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: 10348683
• 负责人: Bruce R Blazar
• 金额: $ 66.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10348683
• 关键词: Acute Graft Versus Host Disease; Affect; Affinity; Agonist; Allogenic; Anti-Inflammatory Agents; Antibody Activation; Antigens; Autoimmunity; Binding; Biological; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcineurin inhibitor; Cell Therapy; Cells; Chemotaxis; Clinical Trials; Cyclic GMP; Data; Disease model; Dose; Down-Regulation; Foundations; Frequencies; Functional disorder; Generations; Grant; Hematopoietic stem cells; Human; Immune; Immune system; Immunoglobulins; In complete remission; Infiltration; Inflammation; Inflammatory; Interleukin-10; Link; Maintenance; Mediating; Memory; Minor; Modeling; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Myeloid Leukemia; Organ; P-selectin ligand protein; Pathogenesis; Patients; Peer Review; Peripheral; Pharmaceutical Preparations; Prevention therapy; Prophylactic treatment; Receptor Signaling; Refractory; Refractory Disease; Regulatory T-Lymphocyte; Rest; Role; Severities; Side; Solid; Steroids; Suppressor-Effector T-Lymphocytes; Survival Rate; T cell response; T memory cell; T-Cell Activation; T-Cell Activation Pathway; T-Cell Receptor; T-Lymphocyte; Testing; Transgenic Organisms; Translating; Translations; Transplantation; anergy; conditioning; cytokine; disorder control; disorder prevention; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; in vivo; inflammatory milieu; inhibiting antibody; insight; leukemia; macrophage; monocyte; novel strategies; operation; prevent; public health relevance; response; side effect; tumor

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。