Mechanisms controlling transfusion-associated antibody responses in SCD alloimmunization

SCD 同种免疫中控制输血相关抗体反应的机制

• 批准号: 9266812
• 负责人: Karina Yazdanbakhsh
• 金额: $ 42.65万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266812
• 关键词: Address; Affect; Agonist; Allogenic; Alloimmunization; Antibodies; Antibody Formation; Antibody Response; Antigens; Autoantibodies; Automobile Driving; B-Lymphocytes; BLR1 gene; Biological Assay; Biology; Blood; Blood Circulation; Blood Transfusion; Cells; Chronic; Coculture Techniques; Complication; Data; Development; Diagnostic; Disease; Disease Progression; Exhibits; Foundations; Future; Generations; Helper-Inducer T-Lymphocyte; Human; Immune; Immunoglobulin G; In Vitro; Inferior; Inflammatory; Interferon Type II; Isoantibodies; Kinetics; Knowledge; Lead; Life; Lymphoid; Modality; Modeling; Molecular; Molecular Target; Mus; Pathway interactions; Patients; Phenotype; Play; Prevention; Production; Property; Regulation; Reporting; Role; Savings; Sickle Cell Anemia; Signal Transduction; System; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Therapeutic; Therapeutic Intervention; Transfusion; Up-Regulation; Vaccination; Vulnerable Populations; base; biomarker identification; cytokine; exhaustion; immune checkpoint; improved; in vivo; insight; prevent; public health relevance; response; screening; therapeutic development; therapeutic target; therapy development

 DESCRIPTION (provided by applicant): Transfusion therapy remains an important treatment modality for patients with sickle cell disease (SCD). However, some patients develop antibodies against the allogeneic transfused cells, causing major life- threatening complications for the patient. Understanding the immune triggers of alloimmunization and why some patients develop these antibodies is likely to lead to development of diagnostic as well as therapeutic interventions. T follicular helper (TFH) cells provide help to B cells in the generation of antibod responses as well as in production of long-lasting IgG antibodies and are likely to be involved in alloimmunization biology. Exiting new studies have found TFH related cells in the circulation in humans and mice expressing similar markers as lymphoid TFH cells (including CXCR5, ICOS, CD40L, IL-21) that can promote antibody production and their levels correlate with autoantibodies and levels of protective antibodies. Different circulating TFH subsets displaying TH1, TH2 and TH17 like effector functions have been identified. Intriguingly, TIGIT and PD-1 are also expressed on TFH cells, although their relationship to specific effector functions has not been described. These molecules are considered "exhaustion markers" or "immune checkpoints" expressed following chronic antigen stimulation and associated with low type I responses. Alloimmunization occurring after repeated transfusions could embody a similar model of repeated/chronic stimulation and be impacted by the expression of these 2 molecules on TFH cells. Our preliminary data indicate that TIGIT can indeed identify a subset of blood TFH cells with potent TFH functions and low TH1 like response as compared to TFH cells lacking TIGIT. These data suggest that upregulation of TIGIT (and PD-1) pathways on TFH cells may be directly involved in phenotype plasticity from differentiated CD4+ TFH cells displaying type 1 like properties toward strong B cell help. We further hypothesize that TIGIT (and PD-1) triggering on TFH cells is heightened in alloimmunized as compared to non-alloimmunized patients. To test these hypotheses, we will first examine the molecular regulation by TIGIT pathway on circulating TFH cells in driving robust TFH versus type-1 responses. We will then determine whether PD-1 on TIGIT-expressing TFH cells has overlapping or additive role to TIGIT in TFH function and polarization. Finally, we will determine whether TIGIT-dependent T FH functions differ in chronically transfused alloimmunized as compared to non-alloimmunized patients with SCD patients. Together, these data will determine whether alterations in TIGIT (and PD-1) pathway contributes to the plasticity of TFH effector functions and provide a better understanding of the TFH-related correlates of alloantibody response in SCD patients . Understanding the molecular mechanisms of how TFH cells drive alloimmunization in SCD m ay help toward future identification of biomarkers of alloimmunization and therapeutic strategies for its prevention in this vulnerable population.

 描述（适用提供）：输血疗法仍然是镰状细胞病（SCD）患者的重要治疗方式。但是，一些患者会产生针对同种异体输血细胞的抗体，从而导致患者的重大威胁并发症。了解同种异体免疫化的免疫触发因素以及某些患者为什么开发这些抗体可能会导致诊断和治疗干预的发展。 T卵泡辅助器（TFH）细胞为B细胞提供抗体反应以及长期持久IgG抗体的生成，并可能参与同种免疫生物学。退出的新研究发现，在人类和小鼠的循环中，与淋巴样TFH细胞相似的小鼠（包括CXCR5，ICOS，CD40L，IL-21）中的TFH相关细胞可以促进抗体产生及其水平与自身抗体和保护抗体的水平相关。已经确定了显示TH1，TH2和TH17效应子功能的不同循环TFH子集。有趣的是，Tigit和PD-1也在TFH细胞上表达，尽管它们与特定效应子函数的关系尚未 这些分子被认为是在慢性抗原刺激后表达的“疲惫标记”或“免疫检查点”，并且与低I型反应有关。反复输血可能体现相似的重复/慢性刺激模型，并受到TFH细胞上这两个分子的表达影响，发生同种异体免疫。我们的初步数据表明，与缺乏Tigit的TFH细胞相比，Tigit确实可以鉴定具有有效TFH功能的血液TFH细胞的子集和低Th1的反应。这些数据表明，TIGIT（和PD-1）途径在TFH细胞上的上调可能直接参与来自分化的CD4+ TFH细胞的表型可塑性，这些细胞表现出1型类型的特性，例如对强B细胞帮助。我们进一步假设，与非征服患者相比，在同种免疫中，TIGIT（和PD-1）在TFH细胞上触发了触发。为了检验这些假设，我们将首先检查TIGIT途径在循环TFH细胞上通过鲁棒TFH与1型1响应的分子调节。然后，我们将确定表达TigIT的TFH细胞上的PD-1是否在TFH功能和极化中对Tigit的作用重叠或添加了作用。最后，我们将确定与患有SCD患者的非通量免疫的患者相比，长期翻译的同种异体免疫的依赖性T FH的功能是否不同。总之，这些数据将决定TigIT（和PD-1）途径的改变是否有助于TFH效应子功能的可塑性，并更好地了解SCD患者中同抗体反应的TFH相关相关性。了解TFH细胞如何驱动SCD中的同种异体免疫的分子机制有助于将来鉴定同种免疫化和理论策略的生物标志物，以预防该脆弱人群。