Immune Mechanisms in Ocular Graft versus Host Disease

眼移植物抗宿主病的免疫机制

基本信息

批准号：
10596531
负责人：
Robert Benjamin Levy
金额：
$ 41万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596531
关键词：
Affect Alloantigen Allogenic Anemia Anti-Inflammatory Agents Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Biological Bromodomain Bromodomains and extra-terminal domain inhibitor CD4 Positive T Lymphocytes CD8B1 gene Cells Chimera organism Chimeric Proteins Complex Cornea Critical Pathways Development Disease Dry Eye Syndromes Eragrostis Eye Eye Development FOXP3 gene Family Formulation Frequencies Funding Future Gastrointestinal tract structure Genes Genetic Diseases Genetic Transcription Grant Hematologic Neoplasms Hematopoietic Hematopoietic Stem Cell Transplantation IL2RA gene Image Cytometry Immune Immune Targeting Immunologic Deficiency Syndromes Immunologics Immunotherapy Infiltration Inflammatory Interleukin-2 Keratopathy Kinetics Lacrimal gland structure Life Liver Malignant lymphoid neoplasm Mediating Metabolic Diseases Modeling Mus Nerve Oncogenic Organ Pain Palliative Care Pathologic Pathway interactions Patient Care Patients Pattern Perforation Pharmaceutical Preparations Population Pre-Clinical Model Prevention Proteins Quality of life Reagent Receptor Signaling Regulatory T-Lymphocyte Reporter Role Skin Structure Survival Rate T-Lymphocyte TNF gene Testing Thalassemia Therapeutic Time Tissues Transgenic Organisms Translating Tumor Necrosis Factor Receptor Vision Visual impairment conjunctiva cytokine druggable target epigenetic regulation experimental study eye dryness genetic signature graft vs host disease improved in vivo Model inhibitor insight lacrimal nano-string novel ocular surface disease prevent receptor standard of care

项目摘要

Abstract Allogeneic hematopoietic stem cell transplantation (aHSCT) has become the standard of care for treatment of several life-threatening hematologic malignancies, immunodeficiency and genetic diseases. Unfortunately, as the survival rate of these patients is improved, the quality of life is negatively impacted by Graft vs Host Disease (GVHD). GVHD is a complex, multi-organ disorder arising from immunological attack by donor allo-reactive T cells that results in damage to the GI tract, liver, skin and the eye. Ocular GVHD (oGVHD) occurs in >60% of patients with GVHD and can threaten vision due to lacrimal gland and conjunctival damage leading to dry eye, keratopathy and corneal perforation. Despite the high frequency of eye involvement in GVHD patients, little is known regarding the underlying immune mechanisms responsible for oGVHD that lead to keratoconjunctivitis sicca. Unfortunately, the ophthalmic care of these patients is restricted to palliative therapies and anti- inflammatory drugs with limited mechanisms of action and efficacy. Our recent exciting findings using nanostring analysis, support the notion that selected genes including cytokines, antigen presenting / MHC, T cell, and TNF superfamily (TNFRSF) pathways are differentially regulated and involved in oGVHD affecting the conjunctiva and lacrimal gland (Conj+LaGL). In this application, we continue to use pre-clinical models to understand why the eye is a target tissue in GVHD and propose to develop new translational targeted immunotherapies to locally prevent and treat oGVHD. Experiments here will investigate CD4 and CD8 Teff mediated damage to Conj+LaGL (Aim 1). We will utilize our TCR transgenic (Tg) and newly developed double reporter (B6-nur77GFPFoxP3RFP) mice to understand local activation of CD4 and CD8 Teff & Tregs. Using scRNAseq and mass cytometry imaging, studies will provide insights into local T cells receiving alloantigen stimulation. Next, we will interrogate for the first time, hematopoietic and non-hematopoietic antigen presenting cell (APC) pathways in oGVHD (Aim 2). We will apply in vivo models combining TCR Tg donors with hematopoietic chimeras to enable precise interrogation of direct and indirect antigen presentation pathways in the Conj+LaGL damage. These studies will drive development of new strategies using biological reagents and epigenetic regulation for prevention and treatment of aHSCT that can be translated to patients (Aim 3). Notably, our 2-receptor pathway strategy using a novel fusion protein (TL1A-Ig) targeting TNFRSF25 and IL-2, which targets CD25 locally expands ocular Tregs. Because bromodomain proteins have a central role in regulating transcription of inflammatory genes, we propose to use inhibitors of these proteins (BETi), applied as a local ocular formulation to suppress cytokines by infiltrating and parenchymal Conj+LaGL cell populations. Furthermore, we will generate a new oGVHD treatment approach by combining our local 2-pathway Treg expansion strategy with this epigenetic regulation. Our overall objective is to test the hypothesis that immune mediated damage to the Conj+LaGL underlie development of sicca which can be prevented by targeted immune therapy.

