Biology and Therapy of Lymphopenia

淋巴细胞减少症的生物学和治疗

• 批准号: 8349312
• 负责人: Crystal Mackall
• 金额: $ 88.08万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349312
• 关键词: Adverse effects; Age; Animal Model; Animals; Antiviral Response; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Biological; Biology; Blood; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chronic; Clinical; Clinical Trials; Consumption; Development; Effectiveness; Engraftment; Genes; Genetic; Genetic Polymorphism; Goals; HIV Infections; Homeostasis; Human; IL7 gene; IL7R gene; Immune; Immunology; Immunomodulators; Interleukin 7 Receptor; Interleukin-7; Journals; Laboratories; Lead; Left; Life; Light; Link; Lymphocyte; Lymphocyte Depletion; Lymphopenia; Malignant Neoplasms; Morbidity - disease rate; Multiple Sclerosis; Nutrient; Patients; Physiology; Play; Predisposition; Publications; Publishing; Recovery; Reporting; Role; Self Tolerance; Signal Transduction; Staging; Stem cells; T-Cell Depletion; T-Cell Proliferation; T-Lymphocyte; Therapeutic Agents; Toxic effect; Tumor Antigens; Tyrosine Kinase Inhibitor; Vaccines; Virus Diseases; Work; base; bench to bedside; cancer immunotherapy; cancer therapy; clinical application; cytokine; improved; in vivo; insight; killings; mortality; novel strategies; progenitor; reconstitution; response; small molecule; therapy development

We previously demonstrated that thymic function is a rate limiting factor in reconstitution of T cells following lymphocyte depletion. Thymic function is inhibited by age associated decreases as well as the toxicity of therapies administered to patients undergoing bone marrow transplantation and cancer therapy. The first major accomplishment of this project in FY2010 was the publication of a report demonstrating that non-toxic, a small molecule tyrosine kinase inhibitor (sunitinib) could enhance thymic and bone marrow engraftment as a single agent following bone marrow transplantation (Fewkes et al, Blood, 2010). This is notable since this agent does not function by killing thymic stroma or progenitor cells, but rather transiently starves early thymic progenitors of critical nutrients, but leaving overall long term function intact. This holds promise in the development newer, less toxic approaches to bone marrow transplantation and cell based therapies, which as a result would lead to enhanced immune reconstitution in these settings. A second major accomplishment of this project in FY11 was publication of the results of our first clinical trial of rhIL7 in humans, which demonstrated potent effects on early B cells and documented prolonged T1/2 of this cytokine agent. These results were surprising as previous work had demonstrated cytokines to be very short lived in vivo (Sportes et al, Clin Can Res 2010). The results also clearly documented the potent immunorestorative effects of rhIL7 and demonstrated minimal toxicity, thus setting the stage for use of this agent in a variety of settings aimed at enhancing immune reconstitution, vaccine responses and antiviral responses in the setting of chronic viral infection. Indeed, based upon the results of this study, there are currently over 20 studies worldwide underway utilizing IL7 as an immunomodulator and this agent holds great promise for eventual approval for use in a variety of clinical settings. A third accomplishment of this project during FY11 was publication of a summary article detailing the promising of interleukin-7 for clinical use in the premier immunology review journal worldwide (Mackall et al, Nat Rev Immunology). A fourth accomplishment of this project during FY11 has been to extend work previously published by this laboratory in 2009 (Guimond et al, Nat Imm) where we demonstrated the importance of IL7 signaling on non-T cells in regulating CD4+ T cell homesotasis. In these as yet unpublished studes, we have observed that animals deficient in IL7R expression on non-T cells show paradoxically increased T cell proliferation to self antigens and tumors antigens and these observations could potentially be exploited for antitumor effects in clinical settings. They may also shed light on susceptibility to autoimmune disease and these studies are ongoing. The fifth accomplishment of this project for the FY2011 was completion of studies demonstrating an important role for soluble IL7 receptor in modulating bioactivity of IL7. We initiated a project studying the biology of IL7 receptor because polymorphisms in this gene have been linked to differential susceptibility to multiple sclerosis. Despite this, there was essentially no understanding of the biology surrounding soluble IL7R and therefore this genetic finding could not be placed in a biological context. Through these studies, we found that when soluble IL7R is present, very short term "high burst" signaling of IL7 is diminished but over the longer term (e.g. days) there is diminished IL7 consumption and as a result, over the long term there is increased biologic activity of IL7. These results provide fundamental insights into the important role that IL7R plays in modulating IL7 bioactivity in vivo, provide further insight how genetic polymorphisms increase susceptibility to multiple sclerosis when increased levels of soluble IL7R are present and could be used to enhance the effectiveness of IL7 when used as a therapeutic agent.

