Immune Profiles to Better Understand Chronic Allograft Dysfunction and Successful Long-term Clinical Outcomes after Human Lung Transplantation

项目总结/摘要 候选人：该K23奖项将支持Jamie托德博士的研究培训，并加速她向 一项独立的研究，重点是通过预防和治疗肺移植， 慢性肺移植物功能障碍（CLAD）。托德博士是杜克大学的一名医生兼科学家， 肺移植的专业知识和非常成功的转化研究基础。通过这个奖项 博士托德将增加免疫学，免疫分析和生物统计学方面的新专业知识，并将扩大她的 临床和转化研究能力。她将通过精心指导的双手掌握这些技能- 研究经验，完成临床和转化研究硕士学位，以及 参与补充研究生水平的免疫学教学。环境：杜克是一个例外， 一个非常适合的环境，在其中追求这个奖项，因为它结合了全国最大的肺移植之一， 在免疫学，移植研究和转化研究方面具有高水平专业知识的课程 基础设施演进托德博士的研究和职业发展将由多学科指导 团队投资于她的成功，包括主要导师Scott Palmer博士，肺部的国际领导者 肯特温霍尔德博士，在免疫学和免疫分析的权威，和共同导师 博士Megan Neely是一名生物统计学家，具有临床和翻译数据分析方面的专业知识。研究：CLAD是 肺移植后晚期死亡的主要原因。尽管常规免疫抑制大多数，但不是全部， 肺受体发生CLAD。托德博士的研究建立在她的新的观察，CLAD可以是 区别于两种临床表型，闭塞性细支气管炎综合征（BOS）和限制性CLAD（R- CLAD）与不同类型的同种异体移植物纤维化和不同的移植物变性有关。在这一建议博士。 托德将追求重点假设，以确定临床风险和移植物内免疫反应的基础上，每一个 CLAD表型，并定义与维持无CLAD状态相关的免疫概况。 长期随访。特别是在完成这项奖励博士托德将1）执行补充 转化和临床研究，以调查两个CLAD风险因素的作用，肺曲霉菌和 急性排斥反应，对同种异体移植物中Th 2或Th 17免疫的极化以及 R-CLAD或BOS，和2）定义淋巴细胞概况，包括调节性T-和B-细胞，在长- 无CLAD的患者与R-CLAD或BOS患者相比。这项工作产生的数据将指导 R 01在选择性肺移植中干预Th 2或Th 17免疫调节剂的未来应用 以预防CLAD，并使用同种异体移植物或外周血免疫特征来预测肺 接受者的结果或治疗反应。这项指导性研究将加速托德博士的职业目标， 肺移植的独立研究，重点是预防CLAD，促进成功的长期 长期移植后结果，并实现个性化的肺受体护理。

Project Summary/Abstract Candidate: This K23 award will support Dr. Jamie Todd's research training and accelerate her transition to independent investigation focused on improving lung transplant outcomes through prevention and treatment of chronic lung allograft dysfunction (CLAD). Dr. Todd is a physician-scientist at Duke University with clinical expertise in lung transplantation and a highly successful translational research foundation. Through this award Dr. Todd will add new expertise in immunology, immune profiling, and biostatistics and will expand her capabilities in clinical and translational research. She will master these skills through carefully mentored hands- on research experiences, completion of a Masters degree in clinical and translational research, and participation in supplementary graduate-level immunology didactics. Environment: Duke is an exceptionally well-suited environment in which to pursue this award as it combines one of the nation's largest lung transplant programs with a high level of expertise in immunology, transplant research, and translational research infrastructure. Dr. Todd's research and career development will be guided by a multidisciplinary mentorship team invested in her success including primary mentor Dr. Scott Palmer, an international leader in lung transplantation, co-mentor Dr. Kent Weinhold, an authority in immunology and immune profiling, and co-mentor Dr. Megan Neely a biostatistician with expertise in clinical and translational data analysis. Research: CLAD is the leading cause of late death after lung transplantation. Despite routine immunosuppression most, but not all, lung recipients develop CLAD. Dr. Todd's research builds upon her novel observation that CLAD can be distinguished to two clinical phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (R- CLAD) that associate with different patterns of allograft fibrosis and distinct prognoses. In this proposal Dr. Todd will pursue focused hypotheses to identify clinical risks and intragraft immune responses underlying each CLAD phenotype and to define the immune profile associated with maintenance of a CLAD-free state over long-term follow-up. Specifically in completion of this award Dr. Todd will 1) perform complementary translational and clinical studies to investigate the role of two CLAD risk factors, pulmonary aspergillus and acute rejection, on polarization toward Th2 or Th17 immunity in the allograft and the differential clinical risk for R-CLAD or BOS, respectively, and 2) define the lymphocyte profile, including regulatory T- and B-cells, in long- term CLAD-free patients as compared to those with R-CLAD or BOS. Data generated from this work will guide future R01 applications to intervene with Th2 or Th17 immune modulating agents in select lung transplant recipients so as to prevent CLAD and use allograft or peripheral blood immune signatures to predict lung recipient outcomes or treatment responses. This mentored research will accelerate Dr. Todd's career goal of independent investigation in lung transplantation with a focus on preventing CLAD, promoting successful long- term posttransplant outcomes, and enabling personalized lung recipient care.