Biology and Therapy of Lymphopenia

我们先前证明，胸腺功能是淋巴细胞耗尽后T细胞重建的一个速率限制因素。胸腺功能受到年龄相关性下降的抑制，以及接受骨髓移植和癌症治疗的患者接受治疗的毒性。该项目在2010财年的第一个主要成果是发表了一份报告，证明无毒的小分子酪氨酸激酶抑制剂(孙尼替尼)可以作为骨髓移植后的单一药物促进胸腺和骨髓的植入(Fewkes等人，布拉德，2010)。这一点值得注意，因为这种药物的功能不是通过杀死胸腺基质或祖细胞，而是瞬时饥饿早期胸腺祖细胞的关键营养物质，但保持整体长期功能不变。这为开发新的、毒性较低的骨髓移植方法和基于细胞的疗法带来了希望，因此将导致这些环境下增强免疫重建。该项目在2011财年的第二个主要成就是公布了我们在人类身上进行的第一次临床试验的结果，该结果证明了对早期B细胞的有效影响，并证明了这种细胞因子制剂的T1/2延长。这些结果令人惊讶，因为以前的工作已经证明细胞因子在体内是非常短暂的(Sportes等人，Clin Can Res 2010)。这些结果还清楚地证明了重组人白细胞介素7的强大免疫修复作用，并显示出极低的毒性，从而为在各种环境中使用这种制剂奠定了基础，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多项研究正在使用IL7作为免疫调节剂，这种药物最终有望被批准在各种临床环境中使用。该项目在2011财年期间的第三项成就是在全球主要的免疫学综述杂志上发表了一篇摘要文章，详细介绍了白细胞介素7在临床上的应用前景(Mackall等人，NAT Rev免疫学)。该项目在2011财年的第四个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)，在该工作中，我们证明了非T细胞上IL7信号在调节CD4+T细胞自我调节中的重要性。在这些尚未发表的研究中，我们观察到在非T细胞上IL7R表达不足的动物表现出矛盾的增加T细胞对自身抗原和肿瘤抗原的增殖，这些观察结果可能被用于临床环境中的抗肿瘤效果。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果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，因为该基因的多态与多发性硬化症的不同易感性有关。尽管如此，对可溶性IL7R周围的生物学基本上没有了解，因此这一遗传学发现不能放在生物学的背景下。通过这些研究，我们发现，当存在可溶性IL7R时，IL7的非常短期的“高突发”信号被减弱，但在较长的时间(例如几天)，IL7的消耗减少，结果是从长期来看IL7的生物学活性增加。这些结果提供了对IL7R在体内调节IL7生物活性的重要作用的基本见解，进一步揭示了当可溶性IL7R水平增加时，基因多态如何增加多发性硬化症的易感性，并可用于提高IL7作为治疗剂的有效性。

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.