Mechanisms controlling transfusion-associated antibody responses in SCD alloimmunization

 描述(申请人提供)：输血疗法仍然是镰状细胞病(SCD)患者的一种重要治疗方式。然而，一些患者会产生针对异体输血细胞的抗体，从而导致危及患者生命的主要并发症。了解同种异体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。T滤泡辅助细胞(TFH)帮助B细胞产生抗BOD反应和产生持久的免疫球蛋白抗体，可能参与同种异体免疫生物学。现有的新研究发现，在人类和小鼠的循环中，TFH相关细胞表达与淋巴样TFH细胞(包括CXCR5、ICOS、CD40L、IL-21)相似的标记，可以促进抗体的产生，它们的水平与自身抗体和保护性抗体的水平相关。已经鉴定了不同的循环TFH亚群，显示TH1、TH2和TH17类似的效应功能。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得到证实 都被描述过。这些分子被认为是慢性抗原刺激后表达的“耗竭标记”或“免疫检查点”，与I型反应低有关。重复输血后的同种异体免疫可以体现类似的重复/慢性刺激模型，并受这两个分子在TFH细胞上的表达的影响。我们的初步数据表明，与缺乏TIGIT的TFH细胞相比，TIGIT确实可以识别出具有强大的TFH功能和较低的TH1样反应的血液TFH细胞亚群。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了分化后的CD4+TFH细胞从表现出1型特性的表型可塑性向强B细胞帮助方向的转变。我们进一步假设，与非同种免疫的患者相比，同种免疫的患者TIGIT(和PD-1)对TFH细胞的触发作用更高。为了验证这些假说，我们将首先研究TIGIT通路对循环TFH细胞驱动强大的TFH与1型反应的分子调控。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重叠或相加。最后，我们将确定长期输血同种异体免疫的SCD患者与非同种异体免疫的SCD患者相比，TIGIT依赖的T-FH功能是否不同。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患者同种异体抗体反应与TFH相关的更好的理解。了解TFH细胞如何在SCD中驱动同种异体免疫的分子机制可能有助于未来识别同种异体免疫的生物标志物，并在这一脆弱人群中预防其治疗策略。

 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.