Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
基本信息
- 批准号:10348683
- 负责人:
- 金额:$ 66.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Graft Versus Host DiseaseAffectAffinityAgonistAllogenicAnti-Inflammatory AgentsAntibody ActivationAntigensAutoimmunityBindingBiologicalBiologyCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCalcineurin inhibitorCell TherapyCellsChemotaxisClinical TrialsCyclic GMPDataDisease modelDoseDown-RegulationFoundationsFrequenciesFunctional disorderGenerationsGrantHematopoietic stem cellsHumanImmuneImmune systemImmunoglobulinsIn complete remissionInfiltrationInflammationInflammatoryInterleukin-10LinkMaintenanceMediatingMemoryMinorModelingMonoclonal AntibodiesMusMyelogenousMyeloid CellsMyeloid LeukemiaOrganP-selectin ligand proteinPathogenesisPatientsPeer ReviewPeripheralPharmaceutical PreparationsPrevention therapyProphylactic treatmentReceptor SignalingRefractoryRefractory DiseaseRegulatory T-LymphocyteRestRoleSeveritiesSideSolidSteroidsSuppressor-Effector T-LymphocytesSurvival RateT cell responseT memory cellT-Cell ActivationT-Cell Activation PathwayT-Cell ReceptorT-LymphocyteTestingTransgenic OrganismsTranslatingTranslationsTransplantationanergyconditioningcytokinedisorder controldisorder preventiongraft vs host diseasegraft vs leukemia effecthematopoietic cell transplantationin vivoinflammatory milieuinhibiting antibodyinsightleukemiamacrophagemonocytenovel strategiesoperationpreventpublic health relevanceresponseside effecttumor
项目摘要
Abstract Despite multi-drug prophylaxis, aGVHD affects 20-70% of allogeneic hematopoietic cell transplant
(allo-HCT) patients. V-region Immunoglobulin-containing Suppressor of T cell Activation (VISTA), a negative
checkpoint regulator expressed on resting naïve mouse and human T cells. A single dose of agonist VISTA
monoclonal antibody (mAb) on allo-HCT day 0 causes antigen-specific operational tolerance by deletion and
anergy in resting naïve T cells that have concurrent T cell receptor (TCR) signals and 90-100% long-term
survival. VISTA has been linked to induced Treg generation, expansion, stability and maintenance. In acute
graft-vs-host disease (aGVHD), agonist mAb increases peripheral Tregs; the extent to which pTregs contribute
to operational tolerance will be explored (aim 1A). Limited data exist for aGVHD prevention. Polyclonal CD4 T
cells are the dominant aGVHD effectors in MHC disparate aGVHD models and TCR signaling is critical for
deletion/anergy; studies are proposed using high affinity donor TCR transgenic and polyclonal CD4 and/or
CD8 T cells will assess operation tolerance and long-term survival in MHC and minor antigen disparate
models. Tetramers will track polyclonal and monoclonal donor allospecific T cells in agonist mAb treated mice.
Frequently used calcineurin inhibitors (CNIs) may alter TCR signals below a threshold needed for agonist mAb
effects; testing is required before translation (aim 1C). A unique feature of VISTA is downregulation with T cell
activation. Non-alloreactive T cells and alloreactive T cells escaping agonist mAb induced deletion/anergy may
permit generation of leukemia-specific T cells (aim 1B). Steroids are first line therapy for aGVHD patients but
only half the patients have day 28 complete responses; 1-year survival rate for steroid refractory (SR) aGVHD
patients is dismal. In mice and patients, we show myeloid cell infiltration is 2.5-fold higher than T cells in gut, a
primal aGVHD organ in SR aGVHD. VISTA is expressed on myeloid cells at >10-fold higher levels than T cells.
Agonist mAb inhibits myeloid cell chemotaxis and reprograms inflammatory monocytes/macrophages into anti-
inflammatory cells. We hypothesize that agonist mAb reprograming of gut monocytes/macrophages can treat
SR aGVHD (aim 2). Our central hypothesis is agonist VISTA mAb has dual uses for aGVHD prevention,
inducing T cell operational tolerance, and SR aGVHD therapy, reprogramming myeloid cells to be anti-
inflammatory. Our aims will test the hypotheses that: Operational tolerance induced by agonist mAb
allospecific deletion/anergy of donor T cells depends on in vivo Treg induction, permits unaffected T cells to
generate leukemia-specific responses, and is subverted by day 0 inflammation or CNIs initiated pre-transplant
(aim 1). In aim 2, we will test the hypothesis that agonist mAb reprograms inflammatory monocytes and
macrophages in the gut to be anti-inflammatory and locally release of immune suppressive cytokines,
ameliorating SR aGVHD without systemic side-effects of exogenous cytokines. Our studies are foundational
for translation of Noelle’s agonist human VISTA mAb for aGVHD prevention and SR aGVHD therapy.
