Defining the Pathogenic Contribution of High Genotypic MIF Expression

定义高基因型 MIF 表达的致病贡献

基本信息

批准号：
10624334
负责人：
RICHARD J BUCALA
金额：
$ 36.85万
依托单位：
YALE UNIVERSITY
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：
2021-06-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624334
关键词：
Acceleration Adoptive Transfer Alleles Arthritis Autoimmune Diseases Binding Biological Response Modifier Therapy Blood CD44 gene Cardiovascular Diseases Cell Culture Techniques Cells Chronic Childhood Arthritis Clinical Collagen Data Disease Disease Progression Evaluation Exons Experimental Arthritis Fc Receptor Fibroblasts Genes Genetic Genetic Polymorphism Genotype Glucocorticoids Human Immunology Induction of Apoptosis Inflammation Inflammatory Inflammatory Arthritis Joints Laboratories Longevity Macrophage Mediating Memory Microsatellite Repeats Migration Inhibitory Factor Morbidity - disease rate Mouse Strains Mus Pathogenicity Pathologic Pathology Pathway interactions Patients Phase Phenotype Play Population Production Protein Isoforms RNA Splicing Recurrent disease Refractory Relapse Rheumatoid Arthritis Role Scleroderma Signal Transduction Site Symptoms Synovial Fluid Synovial Membrane Synovial joint Synovitis Systemic Lupus Erythematosus T cell response T memory cell T-Lymphocyte Testing Tissues United States Variant Vasculitis Work arthropathies cytokine drug-like compound effective therapy experience experimental study human migration immunopathology inhibitor insight joint destruction mouse model novel peripheral blood programs promoter prototype receptor research clinical testing response risk variant tool trafficking transcription factor translational impact treatment response

项目摘要

PROJECT SUMMARY Rheumatoid arthritis (RA) remains incurable despite biologic therapies. We previously identified a functional promoter polymorphism in the gene for macrophage migration inhibitory factor (MIF) - a cytokine our group first cloned, that is associated with erosive joint destruction in RA. MIF is known to regulate the innate response by inhibiting glucocorticoid action, suppressing activation-induced apoptosis, and promoting macrophage retention in tissues. The role of MIF and high expression MIF alleles is not fully understood however, especially with respect to alterations in the adaptive response that perpetuate inflammation, pathologic progression, and disease persistence. We have discovered a novel T cell subpopulation that expresses the MIF receptor (CD74), expands during arthritis, and recapitulates disease when transferred into naïve hosts. A similar population exists in human rheumatoid synovium. We hypothesize that CD4+CD74+ T cells play a key role in rheumatoid inflammation, disease progression, and relapse. We will pursue three Specific Aims in this proposal: 1. Define the pathogenic role of a novel, MIF receptor expressing T cell sub-population (CD4+CD74+ T cells) in inflammatory arthritis. We hypothesize that CD4+CD74+ T cells express inflammatory cytokines and chemotactic receptors that contribute to synovial joint destruction. We will characterize the MIF signaling and effector responses of mouse and human CD4+CD74+ T cells, identify trafficking factors/receptors, and establish their pathogenic potential. 2. Define the impact of high-genotypic MIF expression on joint immunopathology in a novel humanized MIF mouse model. We hypothesize that MIF expression drives pathologic CD4+CD74+ T cell trafficking and effector responses, and unremitting arthritis. We will test this hypothesis using novel humanized MIF mice that express low-expression and high-expression human MIF alleles. 3. Evaluate the impact of ICBP90 inhibition on MIF expression in humanized MIF mice and in high genotypic MIF expressing human cells. We identified both the transcription factor (ICBP90) that upregulates MIF transcription at its variant promoter microsatellite (-794 CATT5-8), and a drug-like molecule (CMFT) that blocks ICBP90 binding to this promoter site. We hypothesize that ICBP90 inhibition will ameliorate the MIF- dependent expansion and effector response of CD4+CD74+ T cells. We will test this possibility in experimental arthritis and examine ICBP90 inhibition in high-genotypic MIF expressing human cells obtained from peripheral blood and from rheumatoid synovial tissue. The completion of these Aims will provide insight into the pathologic role of a novel, MIF receptor expressing T cell population and the contribution of MIF risk alleles to rheumatoid inflammation. These studies also will accelerate consideration of a precision-based approach for treating RA joint destruction.

