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

同种异体造血干细胞移植后免疫激活的新机制

• 批准号: 8856645
• 负责人: KENNETH R COOKE
• 金额: $ 39.03万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-19 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856645
• 关键词: Acute; Acute Graft Versus Host Disease; Adult; Alloantigen; Allogenic; Antigen-Presenting Cells; Benign; Brain; CDK5 gene; Cancer Immunology Science; Cells; Chimera organism; Chronic; Clinical Data; Complex; Cyclin-Dependent Kinase 5; Data; Defect; Development; Disease; Disease model; Embryo; Engraftment; Event; Experimental Autoimmune Encephalomyelitis; Functional disorder; Gene Deletion; Generations; Graft-Versus-Tumor Induction; Health; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Imaging technology; Immigration; Immune; Immune Cell Activation; Immunologics; Industry; Inflammation; Inflammatory; Laboratories; Life; Lymphocyte; Lymphocyte Activation; Lymphocyte Biology; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Mitotic; Modeling; Mus; Nerve Degeneration; Neurons; Neurosciences; Non-Malignant; Opportunistic Infections; Outcome; Patients; Peptides; Phase; Physicians; Process; Proline; Protein-Serine-Threonine Kinases; Proteins; Regimen; Relapse; Research Personnel; Residual state; Resistance; Role; Scientist; Secondary to; Severity of illness; Signal Transduction; Structure; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic immunosuppression; Tissues; cancer cell; cancer therapy; conditioning; cytokine; graft vs host disease; immune activation; improved; in vivo; inhibitor/antagonist; innovation; intravital imaging; leukemia; migration; mortality; mouse model; novel; novel strategies; prevent; protective effect; reconstitution; small molecule; Acute; Acute Graft Versus Host Disease; Adult; Alloantigen; Allogenic; Antigen-Presenting Cells; Benign; Brain; CDK5 gene; Cancer Immunology Science; Cells; Chimera organism; Chronic; Clinical Data; Complex; Cyclin-Dependent Kinase 5; Data; Defect; Development; Disease; Disease model; Embryo; Engraftment; Event; Experimental Autoimmune Encephalomyelitis; Functional disorder; Gene Deletion; Generations; Graft-Versus-Tumor Induction; Health; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Imaging technology; Immigration; Immune; Immune Cell Activation; Immunologics; Industry; Inflammation; Inflammatory; Laboratories; Life; Lymphocyte; Lymphocyte Activation; Lymphocyte Biology; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Mitotic; Modeling; Mus; Nerve Degeneration; Neurons; Neurosciences; Non-Malignant; Opportunistic Infections; Outcome; Patients; Peptides; Phase; Physicians; Process; Proline; Protein-Serine-Threonine Kinases; Proteins; Regimen; Relapse; Research Personnel; Residual state; Resistance; Role; Scientist; Secondary to; Severity of illness; Signal Transduction; Structure; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic immunosuppression; Tissues; cancer cell; cancer therapy; conditioning; cytokine; graft vs host disease; immune activation; improved; in vivo; inhibitor/antagonist; innovation; intravital imaging; leukemia; migration; mortality; mouse model; novel; novel strategies; prevent; protective effect; reconstitution; small molecule

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.

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）是许多血液病恶性肿瘤和其他血液疾病患者的唯一治疗疗法。除了提供有效的抗癌治疗外，同种异体HSCT的治疗潜力还取决于移植物 - 肿瘤（GVT）效应，这些作用通过免疫学机制消除了残留的恶性细胞。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因素，这仍然是不可接受的。 GVHD的标准疗法通常在治疗上是最佳的，易于机会感染和基础疾病的复发。因此，在同种异体HSCT之后减少GVHD并增强生存的新型策略的发展仍然是医师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，从根本上讲，供体T细胞与宿主抗原呈递细胞之间的相互作用。实验和临床数据支持以下假设：GVHD期间的细胞因子失调发生在三个不同的阶段，包括：1）调节方案对宿主组织的影响，2）宿主抗原通过宿主抗原的细胞激活供体T细胞和3）3）生成细胞和炎症效应。尽管简单化，但这个三步假设发现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 - 硫代激酶，主要在有丝分裂后神经元中活跃，其中其强制性伴侣蛋白（p35和p39）的表达最丰富。 CDK5活性在各种神经元过程中都是必不可少的，因此，当前的范式表明CDK5功能在很大程度上仅限于CNS。然而，CDK5/p35复合物的激活与炎症性疾病有关，但是CDK5活性对淋巴细胞生物学的贡献尚未得到充分理解。 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)揭示了成人CDK5 - / - C小鼠的CDK5-/ - T细胞激活和迁移的缺陷； 4）表明在用mog肽免疫的CDK5 - / - C小鼠中诱导实验性自身免疫性脑脊髓炎。令人兴奋的初步数据也强烈表明CDK5在调节GVHD严重程度中的作用。但是，必须进一步定义这种保护效果的机制。这些发现很重要，因为它们确定了针对标准免疫抑制方法反应性的新型细胞治疗策略的潜在靶标，因此有潜力降低GVHD严重性，同时保持免疫重建和GVT效应。