure. In order to avoid immune-mediated rejection of the grafted tissue, recipients receive life-long immunosuppression. Calcineurin and mTOR inhibitors for immunosuppression are successful in preventing graft rejection but are associated with significant adverse off- target toxicities. In order to better preserve the health of both the graft and the transplant recipient, alternative immunosuppressive therapies have been sought. Belatacept, a CTLA-4Ig fusion protein, suppresses the immune system by binding to CD80 and CD86 on antigen presenting cells (APCs) to block CD28 (costimulatory) and CTLA-4 (coinhibitory) signaling on T cells. By blocking interactions that are specific for immune cells, the use of CTLA-4Ig mitigates off-target toxicities associated with calcineurin inhibitors and increases the longevity of the graft and health of the patient. However, CTLA-4Ig is associated with increased risk of acute rejection episodes compared to calcineurin inhibitors, which has prohibited its widespread clinical adoption despite the improved long-term outcomes. Regulatory T cells are essential to maintaining immune homeostasis and promoting tolerance in transplant, but the blockade of signaling through CD28 and CTLA-4 is detrimental to their survival and function. Therefore, CTLA-4Ig therapy inhibits Tregs from controlling CD8+ T cells as they execute acute rejection. Identifying costimulatory and coinhibitory pathways that can be targeted to enhance the suppressive capacity of Tregs in the setting of CTLA-4Ig therapy is essential to improving targeted immunosuppressive therapies. TIGIT is a T-cell inhibitory receptor with Ig and ITIM domains expressed on Tregs that can be targeted with antibodies to fine-tune Treg function. Agonistic anti-TIGIT antibodies have been shown to induce apoptosis of costimulation blockade-resistant memory T cells in a Treg- dependent manner. The experiments outlined in this proposal study the mechanisms by which TIGIT signaling on Tregs enhances Treg function in the face of CTLA-4Ig therapy to reduce CD8 + T cell responses to allograft challenge. In Aim 1 we will determine if cell-autonomous TIGIT signaling increases the abundance of Tregs within grafted tissue and increases the secretion of suppressive molecules to enhance Treg function. In Aim 2 we will determine the impact of Treg-specific TIGIT signaling on effector CD8+ T cell responses to allograft. These studies will be performed using novel Treg-specific TIGIT knockout animals (Foxp3-Cre x TIGITfl/fl). Together, these data will illuminate the therapeutic potential of TIGIT agonism in combination with costimulation blockade therapeutics to mitigate acute allograft rejection.

摘要/摘要 移植是终末期器官衰竭的一种治疗策略。为了避免免疫介导的排斥反应 移植组织后，受者将接受终生免疫抑制。钙调神经磷酸酶和 mTOR 抑制剂 免疫抑制可成功预防移植排斥，但与显着的不良反应相关。 目标毒性。为了更好地保护移植物和移植受者的健康，替代方案 已经寻求免疫抑制疗法。 Belatacept 是一种 CTLA-4Ig 融合蛋白，可抑制 免疫系统通过与抗原呈递细胞 (APC) 上的 CD80 和 CD86 结合来阻断 CD28 T 细胞上的（共刺激）和 CTLA-4（共抑制）信​​号传导。通过阻止特定的交互 免疫细胞，CTLA-4Ig 的使用减轻了与钙调神经磷酸酶抑制剂相关的脱靶毒性， 延长移植物的寿命和患者的健康。然而，CTLA-4Ig 与增加 与钙调神经磷酸酶抑制剂相比，存在急性排斥反应的风险，这阻碍了其广泛的临床应用 尽管长期成果有所改善，但仍被采用。调节性 T 细胞对于维持免疫至关重要 体内平衡并促进移植耐受，但通过 CD28 和 CTLA-4 信号传导的阻断 不利于它们的生存和功能。因此，CTLA-4Ig 治疗抑制 Tregs 控制 CD8+ T 细胞执行急性排斥反应。识别可靶向的共刺激和共抑制途径 在 CTLA-4Ig 治疗的情况下增强 Tregs 的抑制能力对于改善 靶向免疫抑制治疗。 TIGIT 是一种 T 细胞抑制性受体，具有 Ig 和 ITIM 结构域 表达在 Tregs 上，可以用抗体靶向来微调 Treg 功能。激动性抗TIGIT 抗体已被证明可以诱导 Treg 中抗共刺激阻断的记忆 T 细胞凋亡 依赖方式。本提案中概述的实验研究了 TIGIT 信号传导的机制 on Tregs 增强 Treg 功能面对 CTLA-4Ig 治疗，减少 CD8+ T 细胞对同种异体移植物的反应 挑战。在目标 1 中，我们将确定细胞自主 TIGIT 信号传导是否会增加 Tregs 的丰度 在移植组织内增加抑制分子的分泌以增强 Treg 功能。目标 2 我们将确定 Treg 特异性 TIGIT 信号传导对效应 CD8+ T 细胞对同种异体移植物反应的影响。 这些研究将使用新型 Treg 特异性 TIGIT 敲除动物 (Foxp3-Cre x TIGITfl/fl) 进行。 总之，这些数据将阐明 TIGIT 激动剂与 共刺激阻断疗法可减轻急性同种异体移植排斥反应。