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（伊萨）随着时间的推移而有所改善，但它们仍然是 不能一致地消除急性和慢性排斥反应，并且它们与发病机制有关 器官衰竭（即，钙调磷酸酶抑制剂毒性）。传统伊萨的主要问题之一是， 移植过程中的调控途径。因此，最高未满足的需求之一， 移植是确定新的免疫调节策略，选择性地抑制致病性 同种异体反应性免疫细胞，但保留调节性体液和细胞途径，如T调节细胞 （Tennis）.磷脂酰肌醇-3激酶（PI 3 K）是脂质激酶，其产生对于细胞内信号转导至关重要的信使。 免疫细胞功能在PI 3 K的各种亚类中，PI 3 K γ因其在细胞内的表达而受到广泛关注。 在白细胞中的限制性表达以及在免疫细胞和炎症中的调节作用。但 在移植中靶向PI 3 K γ信号通路的重要性仍然未被探索。 我们已经产生了大量的数据，表明PI 3 K γ抑制显著降低急性心脏病 移植排斥反应值得注意的是，PI 3 K γ抑制和低剂量CTLA 4-IG之间存在显著的协同作用 这导致心脏移植物存活的无限期延长。从机制上讲，PI 3 K γ抑制导致 选择性抑制T效应细胞（Teff），同时增加Teff。我们的机械数据还表明， PI 3 K γ抑制激活已知促进FOXP 3启动子的基因。PI 3 K γ抑制显著降低了 诱导同种异体免疫的炎性细胞因子的产生。我们的总体目标是破译 PI 3 K γ亚类在T细胞依赖性同种异体免疫中的相对贡献，并使用新信息 支持发现具有增强同种免疫中的免疫调节的高潜力的治疗剂。 我们推测，通过Teff/Teff的平衡向Teff倾斜，PI 3 K γ抑制有效地 抑制移植排斥反应在目的1中，我们将研究PI 3 K γ的药理学抑制在 抑制急性和慢性排斥反应。在目标2中，我们将研究PI 3 K γ 抑制抑制同种免疫应答。我们还将研究PI 3 K γ抑制对同种异体抗原的影响。 具体的THEORY。在目标3中，我们将研究抑制PI 3 K γ和B7-CD 28通路的协同作用， 耐受诱导同种免疫应答由Teff和Teff的平衡决定。 确定控制这种平衡的新的调节途径对未来的设计有重大影响。 移植中的免疫调节疗法。这些研究将提供关键信息， PI 3 K γ在调节Teff/Teff平衡中的作用这些数据可以作为未来基于PI 3 K γ的 移植治疗。

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.