Distinct functional phases in innate reconstitution

描述(申请人提供)：造血干细胞移植(HSCT)治愈了许多恶性和非恶性疾病。然而，在移植本身及其相关并发症，如移植物抗宿主病(GVHD)引起的严重细胞减少和免疫缺陷期间，移植受者会招致显著的感染发病率和死亡率。随着移植受者的捐献者造血功能的重建，感染风险大幅下降。与获得性免疫重建不同，先天细胞免疫(ICMI)的恢复在很大程度上是未知的，尽管它具有良好的抗感染特性。 研究建议假设，HSCT后重建的ICMI有助于保护宿主免受感染，使用FIt3L(FMS样酪氨酸激酶3配体)的细胞因子治疗可以增强其抗微生物特性。为了支持这一假设，使用已建立的自体骨髓移植小鼠模型的初步数据定义了双相功能性ICMI重建。此外，FIt3L加速树突状细胞和自然杀伤(NK)细胞的重建，导致白细胞介素12(IL-12)的增加和IL-12诱导的早期干扰素-伽马(干扰素-伽马)的产生。 该提案将使用标准的免疫学研究技术，如细胞因子增强、单抗去除和体外细胞培养刺激，进一步表征已建立的小鼠模型中的相性ICMI重建。具体地说，该提案将定义不同细胞群体和细胞因子反应之间的关系，以及重组的Toll样受体在移植宿主防御中的作用。一旦确定，ICMI的抗感染特性将在存在和不存在FIt3L的情况下使用系统性白色念珠菌和金黄色葡萄球菌挑战进行测试。未来的方向包括分别在免疫抑制治疗和GVHD存在的情况下定义ICMI的重建，并使用结合环孢素A给药和同种异体移植的小鼠模型。这一研究重点补充了申请人在血液学/肿瘤学和传染病方面的双重培训，并为他作为内科科学家探索免疫受损宿主的宿主防御缺陷的职业生涯提供了催化剂。健全的指导和已建立的基础设施将与申请人个人的承诺相结合，以促进其发展成为一名全额资助的独立调查员。

DESCRIPTION (provided by applicant): Hematopoietic stem-cell transplantation (HSCT) cures many malignant and non-malignant diseases. However, the transplant recipient incurs significant infectious morbidity and mortality during periods of profound cytopenia and immunodeficiency caused by transplantation itself and its associated complications, such as graft-versus-host-disease (GVHD). Infection risk dramatically declines as donor hematopoiesis is functionally reconstituted in the transplant recipient. Unlike adaptive immune reconstitution, innate cellular mediated immune (iCMI) recovery is largely undefined despite its having well-characterized anti-infective properties. The research proposal hypothesizes that reconstituted iCMI following HSCT serves to protect the host against infection and that cytokine therapy using FIt3L (fms-like tyrosine kinase 3 ligand) can augment its anti-microbial properties. In support of this hypothesis, preliminary data using an established murine model of autologous bone marrow transplantation defines biphasic functional iCMI reconstitution. In addition, FIt3L accelerates dendritic and natural killer (NK) cell reconstitution, leading to enhanced interleukin 12 (IL-12) and earlier IL-12-induced interferon-gamma (IFN-gamma) production. The proposal will further characterize phasic iCMI reconstitution in the established murine model using standard techniques of immunology research, such as cytokine augmentation, monoclonal antibody depletion and ex vivo cell-culture stimulation. Specifically, the proposal will define relationships between distinct cell populations and cytokine responses and the role of reconstituted Toll-like receptors in transplant host defense. Once defined, anti-infective properties of iCMI will be tested using systemic Candida albicans and Staphylococcus aureus challenge in the presence and absence of FIt3L. Future directions include defining iCMI reconstitution in the presence of immunosuppressive therapy and GVHD using murine models incorporating cyclosporine administration and allogeneic transplantation, respectively. This research focus complements the applicant's dual training in hematology/oncology and infectious diseases and serves as a catalyst for his career as a physician scientist exploring host defense defects in immunocompromised hosts. Sound mentorship and established infrastructure will combine with the applicant's personal commitment in fostering his development into a fully funded independent investigator.