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：
Bruce R Blazar
金额：
$ 66.24万
依托单位：
UNIVERSITY OF MINNESOTA
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：
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

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.

摘要尽管采用多种药物预防，aGVHD 仍影响 20-70% 的同种异体造血细胞移植 (allo-HCT) 患者，含有 V 区免疫球蛋白 T 细胞激活抑制剂 (VISTA)，阴性。在静息状态的幼鼠和人类 T 细胞上表达的检查点调节剂单剂量的激动剂 VISTA。同种异体 HCT 第 0 天的单克隆抗体 (mAb) 通过删除和具有并发 T 细胞受体 (TCR) 信号和 90-100% 长期的静息初始 T 细胞无反应性 VISTA 的存活与诱导的 Treg 生成、扩增、稳定性和维持有关。移植物抗宿主病 (aGVHD)，激动剂 mAb 增加外周 Tregs 的贡献程度；将探讨多克隆 CD4 T 的操作耐受性（目标 1A）。细胞是 MHC 不同 aGVHD 模型中的主要 aGVHD 效应器，TCR 信号传导对于缺失/无反应性；建议使用高亲和力供体 TCR 转基因和多克隆 CD4 和/或 CD8 T 细胞将评估 MHC 和次要抗原不同的操作耐受性和长期生存四聚体模型将追踪激动剂 mAb 治疗小鼠中的多克隆和单克隆供体同种异体特异性 T 细胞。常用的钙调神经磷酸酶抑制剂 (CNI) 可能会将 TCR 信号改变到激动剂 mAb 所需的阈值以下效果；翻译前需要进行测试（目标 1C）。VISTA 的一个独特功能是 T 细胞下调。非同种异体反应性 T 细胞和逃避激动剂 mAb 诱导的缺失/无反应的同种异体反应性 T 细胞可能会被激活。允许产生白血病特异性 T 细胞（目标 1B），类固醇是 aGVHD 患者的一线治疗方法。对于类固醇难治性 (SR) aGVHD，只有一半患者在第 28 天有完全缓解；在小鼠和患者中，我们发现骨髓细胞浸润比肠道中的 T 细胞高 2.5 倍。 SR aGVHD 中的原始 aGVHD 器官在骨髓细胞上的表达水平比 T 细胞高 10 倍。激动剂单克隆抗体抑制骨髓细胞趋化性并将炎症单核细胞/巨噬细胞重新编程为抗我们勇敢地说，激动剂单克隆抗体重编程可以治疗肠道单核细胞/巨噬细胞。 SR aGVHD（目标 2）。我们的中心假设是激动剂 VISTA mAb 对于预防 aGVHD 有双重用途，诱导 T 细胞操作耐受和 SR aGVHD 治疗，将骨髓细胞重新编程为抗- 我们的目标将测试以下假设：激动剂单克隆抗体诱导的操作耐受性。供体 T 细胞的同种异体特异性缺失/无反应性取决于体内 Treg 诱导，允许未受影响的 T 细胞产生白血病特异性反应，并被移植前第 0 天的炎症或 CNI 所破坏（目标 1）在目标 2 中，我们将检验激动剂 mAb 重新编程炎症单核细胞的假设。肠道中的巨噬细胞具有抗炎作用并局部释放免疫抑制细胞因子，我们的研究是基础性的，可以改善 SR aGVHD，且不会产生外源性细胞因子的全身副作用。用于翻译 Noelle 激动剂人 VISTA mAb，用于 aGVHD 预防和 SR aGVHD 治疗。