Distinct functional phases in innate reconstitution

描述（由申请人提供）：造血干细胞移植（HSCT）治疗许多恶性和非恶性疾病。 然而，在由移植本身及其相关并发症（如移植物抗宿主病（GVHD））引起的严重血细胞减少和免疫缺陷期间，移植受体会引起显著的感染性发病率和死亡率。随着供体造血功能在移植受体中重建，感染风险显著下降。与适应性免疫重建不同，先天细胞介导的免疫（iCMI）恢复在很大程度上是不确定的，尽管它具有良好的抗感染特性。 该研究提案假设HSCT后重建的iCMI用于保护宿主免受感染，并且使用Flt 3L（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，FIt 3L加速树突状细胞和自然杀伤（NK）细胞重建，导致增强的白细胞介素12（IL-12）和更早的IL-12诱导的干扰素-γ（IFN-γ）产生。 该提案将使用免疫学研究的标准技术（如细胞因子增强、单克隆抗体耗竭和离体细胞培养物刺激）进一步表征已建立的小鼠模型中的阶段性iCMI重建。具体来说，该提案将定义不同的细胞群体和细胞因子反应之间的关系，以及重建Toll样受体在移植宿主防御中的作用。一旦确定，将在存在和不存在FIt 3L的情况下，使用全身性白色念珠菌和金黄色葡萄球菌挑战来检测iCMI的抗感染特性。未来的方向包括定义iCMI重建免疫抑制治疗和GVHD的存在下，使用小鼠模型，包括环孢素管理和同种异体移植，分别。 这项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，并作为他作为一名医生科学家探索免疫功能低下宿主中宿主防御缺陷的职业生涯的催化剂。良好的指导和建立的基础设施将联合收割机与申请人的个人承诺相结合，以促进他发展成为一个完全资助的独立调查员。

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.