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

项目摘要/摘要 候选人：这个K23奖项将支持杰米·托德博士的研究培训，并加速她向 独立研究的重点是通过预防和治疗来改善肺移植结果 慢性移植肺功能障碍(CLAD)。托德博士是杜克大学临床研究中心的内科科学家 在肺移植方面的专业知识和非常成功的翻译研究基础。通过这个奖项 托德博士将增加免疫学、免疫图谱和生物统计学方面的新专业知识，并将扩大她的 具有临床和转化性研究能力。她将通过精心指导的双手掌握这些技能- 在研究经验方面，完成临床和翻译研究的硕士学位，以及 参加研究生级别的辅助性免疫学教学。环境：杜克大学是一个特殊的 非常适合追求这一奖项的环境，因为它结合了美国最大的肺移植之一 在免疫学、移植研究和转化研究方面拥有高水平专业知识的项目 基础设施。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，包括主要导师斯科特·帕尔默博士，他是肺科的国际领先者 移植，共同导师肯特·温霍尔德博士，免疫学和免疫图谱方面的权威，以及共同导师 Megan Neely博士是一位生物统计学家，在临床和转换数据分析方面拥有专业知识。研究：着装是 肺移植后晚期死亡的主要原因。尽管有常规的免疫抑制，但不是全部， 肺接受者会变得衣冠楚楚。托德博士的研究建立在她的新观察基础上，即穿着可以 可分为两种临床表型：闭塞性毛细支气管炎综合征(BOS)和限制性包裹型(R- 包膜)与不同的移植肝纤维化类型和不同的预后相关。在这份提案中，Dr。 托德将继续进行有重点的假设，以确定临床风险和移植物内免疫反应。 并定义与维持无包膜状态相关的免疫特征。 长期随访。具体地说，在完成这一奖项时，托德博士将1)发挥补充作用 两种危险因素肺曲霉菌和肺曲霉的作用的转化和临床研究 同种异体移植物向Th2或Th17免疫分化的急性排斥反应及其不同的临床风险 分别是R-CLAD或BOS，以及2)定义淋巴细胞类型，包括调节性T细胞和B细胞。 无足月包衣的患者与有R包衣或BOS的患者相比。这项工作产生的数据将指导 未来R01在部分肺移植中应用Th2或Th17免疫调节剂进行干预 受者，以防止包皮和使用同种异体移植或外周血免疫标志来预测肺 接受者的结果或治疗反应。这项有指导意义的研究将加速托德博士的职业目标 肺移植中的独立研究，重点是预防包膜，促进成功的长期移植 移植后的长期结果，并实现个性化的肺部受者护理。

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.