Mechanisms controlling transfusion-associated antibody responses in SCD alloimmunization

 描述（由申请人提供）：输血治疗仍然是镰状细胞病（SCD）患者的重要治疗方式。然而，一些患者产生了针对同种异体输注细胞的抗体，从而导致患者的严重危及生命的并发症。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。滤泡辅助性T细胞（TFH）在产生抗体应答以及产生持久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。现有的新研究已经发现人和小鼠循环中的TFH相关细胞表达与淋巴TFH细胞（包括CXCR 5、ICOS、CD 40 L、IL-21）相似的标志物，其可以促进抗体产生，并且其水平与自身抗体和保护性抗体的水平相关。已经鉴定了显示TH 1、TH 2和TH 17样效应子功能的不同循环TFH亚群。有趣的是，TIGIT和PD-1也在TFH细胞上表达，尽管它们与特异性效应子功能的关系还不清楚。 被描述。这些分子被认为是在慢性抗原刺激后表达的“耗竭标记物”或“免疫检查点”，并且与低I型应答相关。重复输注后发生的同种异体免疫可体现重复/慢性刺激的类似模型，并受到TFH细胞上这2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确实可以鉴定具有有效TFH功能和低TH 1样应答的血液TFH细胞亚群。这些数据表明，TFH细胞上TIGIT（和PD-1）途径的上调可能直接涉及来自分化的CD 4 + TFH细胞的表型可塑性，所述分化的CD 4 + TFH细胞显示1型样性质，朝向强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TIGIT（和PD-1）对TFH细胞的触发增强。为了测试这些假设，我们将首先检查TIGIT途径对循环TFH细胞在驱动稳健的TFH相对于1型应答中的分子调节。然后，我们将确定表达TIGIT的TFH细胞上的PD-1是否与TIGIT在TFH功能和极化中具有重叠或相加作用。最后，我们将确定与SCD患者的非同种免疫患者相比，长期输血同种免疫患者中TIGIT依赖性T FH功能是否不同。总之，这些数据将确定TIGIT（和PD-1）途径的改变是否有助于TFH效应子功能的可塑性，并提供对SCD患者中同种抗体应答的TFH相关关联的更好理解。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和在该易感人群中预防同种异体免疫的治疗策略。

 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.