MICROCHIMERISM IN TRANSFUSION MEDICINE AND ORGAN TRANSPLANT REJECTION

微嵌合（MC）发生在造血干细胞和实体器官移植、妊娠、妊娠和输血后。MC可能有助于建立成功妊娠或器官移植所需的耐受性，并可能在病因上与多种病理条件有关。在这个项目中，我们专注于开发独特的敏感分子技术，适用于白细胞、血浆和血清中MC的检测和表征。我们将这些技术前瞻性地应用于输血后MC的研究。我们的研究结果表明，供体白细胞（DL）的生存范围从镰状细胞病和HIV输血患者的迅速和完全清除到一些创伤输血患者的高水平多谱系嵌合持续数月至数年。为了在特定的临床环境（免疫性细胞减少症、自身免疫性疾病、母胎界面）中使用存储库样本扩大MC调查，我们已经开发并开始应用MC筛查策略，该策略既不需要前瞻性患者随访，也不需要了解嵌合基因型。为了了解受体和血液制品特性对DL存活的影响，我们建立了小鼠输血模型。我们计划在这项拨款的续期阶段实现以下4个目标：小鼠输血模型。我们计划在此拨款的续期阶段实现以下4r目标：1。确定在输血创伤患者中观察到的DL - MC的患病率、程度、临床意义和相关因素。2. 确定免疫细胞减少中微嵌合的发生率、程度和意义。3. 探讨血清/血浆嵌合供体器官来源DNA作为实体器官移植患者移植排斥反应标志物的预后价值。4. 在我们的小鼠输血模型中，利用一组敲除小鼠来表征在同基因（MHC匹配）和异体（MHC错配）输注中促进延长DL存活的免疫系统因素，这些免疫系统因素在同基因（MHC匹配）和异体（MHC错配）输注中促进延长DL存活的免疫系统因素。这些研究应该建立MC在几种输血相关疾病中的患病率和病因学作用，并阐明输血白细胞清除的免疫学机制。器官来源的DNA作为移植排斥反应的预测标志物的作用的文献记录可能对临床移植有重大影响。

Microchimerism (MC) occurs following hematopoietic stem cell and solid organ transplantation , pregnancy, pregnancy and blood transfusion. MC may aid in establishing tolerance required for successful pregnancy or organ transplantation, and may be etiologically related to diverse pathological conditions. In this project, we have focused on the development of sensitive molecular techniques uniquely adapted to the detection and characterization of MC in leukocytes, plasma and serum. We have applied these techniques prospectively to investigate MC following transfusion. Our findings indicate a spectrum of donor leukocyte (DL) survival ranging from a prompt and complete clearance in transfused patients with sickle cell disease and HIV to a high-level multi- lineage chimerism persisting months to years in some patients transfused for trauma. To expand MC investigations using repository samples in specific clinical settings (immune cytopenias, autoimmune diseases, maternal-fetal interface), we have developed and begun to apply a MC screening strategy that requires neither prospective patient follow-up nor knowledge of the chimeric genotype. To understand the recipient and blood product characteristics influence DL survival, we have established a murine transfusion model. We plan to pursue the following 4 aims during the renewal phase of this grant: murine transfusion model. We plan to pursue the following 4r aims during the renewal phase of this grant: 1. Determine the prevalence, magnitude, clinical significance, and factors associated with the DL MC observed in transfused trauma patients. 2. Determine the prevalence, magnitude, and significance of microchimerism in immune cytopenias. 3. Investigate the prognostic value of chimeric donor organ-derived DNA in serum/plasma as marker of graft rejection patients with solid organ transplants. 4. Utilize a panel of knockout mice in our murine transfusion model to characterize elements of the immune system that contribute to extended DL survival in syngeneic (MHC-matched) versus allogeneic immune system that contribute to extended DL survival in syngeneic (MHC- matched) versus allogeneic (MHC-mismatched) transfusions. These studies should establish the prevalence and etiological role of MC in several transfusion-related disorders, and elucidate the immunological mechanisms underlying clearance of transfused leukocytes. Documentation of a role for organ-derived DNA as a predictive marker of graft rejection could have major impact in clinical transplantation.