抽象的异基因造血干细胞移植（aHSCT）已成为治疗以下疾病的标准疗法几种危及生命的血液系统恶性肿瘤、免疫缺陷和遗传疾病。不幸的是，作为这些患者的生存率得到提高，生活质量受到移植物抗宿主病的负面影响（移植物抗宿主病）。 GVHD 是一种复杂的多器官疾病，由供体同种异体反应性 T 的免疫攻击引起细胞会导致胃肠道、肝脏、皮肤和眼睛受损。眼部 GVHD (oGVHD) 发生于 >60% 患有 GVHD 的患者，可能会因泪腺和结膜损伤而威胁视力，导致干眼症，角膜病变和角膜穿孔。尽管 GVHD 患者眼睛受累的频率很高，但很少有已知导致 oGVHD 并导致角结膜炎的潜在免疫机制干燥。不幸的是，这些患者的眼科护理仅限于姑息治疗和抗- 作用机制和功效有限的炎症药物。我们最近使用纳米线的令人兴奋的发现分析，支持以下观点：所选基因包括细胞因子、抗原呈递/MHC、T 细胞和 TNF 超家族 (TNFRSF) 途径受到差异性调节并参与影响结膜的 oGVHD 和泪腺（Conj+LaGL）。在此应用中，我们继续使用临床前模型来了解原因眼睛是 GVHD 的靶组织，建议开发新的转化靶向免疫疗法以局部治疗预防和治疗oGVHD。这里的实验将研究 CD4 和 CD8 Teff 介导的 Conj+LaGL 损伤（目标 1）。我们将利用我们的TCR转基因（Tg）和新开发的双报告基因（B6-nur77GFPFoxP3RFP）小鼠了解 CD4 和 CD8 Teff 和 Tregs 的局部激活。使用 scRNAseq 和质谱流式成像，研究将深入了解接受同种抗原刺激的局部 T 细胞。接下来，我们将询问首次研究 oGVHD 中的造血和非造血抗原呈递细胞 (APC) 途径（目标 2）。我们将应用将 TCR Tg 供体与造血嵌合体相结合的体内模型，以实现精确审讯 Conj+LaGL 损伤中直接和间接抗原呈递途径的研究。这些研究将推动使用生物试剂和表观遗传调控制定预防和治疗的新策略可以转化为患者的 aHSCT（目标 3）。值得注意的是，我们的 2 受体途径策略使用了一种新颖的靶向 TNFRSF25 和 IL-2 的融合蛋白 (TL1A-Ig)，其靶向 CD25 局部扩展眼部 Tregs。由于溴结构域蛋白在调节炎症基因的转录中具有核心作用，我们建议使用这些蛋白质的抑制剂 (BETi)，作为局部眼部制剂，通过渗透抑制细胞因子和实质Conj+LaGL细胞群。此外，我们将产生一种新的oGVHD治疗方法通过将我们的局部 2 通路 Treg 扩展策略与这种表观遗传调控相结合。我们的总体目标目的是检验以下假设：免疫介导的 Conj+LaGL 损伤是干燥症发生的基础可以通过靶向免疫治疗来预防。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recipient Tregs: Can They Be Exploited for Successful Hematopoietic Stem Cell Transplant Outcomes?

受体 Tregs：能否利用它们获得成功的造血干细胞移植结果？

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Copsel, Sabrina N;Wolf, Dietlinde;Pfeiffer, Brent;Barreras, Henry;Perez, Victor L;Levy, Robert B
通讯作者：
Levy, Robert B

Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model.

通过 TL1A-Ig 和低剂量 IL-2 在供体中扩增的 CD4 – FoxP3 – Tregs 数量极低，在临床前模型中表现出独特的激活/功能特征并抑制 GVHD。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Copsel, Sabrina;Wolf, Dietlinde;Kale, Brandon;Barreras, Henry;Lightbourn, Casey O;Bader, Cameron S;Alperstein, Warren;Altman, Norman H;Komanduri, Krishna V;Levy, Robert B
通讯作者：
Levy, Robert B

Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.

通过白细胞介素 2 和 TL1A-Ig 刺激进行的体内供体调节性 T 细胞扩增可改善移植物抗宿主病，但在造血干细胞移植后保留受者的移植物抗白血病。

DOI：
发表时间：
2017-05
期刊：
影响因子：
0
作者：
Wolf, Dietlinde;Barreras, Henry;Bader, Cameron S;Copsel, Sabrina;Lightbourn, Casey O;Pfeiffer, Brent J;Altman, Norman H;Podack, Eckhard R;Komanduri, Krishna V;Levy, Robert B
通讯作者：
Levy, Robert B

STING and transplantation: can targeting this pathway improve outcomes?

STING 和移植：针对该途径可以改善结果吗？

DOI：
发表时间：
2021
期刊：
影响因子：
20.3
作者：
Bader, Cameron S;Jin, Lei;Levy, Robert B
通讯作者：
Levy, Robert B

The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success.

造血干细胞移植的诱惑和危险：克服免疫挑战以提高成功率。

DOI：
发表时间：
2013-12
期刊：
影响因子：
4.4
作者：
Newman, Robert G;Ross, Duncan B;Barreras, Henry;Herretes, Samantha;Podack, Eckhard R;Komanduri, Krishna V;Perez, Victor L;Levy, Robert B
通讯作者：
Levy, Robert B