Novel mechanisms of immune activation following allogeneic, hematopoietic stem ce

描述(申请人提供)：异基因造血干细胞移植(HSCT)是许多恶性血液病和其他血液疾病患者的唯一治疗方法。除了提供有效的抗癌治疗外，异基因HSCT的治疗潜力还依赖于移植物抗肿瘤(GVT)效应，GVT通过免疫机制消除残留的恶性细胞。不幸的是，GVT效应与移植物抗宿主病(GVHD)的发展密切相关。移植物抗宿主病和恶性复发是死亡率的两个主要因素，死亡率仍然高得令人无法接受。GVHD的标准疗法通常在治疗上是次优的，容易发生机会性感染和潜在疾病的复发。因此，开发新的策略来减少GVHD并提高异基因HSCT后的存活率仍然是内科科学家和我们的患者面临的最大挑战。移植物抗宿主病的病理生理机制是复杂的，基本上依赖于供体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过程中细胞因子失调的假说，包括：1)预适应方案对宿主组织的影响；2)宿主抗原提呈细胞对供体T细胞的激活；3)细胞和炎症效应的产生。这个三步假说虽然过于简单化，但却揭示了调控这一疾病过程的机会。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，主要存在于有丝分裂后神经元中，其专性配对蛋白(p35和p39)的表达最为丰富。CDK5的活性在各种神经元过程中是必不可少的，因此，目前的研究范式表明，CDK5的功能在很大程度上局限于中枢神经系统。然而，CDK5/p35复合体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，我们的团队首次发现CDK5在淋巴细胞激活中扮演的角色，1)建立了一种新的嵌合小鼠模型，在该模型中，来自CDK5-/-的胚胎的造血干细胞被用于重建致死性照射的成年小鼠受体(CDK5-/-C)，2)显示在T细胞激活过程中CDK5及其专属伴侣p35的快速诱导，3)揭示了来自成年嵌合CDK5-/-C小鼠的CDK5-/-T细胞的激活和迁移方面的缺陷，以及4)对MOG肽免疫的CDK5-/-C小鼠诱导的实验性自身免疫性脑脊髓炎的抵抗。令人兴奋的初步数据有力地表明，CDK5在调节GVHD严重程度中也发挥了作用。然而，这种保护作用的机制必须进一步定义。这些发现具有重要意义，因为它们确定了新的细胞治疗策略的潜在靶点，这些策略与标准的免疫抑制方法无交叉反应，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.