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（由申请人提供）：输血疗法仍然是镰状细胞病（SCD）患者的重要治疗方式。然而，一些患者会产生针对同种异体输注细胞的抗体，从而导致严重危及患者生命的并发症。了解同种免疫的免疫触发因素以及为什么一些患者会产生这些抗体可能会导致诊断和治疗干预措施的发展。滤泡辅助 T (TFH) 细胞在产生抗体反应以及产生持久的 IgG 抗体方面为 B 细胞提供帮助，并且可能参与同种免疫生物学。现有的新研究发现，人类和小鼠循环中的 TFH 相关细胞表达与淋巴 TFH 细胞类似的标记物（包括 CXCR5、ICOS、CD40L、IL-21），可促进抗体产生，其水平与自身抗体和保护性抗体水平相关。已鉴定出显示 TH1、TH2 和 TH17 样效应器功能的不同循环 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功能的关系尚未明确。 被描述。这些分子被认为是在慢性抗原刺激后表达的“耗竭标记”或“免疫检查点”，并与低 I 型反应相关。重复输血后发生的同种免疫可能体现了类似的重复/慢性刺激模型，并受到 TFH 细胞上这两种分子表达的影响。我们的初步数据表明，与缺乏 TIGIT 的 TFH 细胞相比，TIGIT 确实可以识别具有强大 TFH 功能和低 TH1 样反应的血液 TFH 细胞子集。这些数据表明，TFH 细胞上 TIGIT（和 PD-1）通路的上调可能直接参与分化的 CD4+ TFH 细胞的表型可塑性，显示出 1 型样特性，从而获得强大的 B 细胞帮助。我们进一步假设，与非同种免疫患者相比，同种免疫患者中 TFH 细胞上的 TIGIT（和 PD-1）触发增强。为了检验这些假设，我们将首先检查 TIGIT 通路对循环 TFH 细胞驱动强 TFH 与 1 型反应的分子调节。然后我们将确定表达 TIGIT 的 TFH 细胞上的 PD-1 在 TFH 功能和极化中是否与 TIGIT 具有重叠或附加作用。最后，我们将确定长期输血同种免疫的 SCD 患者与非同种免疫的患者相比，TIGIT 依赖性 T FH 功能是否存在差异。总之，这些数据将确定 TIGIT（和 PD-1）通路的改变是否有助于 TFH 效应器功能的可塑性，并提供对 SCD 患者同种抗体反应的 TFH 相关相关性的更好理解。了解 TFH 细胞如何驱动 SCD 的同种免疫的分子机制可能有助于未来识别同种免疫的生物标志物以及在这一弱势群体中预防同种免疫的治疗策略。