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:
    10560605
  • 负责人:
  • 金额:
    $ 66.97万
  • 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

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.
摘要尽管有多种药物预防,aGVHD仍影响20-70%的异基因造血细胞移植。 (Allo-HCT)患者。含V区免疫球蛋白的T细胞激活抑制因子(VistA),阴性 检查点调节因子在静止的幼稚小鼠和人T细胞上表达。单剂激动剂Vista 在allo-HCT第0天的单抗(MAb)通过缺失和 具有并发T细胞受体(TCR)信号和90%-100%长期存活的静息幼稚T细胞的无能 生死存亡。Vista与诱导性Treg的产生、扩展、稳定性和维护有关。在急性期 移植物抗宿主病(AGVHD),激动剂mAb增加外周Tregs;pTregs的作用程度 将探讨对操作容差的要求(目标1A)。预防aGVHD的数据有限。多克隆CD4T细胞 在MHC不同的aGVHD模型中,细胞是主要的aGVHD效应器,TCR信号转导是关键的 缺失/无能;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和次要抗原不同的手术耐受性和长期生存 模特们。四聚体将在激动剂mAb处理的小鼠中追踪多克隆和单克隆供体同种异体T细胞。 频繁使用的钙调神经磷酸酶抑制剂(CNI)可能会改变TCR信号,使其低于激动剂mAb所需的阈值 效果;翻译前需要进行测试(目标1C)。Vista的一个独特功能是下调T细胞的表达 激活。非同种异体反应T细胞和同种异体反应T细胞逃避激动剂mAb诱导的缺失/无能可能 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,但 只有一半的患者在第28天完全缓解;激素难治性(SR)aGVHD的1年存活率 病人是令人沮丧的。在小鼠和患者中,我们发现在肠道中髓系细胞的浸润率是T细胞的2.5倍, SR aGVHD的原始aGVHD器官。VistA在髓系细胞上的表达水平是T细胞的10倍。 激动剂mAb抑制髓系细胞的趋化并将炎性单核/巨噬细胞重新编程为抗 炎性细胞。我们假设激动型单抗重新编程肠道单核细胞/巨噬细胞可以治疗 高级aGVHD(目标2)。我们的中心假设是激动剂Vista mAb具有预防aGVHD的双重用途, 诱导T细胞操作耐受,SR aGVHD治疗,重新编程髓系细胞成为抗 煽动性的。我们的目标将检验以下假设:激动剂单抗诱导的操作耐受性 供者T细胞的同种异体特异性缺失/无能依赖于体内Treg的诱导,允许未受影响的T细胞 产生白血病特异性反应,并被移植前启动的第0天炎症或CNI颠覆 (目标1)。在目标2中,我们将检验激动剂mAb重新编程炎性单核细胞和 肠道中的巨噬细胞可以抗炎和局部释放免疫抑制细胞因子, 改善SR aGVHD,无外源性细胞因子的全身副作用。我们的研究是基础性的 翻译Noelle激动剂人Vista单抗用于aGVHD预防和SR aGVHD治疗。

项目成果

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Bruce R Blazar其他文献

Challenges and solutions for cellular therapy development in autoimmune diseases
自身免疫性疾病中细胞治疗发展的挑战与解决方案
  • DOI:
    10.1016/s2665-9913(24)00274-1
  • 发表时间:
    2024-11-01
  • 期刊:
  • 影响因子:
    16.400
  • 作者:
    Elizabeth R Volkmann;John Varga;Bruce R Blazar;Steven Z Pavletic
  • 通讯作者:
    Steven Z Pavletic
Five-Year Outcomes of the “Abatacept Combined with a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease (GVHD) Prophylaxis: A Randomized Controlled Trial” (‘ABA2‘)
  • DOI:
    10.1182/blood-2024-205130
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Lev Gorfinkel;Muna Qayed;Brandi Bratrude;Kayla Betz;Kyle Hebert;Sung W. Choi;Jeffrey Davis;Christine Duncan;Roger H. Giller;Michael S. Grimley;Andrew Harris;David A Jacobsohn;Nahal Lalefar;Nosha Farhadfar;Michael A. Pulsipher;Shalini Shenoy;Aleksandra Petrovic;Kirk R. Schultz;Gregory Yanik;Bruce R Blazar
  • 通讯作者:
    Bruce R Blazar
IL-33 Induces Paneth Cell Production of EGF and Soluble ST2, Regulating Epithelial Regeneration after Intestinal Injury
  • DOI:
    10.1182/blood-2023-191189
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Marco Calafiore;YA-Yuan Fu;Paola Vinci;Viktor Arnhold;Winston Chang;Suze Jansen;Anastasiya Egorova;Shuichiro Takashima;Jason Kuttiyara;Takahiro Ito;Jonathan Serody;Susumu Nakae;Heth Turnquist;Johan van Es;Hans Clevers;Caroline A. Lindemans;Bruce R Blazar;Alan M. Hanash
  • 通讯作者:
    Alan M. Hanash
Cyclosporine and Voclosporin Resistant Immune Effector Cells to Improve Outcomes after Stem Cell Transplantation
  • DOI:
    10.1182/blood-2023-180218
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Holly Wobma;Jiayi Dong;Francesca Alvarez Calderon;Xianliang Rui;Katherine Michaelis;Bruce R Blazar;Victor Tkachev;Ulrike Gerdemann;Leslie Kean
  • 通讯作者:
    Leslie Kean
Mitochondrial Pyruvate Carrier Inhibition Mitigates Murine Chronic Graft Versus Host Disease By Attenuating the Germinal Center Reaction
  • DOI:
    10.1182/blood-2023-185200
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Fathima A Mohamed;Stephanie Y Rhee;Joanna Ly;Ethan G Aguilar;Haley Melin;Peter T Sage;Tanner Schumacher;Govindarajan Thangavelu;Michael C Zaiken;Juan Liu;Venkatram Mereddy;Jason W Locasale;Bruce R Blazar
  • 通讯作者:
    Bruce R Blazar

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:
    $ 66.97万
  • 项目类别:
In Vivo Prevention of Murine GVHD
小鼠 GVHD 的体内预防
  • 批准号:
    10362877
  • 财政年份:
    2022
  • 资助金额:
    $ 66.97万
  • 项目类别:
Metabolomics of cGVHD
cGVHD 的代谢组学
  • 批准号:
    10698171
  • 财政年份:
    2022
  • 资助金额:
    $ 66.97万
  • 项目类别:
In Vivo Prevention of Murine GVHD
小鼠 GVHD 的体内预防
  • 批准号:
    10610863
  • 财政年份:
    2022
  • 资助金额:
    $ 66.97万
  • 项目类别:
Metabolomics of cGVHD
cGVHD 的代谢组学
  • 批准号:
    10493800
  • 财政年份:
    2022
  • 资助金额:
    $ 66.97万
  • 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:
    $ 66.97万
  • 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:
    10348683
  • 财政年份:
    2021
  • 资助金额:
    $ 66.97万
  • 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:
    $ 66.97万
  • 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:
    $ 66.97万
  • 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:
    $ 66.97万
  • 项目类别:

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