项目摘要类风湿关节炎（RA）仍然是无法治愈的任务生物疗法。我们以前确定了巨噬细胞迁移抑制因子（MIF）的基因中功能启动子多态性 - 细胞因子我们的小组首先克隆，这与RA中的侵蚀性关节破坏有关。已知MIF调节通过抑制糖皮质激素作用，抑制激活诱导的凋亡和促进组织中的巨噬细胞保留。 MIF和高表达MIF等位基因的作用不是完全但是，请理解，尤其是关于永久自适应反应的改变炎症，病理进展和疾病持久性。我们发现了一个新颖的T细胞表达MIF受体（CD74），在关节炎期间扩展并概括疾病的亚群（CD74）当转移到幼稚的宿主中时。人类类风湿滑膜中存在类似的人群。我们假设CD4+ CD74+ T细胞在类风湿注射，疾病进展和复发。我们将在此提案中追求三个具体目标：1。定义小说的致病作用， MIF受体表达T细胞亚群（CD4+ CD74+ T细胞）炎症性关节炎。我们假设CD4+ CD74+ T细胞表达炎性细胞因子和趋化受体，有助于滑膜关节破坏。我们将表征MIF信号传导和效应子响应小鼠和人CD4+ CD74+ T细胞，识别运输因子/受体，并建立其致病性潜在的。 2。定义高基因型MIF表达对A中关节免疫病理学的影响新型的人源化MIF小鼠模型。我们假设MIF表达驱动病理CD4+CD74+ T细胞运输和效应子反应以及不舒服的关节炎。我们将使用新颖的假设检验这一假设人源化的MIF小鼠，表达低表达和高表达人类MIF等位基因。 3。评估 ICBP90抑制对人源化MIF小鼠和高基因型MIF中MIF表达的影响表达人类细胞。我们确定了上调MIF的转录因子（ICBP90）在其变体启动子微卫星（-794 Catt5-8）和药物样分子（CMFT）处转录阻止ICBP90与此启动子站点结合。我们假设ICBP90抑制作用将改善MIF- CD4+ CD74+ T细胞的依赖扩展和效应子响应。我们将在实验性关节炎和检查高基因型MIF表达人类细胞的ICBP90抑制作用从外周血和类风湿滑膜组织获得。这些目标的完成将提供有关一种新型MIF受体表达T细胞群体和的病理作用的见解 MIF风险等位基因对类风湿感染的贡献。这些研究也将加速考虑一种基于精确的治疗RA关节破坏的方法。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interleukin-17 Contributes to Chikungunya Virus-Induced Disease.

DOI：
10.1128/mbio.00289-22
发表时间：
2022-04-26
期刊：
MBIO
影响因子：
6.4
作者：
Liu, Xiang;Poo, Yee-Suan;Alves, Juliana C.;Almeida, Roque P.;Mostafavi, Helen;Tang, Patrick Chun Hean;Bucala, Richard;Teixeira, Mauro M.;Taylor, Adam;Zaid, Ali;Mahalingam, Suresh
通讯作者：
Mahalingam, Suresh

"Near Cure" treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct.

使用双功能 MHCII 衍生分子构建体对 MIF-1 缺陷雌性和雄性小鼠的严重急性 EAE 进行“近乎治愈”治疗。

DOI：
10.1016/j.cellimm.2022.104561
发表时间：
2022
期刊：
Cellular immunology
影响因子：
4.3
作者：
Vandenbark,ArthurA;Meza-Romero,Roberto;Wiedrick,Jack;Gerstner,Grant;Seifert,Hilary;Kent,Gail;Piechycna,Marta;Benedek,Gil;Bucala,Richard;Offner,Halina
通讯作者：
Offner,Halina

Targeting fibrocytes in autoimmunity.

DOI：
10.1073/pnas.2121739119
发表时间：
2022-02-01
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Bucala RJ
通讯作者：
Bucala RJ

Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer.

DOI：
10.1038/s41598-023-38748-9
发表时间：
2023-07-18
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Huth, Sebastian;Huth, Laura;Heise, Ruth;Marquardt, Yvonne;Lopopolo, Linda;Piecychna, Marta;Boor, Peter;Fingerle-Rowson, Guenter;Kapurniotu, Aphrodite;Yazdi, Amir S.;Bucala, Richard;Bernhagen, Juergen;Baron, Jens Malte
通讯作者：
Baron, Jens Malte

Brief report: Enhanced DRα1-mMOG-35-55 treatment of severe EAE in MIF-1-deficient male mice.

DOI：
10.1016/j.cellimm.2021.104439
发表时间：
2021-12
期刊：
Cellular immunology
影响因子：
4.3
作者：
Vandenbark AA;Meza-Romero R;Wiedrick J;Gerstner G;Headrick A;Kent G;Seifert H;Benedek G;Bucala R;Offner H
通讯作者：
Offner H