Novel mechanisms of immune activation following allogeneic, hematopoietic stem cell transplantation

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）是许多血液恶性肿瘤和其他血液疾病患者唯一的治疗方法。除了提供有效的抗癌治疗外，同种异体造血干细胞移植的治疗潜力还依赖于移植物抗肿瘤（GVT）效应，它通过免疫机制根除残留的恶性细胞。不幸的是，GVT效应与移植物抗宿主病（GVHD）的发展密切相关。GVHD和恶性复发是死亡率的两个主要原因，死亡率仍然高得令人无法接受。GVHD的标准治疗通常是治疗次优的，容易发生机会性感染和潜在疾病的复发。因此，开发减少GVHD和提高同种异体造血干细胞移植后存活率的新策略仍然是医生、科学家和我们的患者面临的最重大挑战。GVHD的病理生理是复杂的，从根本上取决于供体T细胞和宿主抗原提呈细胞之间的相互作用。实验和临床数据支持GVHD期间细胞因子失调发生在三个不同阶段的假设，包括：1)调节方案对宿主组织的影响，2)宿主抗原提呈细胞激活供体T细胞，以及3)细胞和炎症效应物的产生。虽然过于简单，但这个三步假说揭示了调节这种疾病过程的机会。我们最近探索了细胞周期蛋白依赖性激酶5 （Cdk5）在免疫细胞中的作用。Cdk5是一种普遍表达的丝氨酸-苏氨酸激酶，在有丝分裂后的神经元中主要活跃，其专性伴侣蛋白（p35和p39）的表达最为丰富。Cdk5活性在各种神经元过程中是必不可少的，因此，目前的范式表明Cdk5的功能主要局限于中枢神经系统。然而，Cdk5/p35复合物的激活与炎症性疾病有关，但Cdk5活性对淋巴细胞生物学的贡献尚未得到充分认识。最近，我们的研究小组首次揭示了Cdk5在淋巴细胞活化中的作用：1)建立了一种新的嵌合小鼠模型，在该模型中，来自Cdk5缺陷（Cdk5-/-）胚胎的造血干细胞被用于重建致命辐照的成年小鼠受体（Cdk5-/- c）； 2)显示了在T细胞活化过程中Cdk5及其特异性伴侣p35的快速诱导；3)揭示了来自成年嵌合Cdk5-/- c小鼠的Cdk5-/- T细胞活化和迁移的缺陷；4)在MOG肽免疫的CDK5-/- c小鼠中显示对诱导实验性自身免疫性脑脊髓炎的抗性。令人兴奋的初步数据有力地表明，Cdk5在调节GVHD的严重程度方面也发挥着作用。但是，必须进一步确定这种保护作用的机制。这些发现意义重大，因为它们确定了与标准免疫抑制方法无交叉反应的新型细胞治疗策略的潜在靶点，因此有可能在保持免疫重建和GVT效果的同时降低GVHD的严重程度。

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with hematologic malignancies and other blood disorders. In addition to delivering effective anti-cancer treatment, the therapeutic potential of allogeneic HSCT relies on graft-versus-tumor (GVT) effects, which eradicate residual malignant cells via immunologic mechanisms. Unfortunately, GVT effects are closely associated with the development of graft-versus-host disease (GVHD). GVHD and malignant relapse are the two primary contributors to mortality, which remains unacceptably high. Standard therapy for GVHD is often therapeutically sub-optimal and predisposes to opportunistic infections and relapse of the underlying disease. Thus, the development of novel strategies that reduce GVHD and enhance survival after allogeneic HSCT remains the most significant challenge facing physician-scientists and our patients. The pathophysiology of GVHD is complex and fundamentally depends upon interactions between donor T cells and host antigen presenting cells. Experimental and clinical data support the hypothesis that cytokine dysregulation during GVHD occurs in three distinct phases including: 1) the effects of conditioning regimens on host tissues, 2) activation of donor T cells by host antigen presenting cells and 3) the generation of cellular and inflammatory effectors. While simplistic, this 3-step hypothesis uncovers opportunities to regulate this disease process. We have recently explored the role of cyclin dependent kinase 5 (Cdk5) in immune cells. Cdk5 is a ubiquitously expressed serine-threonine kinase that is predominantly active in post-mitotic neurons where the expression of its obligate partner proteins (p35 and p39) is most abundant. Cdk5 activity is essential in various neuronal processes, and as such, current paradigms suggest that Cdk5 function is largely restricted to the CNS. Activation of the Cdk5/p35 complex is however associated with inflammatory disorders, but the contribution of Cdk5 activity to lymphocyte biology has not been fully appreciated. Recently, our group was the first to implicate a role for Cdk5 in lymphocyte activation by 1) developing a new chimeric mouse model in which hematopoietic stem cells from Cdk5 deficient (Cdk5-/-) embryos are used to reconstitute lethally irradiated adult mouse recipients (CDK5-/-C), 2) showing the rapid induction of both Cdk5 and its obligate partner p35 during T cell activation, 3) revealing defects in activation and migration of Cdk5-/- T cells from adult chimeric CDK5-/-C mice; and 4) demonstrating a resistance to the induction of experimental autoimmune encephalomyelitis in CDK5-/-C mice immunized with a MOG peptide. Exciting preliminary data strongly suggest a role for Cdk5 in modulating GVHD severity as well. However, the mechanisms for this protective effect must be further defined. These findings are significant because they identify potential targets for novel cellular therapeutic strategies that are non-cross reactive with standard immuno-suppressive approaches and therefore have the potential to reduce GVHD severity while maintaining immune reconstitution and GVT effects.