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
基本信息
- 批准号:10668239
- 负责人:
- 金额:$ 2.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAdoptionAffectAftercareAgonistAllograftingAntibodiesAntigen-Presenting CellsApoptosisB-LymphocytesBindingCD28 geneCD8-Positive T-LymphocytesCD80 geneCD86 geneCTLA4 geneCalcineurin inhibitorCell CountCell SurvivalCell physiologyCellsChimeric ProteinsClinicalDataEnvironmentFDA approvedFOXP3 geneFrequenciesGraft RejectionHealthHomeostasisITIMImmuneImmune systemImmunosuppressionIn VitroIndividualInduction of ApoptosisInfiltrationInterleukin-10Knockout MiceLongevityMediatingMusNatural Killer CellsOrgan TransplantationOutcomePathway interactionsPatientsPhenotypePlayPublicationsRegulatory T-LymphocyteResistanceRiskRoleSignal InductionSignal TransductionSkin graftT cell responseT memory cellT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTherapeuticTherapeutic StudiesTherapeutic immunosuppressionTissue GraftsTissuesToxic effectTransplant RecipientsTransplantationallograft rejectionconditional knockoutcostcurative treatmentscytokineend-stage organ failureexperimental studyimprovedknockout animalmTOR Inhibitornovelpharmacologicpost-transplantpreservationpreventreceptorsynergismtranscriptome sequencingtransplant centers
项目摘要
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
移植是治疗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
在移植的组织中,接受者会接受终身的免疫抑制。钙调神经磷酸酶和mTOR抑制剂
免疫抑制在预防移植物排斥反应方面是成功的,但与严重的不良反应有关。
靶向毒性。为了更好地保护移植物和移植接受者的健康,替代方案
人们一直在寻求免疫抑制疗法。Belatacept,一种CTLA-4Ig融合蛋白,抑制
通过与抗原提呈细胞上的CD80和CD86结合来阻断CD28的免疫系统
(共刺激)和CTLA-4(共抑制)信号在T细胞上。通过阻止特定于
免疫细胞,CTLA-4Ig的使用减轻了与钙调神经磷酸酶抑制剂和
增加移植物的寿命和患者的健康。然而,CTLA-4Ig与
与钙调神经磷酸酶抑制剂相比,发生急性排斥反应的风险较高,这已禁止其在临床上广泛应用
尽管长期结果有所改善,但还是采用了这一方案。调节性T细胞对维持免疫至关重要
移植中的动态平衡和促进耐受性,但通过CD28和CTLA-4的信号传导被阻断
不利于它们的生存和功能。因此,CTLA-4Ig治疗可抑制Tregs控制CD8+T细胞
细胞在执行急性排斥反应时。识别可靶向的共刺激和共抑制通路
提高CTLA-4Ig治疗环境中Tregs的抑制能力是提高疗效的关键
靶向免疫抑制疗法。TIGIT是一种具有Ig和ITIM结构域的T细胞抑制受体
表达在Treg上,可以通过抗体靶向调节Treg功能。激动型抗TIGIT
已有研究表明,抗体可诱导Treg细胞中抗共刺激阻断的记忆T细胞的凋亡。
依赖的态度。这项建议中概述的实验研究了TIGIT信号传递的机制
Tregs增强CTLA-4Ig治疗的Treg功能以降低CD8+T细胞对同种异体移植的反应
挑战。在目标1中,我们将确定细胞自主的TIGIT信号是否增加了Tregs的丰度
在移植组织内,并增加抑制分子的分泌,以增强Treg功能。在AIM 2
我们将确定Treg特异性TIGIT信号对同种异体移植的效应者CD8+T细胞反应的影响。
这些研究将使用新的Treg特异性TIGIT基因敲除动物(Foxp3-Cre x TIGITfl/fl)进行。
总而言之,这些数据将阐明TIGIT激动剂与
共刺激阻断疗法减轻同种异体移植急性排斥反应。
项目成果
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