Biology and Therapy of Lymphopenia

我们以前证明胸腺功能是淋巴细胞耗竭后T细胞重建的限速因子。胸腺功能受到年龄相关降低以及对接受骨髓移植和癌症治疗的患者给予的治疗毒性的抑制。该项目在2010财年的第一个主要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增强胸腺和骨髓移植（Fewkes et al，Blood，2010）。这是值得注意的，因为该试剂不通过杀死胸腺基质或祖细胞起作用，而是短暂地使早期胸腺祖细胞缺乏关键营养素，但保持整体长期功能完整。这在开发更新的、毒性较小的骨髓移植和基于细胞的治疗方法方面有希望，其结果将导致在这些环境中增强免疫重建。该项目在2011财年的第二个主要成就是发表了我们首次在人体中进行的rhIL 7临床试验结果，该试验证明了对早期B细胞的有效作用，并记录了该细胞因子制剂的T1/2延长。这些结果是令人惊讶的，因为先前的工作已经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rhIL 7的有效免疫恢复作用，并证明了最小的毒性，从而为在各种环境中使用该试剂奠定了基础，旨在增强慢性病毒感染环境中的免疫重建、疫苗应答和抗病毒应答。事实上，基于该研究的结果，目前全世界正在进行超过20项利用IL 7作为免疫调节剂的研究，并且该药剂对于最终批准用于各种临床环境具有很大的希望。该项目在2011财年的第三项成就是在全球首屈一指的免疫学评论杂志上发表了一篇总结文章，详细介绍了白细胞介素-7用于临床的前景（Mackall et al，Nat Rev Immunology）。该项目在2011财年期间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 et al，Nat Imm），其中我们证明了非T细胞上的IL 7信号传导在调节CD 4 + T细胞稳态中的重要性。在这些尚未发表的研究中，我们已经观察到非T细胞上IL 7 R表达缺陷的动物显示对自身抗原和肿瘤抗原的T细胞增殖矛盾地增加，并且这些观察结果可以潜在地用于临床环境中的抗肿瘤作用。它们也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财政年度该项目的第五项成就是完成了证明可溶性IL 7受体在调节IL 7生物活性中的重要作用的研究。我们启动了一个研究IL 7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，基本上没有了解可溶性IL 7 R周围的生物学，因此这一遗传发现不能放在生物学背景下。通过这些研究，我们发现当存在可溶性IL 7 R时，IL 7的非常短期的“高爆发”信号传导减少，但在较长期（例如数天）内，IL 7消耗减少，因此，在长期内，IL 7的生物活性增加。这些结果提供了对IL 7 R在体内调节IL 7生物活性中所起的重要作用的基本见解，提供了进一步的见解，当存在增加水平的可溶性IL 7 R时，遗传多态性如何增加对多发性硬化症的易感性，并且可以用于增强IL 7用作治疗剂时的有效性。

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.