我们之前证明胸腺功能是淋巴细胞耗竭后 T 细胞重建的速率限制因素。胸腺功能因年龄相关的下降以及接受骨髓移植和癌症治疗的患者所接受的治疗的毒性而受到抑制。该项目在 2010 财年的第一个重大成就是发表了一份报告，证明无毒的小分子酪氨酸激酶抑制剂（舒尼替尼）作为骨髓移植后的单一药物可以增强胸腺和骨髓移植（Fewkes 等人，血，2010）。这是值得注意的，因为该试剂不是通过杀死胸腺基质或祖细胞发挥作用，而是短暂地使早期胸腺祖细胞缺乏关键营养物质，但保持整体长期功能完整。这为开发更新的、毒性较小的骨髓移植和细胞疗法方法带来了希望，从而增强了这些环境中的免疫重建。该项目在 2011 财年的第二个主要成就是发表了我们首次 rhIL7 人体临床试验的结果，该试验证明了对早期 B 细胞的有效作用，并记录了这种细胞因子制剂的 T1/2 延长。这些结果令人惊讶，因为之前的工作已证明细胞因子在体内的寿命非常短（Sportes 等人，Clin Can Res 2010）。结果还清楚地证明了 rhIL7 的有效免疫恢复作用，并表现出最小的毒性，从而为在各种环境中使用该药物奠定了基础，旨在增强慢性病毒感染环境中的免疫重建、疫苗反应和抗病毒反应。事实上，根据这项研究的结果，目前全球有 20 多项利用 IL7 作为免疫调节剂的研究正在进行中，该药物有望最终获批用于各种临床环境。该项目在 2011 财年的第三项成就是在全球顶级免疫学评论期刊（Mackall 等人，Nat Rev Immunology）上发表了一篇总结文章，详细介绍了白细胞介素 7 的临床应用前景。 2011 财年该项目的第四项成就是扩展了该实验室先前在 2009 年发表的工作（Guimond 等人，Nat Imm），其中我们证明了非 T 细胞上的 IL7 信号传导在调节 CD4+ T 细胞稳态中的重要性。在这些尚未发表的研究中，我们观察到，非 T 细胞上缺乏 IL7R 表达的动物表现出矛盾的是，T 细胞对自身抗原和肿瘤抗原的增殖增加，这些观察结果有可能在临床环境中用于抗肿瘤作用。它们还可能揭示自身免疫性疾病的易感性，这些研究正在进行中。 2011 财年该项目的第五项成就是完成了证明可溶性 IL7 受体在调节 IL7 生物活性中的重要作用的研究。我们发起了一个研究 IL7 受体生物学的项目，因为该基因的多态性与多发性硬化症的不同易感性有关。尽管如此，人们基本上对可溶性 IL7R 的生物学一无所知，因此不能将这一遗传发现置于生物学背景中。通过这些研究，我们发现当可溶性 IL7R 存在时，IL7 的非常短期的“高爆发”信号传导会减少，但从长远来看（例如几天），IL7 的消耗会减少，因此，从长远来看，IL7 的消耗会减少。 IL7的生物活性增加。这些结果为了解 IL7R 在体内调节 IL7 生物活性中发挥的重要作用提供了基本见解，进一步了解当可溶性 IL7R 水平增加时，遗传多态性如何增加对多发性硬化症的易感性，并可用于增强 IL7 使用时的有效性作为治疗剂。