PI3K-gamma regulates T cell mediated alloimmunity

摘要 尽管用于预防排斥反应的免疫抑制剂(ISA)随着时间的推移而有所改善，但它们仍然 不能始终如一地消除急性和慢性排斥反应，它们与发病机制有关 器官衰竭(即钙调神经磷酸酶抑制剂毒性)。传统ISA的主要问题之一是它们抑制了 移植过程中的调控途径。因此，中国最高的未满足需求之一 移植是寻找新的免疫调节策略，选择性地抑制病原体 同种异体免疫细胞，但保留调节性体液和细胞途径，如T调节性细胞 (Tregs)。磷脂酰肌醇-3激酶(PI3K)是一种脂蛋白激酶，可产生重要的信号转导 免疫细胞功能。在PI3K的各个子类中，PI3Kγ以其独特的特性而备受关注 在白细胞中的限制性表达，在免疫细胞和炎症中的调节作用。尽管如此， 靶向PI3Kγ信号通路在移植中的重要性尚不清楚。 我们已经产生了大量的数据，表明抑制PI3Kγ显著减少急性心脏 移植排斥反应。值得注意的是，抑制PI3Kγ和小剂量CTLA4-Ig之间存在显著的协同作用 这会导致同种异体心脏移植物存活时间的无限期延长。从机制上讲，抑制PI3Kγ导致 在增强T细胞的同时选择性抑制T效应细胞。我们的机械数据也表明 抑制PI3Kγ激活已知促进FOXP3启动子的基因。抑制PI3Kγ可显著降低 产生可诱导同种免疫的炎性细胞因子。我们的总体目标是破译 PI3Kγ亚类在T细胞依赖的同种免疫中的相对贡献 支持发现具有增强同种免疫中免疫调节作用的高潜力疗法。 我们推测，通过使TREF/Tregs的平衡向Tregs倾斜，PI3Kγ抑制有效 抑制移植排斥反应。在目标1中，我们将研究PI3Kγ的药理抑制作用。 抑制急性和慢性排斥反应。在目标2中，我们将研究PI3Kγ的机制 抑制会抑制同种免疫反应。我们还将研究抑制PI3Kγ对同种异体抗原的影响 特定的树。在目标3中，我们将研究同时抑制PI3Kγ和B7-CD28通路的协同作用。 耐受性诱导。同种异体免疫反应是由TJeff和Tregs的平衡决定的。 识别控制这种平衡的新的调控途径对未来的设计具有重大影响 移植中的免疫调节治疗。这些研究将提供有关以下方面的重要信息 PI3Kγ在调节T细胞/T细胞平衡中的作用这些数据可以作为未来基于PI3Kγ的基础 移植的治疗方法。

Abstract Though immunosuppressive agents (ISA) used to prevent rejection have improved over time, they are still unable to consistently eliminate acute and chronic rejection and they have been implicated in the pathogenesis of organ failure (i.e., calcineurin inhibitor toxicity). One of the main issues with traditional ISA is that they inhibit the regulatory pathways in transplantation as well. Therefore, one of the highest unmet needs in transplantation is to identify novel immunomodulatory strategies which selectively inhibit the pathogenic alloreactive immune cells but spare regulatory humoral and cellular pathways such as T regulatory cells (Tregs). Phosphoinositide-3 kinases (PI3K) are lipid kinases that generate critically important messengers for immune cell function. Among the various subclasses of PI3K, PI3Kγ has received much attention for its restricted expression in leukocytes and regulatory role in immune cells and inflammation. Nevertheless, the importance of targeting PI3Kγ signaling pathways in transplantation remains unexplored. We have generated a substantial amount of data indicating that PI3Kγ inhibition markedly reduces acute heart transplant rejection. Notably, there was marked synergism between PI3Kγ inhibition and low dose CTLA4-Ig which resulted in indefinite prolongation of heart allograft survival. Mechanistically, PI3Kγ inhibition resulted in selective suppression of T effector cells (Teff) while augmenting Tregs. Our mechanistic data also indicate that PI3Kγ inhibition activates genes known to promote FOXP3 promoter. PI3Kγ inhibition markedly reduced the production of inflammatory cytokines which induce alloimmunity. Our overall objective is to decipher the relative contribution of the PI3Kγ subclass in T cell-dependent alloimmunity and use the new information to support the discovery of therapeutics that have high potential to enhance immunoregulation in alloimmunity. We hypothesize that by tipping the balance of Teff/Tregs toward Tregs, PI3Kγ inhibition effectively suppresses transplant rejection. In Aim 1, we will examine the role of pharmacological inhibition of PI3Kγ in suppressing both acute and chronic rejection. In Aim 2, we will examine the mechanisms by which PI3Kγ inhibition suppresses alloimmune responses. We will also study the impact of PI3Kγ inhibition on alloantigen specific Tregs. In Aim 3, we will study the synergism of inhibiting both the PI3Kγ and B7-CD28 pathways in tolerance induction. Alloimmune responses are critically determined by the balance of Teff and Tregs. Identifying novel regulatory pathways which control this balance has a significant impact on the design of future immunomodulatory therapies in transplantation. These studies will provide critical information on the role of PI3Kγ in controlling the balance of Teff/Tregs. These data can serve as a basis for future PI3Kγ-based therapies for transplantation.