摘要尽管预防了多药,但AGVHD影响了20-70%的同种异体造血细胞移植
(Allo-HCT)患者。 T细胞激活(Vista)的V-区域免疫球蛋白抑制剂,阴性
检查点调节因子以静止的小鼠和人类T细胞表示。单剂量的激动剂远景
在Allo-HCT第0天,单克隆抗体(MAB)导致抗原特异性操作耐受性通过缺失和
具有同时T细胞受体(TCR)信号和90-100%长期的静止的幼稚T细胞的静止ANERGY
生存。 Vista与诱发的Treg产生,扩展,稳定性和维护相关。急性
移植-VS宿主疾病(AGVHD),激动剂mAb增加周围tregs; Ptregs贡献的程度
将探索操作公差(AIM 1A)。预防AGVHD的数据有限。多克隆CD4 t
细胞是MHC不同AGVHD模型中的主要AGVHD效应,TCR信号对于
删除/不含量;使用高亲和力供体TCR转基因和多克隆CD4和/或
CD8 T细胞将评估MHC和较小抗原不同的操作耐受性和长期存活率
型号。四聚体将在激动剂mAb处理的小鼠中跟踪多克隆和单克隆供体的供体供体T细胞。
经常使用的钙调蛋白抑制剂(CNIS)可能会在激动剂mAb所需的阈值以下改变TCR信号
效果;翻译之前需要测试(AIM 1C)。 Vista的独特特征是T细胞下调
激活。非异种反应性T细胞和同种反应性T细胞逃脱了激动剂mAb诱导的缺失/无反应
允许产生白血病特异性T细胞(AIM 1B)。类固醇是针对AGVHD患者的第一线治疗
只有一半的患者有第28天的完整反应;类固醇(SR)AGVHD的1年生存率
病人很沮丧。在小鼠和患者中,我们显示髓样细胞浸润比肠道中的T细胞高2.5倍,A
Sr AGVHD中的Primal AGVHD器官。远景在髓样细胞上以比T细胞高10倍的水平表达。
激动剂mAb抑制髓样细胞趋化性,并将炎症单核细胞/巨噬细胞重新编程为抗 -
炎性细胞。我们假设肠道单核细胞/巨噬细胞的激动剂mAb重编程可以治疗
SR AGVHD(AIM 2)。我们的中心假设是激动剂Vista mab具有双重用途,可用于预防AGVHD,
诱导T细胞的耐受性和SR AGVHD疗法,重编程髓样细胞为抗
炎症。我们的目标将检验以下假设:激动剂mab引起的操作耐受性
供体T细胞的同种缺失/反应取决于体内TREG诱导,允许未受影响的T细胞进入
产生白血病特异性反应,并在第0天发炎或CNIS启动前移植前颠覆
(目标1)。在AIM 2中,我们将检验以下假设:激动剂mAb重新编程炎症单核细胞和
肠道中的巨噬细胞是抗炎和局部释放免疫抑制细胞因子,
改善SR AGVHD,没有外源细胞因子的全身副作用。我们的研究是基础
为了翻译Noelle的激动剂人类远景mAb,以预防AGVHD和SR AGVHD疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bruce R Blazar其他文献
Bruce R Blazar的其他文献
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{{ truncateString('Bruce R Blazar', 18)}}的其他基金
University of Minnesota Clinical and Translational Science Institute (UMN CTSI)
明尼苏达大学临床与转化科学研究所 (UMN CTSI)
- 批准号:
10763967 - 财政年份:2023
- 资助金额:
$ 66.24万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10560605 - 财政年份:2021
- 资助金额:
$ 66.24万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10092348 - 财政年份:2021
- 资助金额:
$ 66.24万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
10305635 - 财政年份:2019
- 资助金额:
$ 66.24万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
10656502 - 财政年份:2019
- 资助金额:
$ 66.24万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
9888096 - 财政年份:2019
- 资助金额:
$ 66.24万 - 项目类别:
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