Mechanisms and clinical effects of microchimerism in transfused trauma patients

描述（由申请人提供）：微嵌合（MC），一个个体的细胞或组织在另一个个体内的稳定持久性，已被描述与妊娠、双胞胎、移植以及最近的常规输血有关。长期MC最近被认为与多种慢性自身免疫性疾病的发展有关。我们已经报道并证实了令人惊讶的发现，在创伤性损伤的临床环境中，来自单个献血者的白细胞可以在输血受体中持续存在至少三年，其水平随着时间的推移上升到受体总循环白细胞的3-4%。在我们的初步研究中，这种输血相关的MC （TA-MC）长期影响10%的输血创伤患者，即使所有输血的血液制品都是白细胞减少（LR），其发生率也相似。多种白细胞谱系似乎参与TA-MC，包括B淋巴细胞和t淋巴细胞以及骨髓单核细胞。这项研究提出的广泛假设是，TA-MC是严重组织损伤患者输血的普遍并发症，具有不良和治疗意义。为了研究这一假设，我们提出了一组密切相关的具体目标来确定：1a)相对于创伤患者，烧伤和骨科手术患者在另外两个可能发生TA-MC的临床人群中的患病率；1b)与长期TA-MC相关的可识别的健康问题；2) TA-MC的动力学和免疫机制；3)长期高水平TA-MC输血受者供体造血干细胞植入程度和供体淋巴细胞克隆性。流行病学目的1a和1b将通过一项回顾性队列研究（n=600）来解决，TA-MC的免疫学机制将在一项对输血创伤患者（n=360）的前瞻性研究中进行详细研究。这些研究将选择具有高水平长期TA-MC的受试者，用于研究目标3 （n=10）的植入和克隆性。研究描述：从血液使用政策的角度来看，我们认为现在确定输血相关微嵌合的患病率以及它是否代表输血的有害后果是至关重要的。TA-MC还为更好地理解和潜在地利用损伤诱导的耐受性提供了机会，以用于未来的治疗目的。

DESCRIPTION (provided by applicant): Microchimerism (MC), the stable persistence of cells or tissues from one individual within another, has been described in association with pregnancy, twinning, transplantation, and, most recently, routine blood transfusion. Long-term MC has recently been implicated in the development of a variety of chronic autoimmune diseases. We have reported and confirmed the surprising finding that, in the clinical setting of traumatic injury, leukocytes from a single blood donor can persist in a transfusion recipient for at least three years at a level which rises over time to as much as 3-4% of the recipient's total circulating leukocytes. In our preliminary studies, this transfusion-associated MC (TA-MC) affected 10% of transfused trauma patients long-term and occurred at a similar rate even when all transfused blood products were leukocyte-reduced (LR). Multiple lineages of leukocytes appear to be involved in TA-MC, including B- and T-lymphocytes as well as myelomonocytes. The broad hypothesis behind this proposed research is that TA-MC is a prevalent complication of blood transfusion in patients with severe tissue injury having both adverse and therapeutic implications. To investigate this hypothesis, we propose a set of closely related Specific Aims to determine: 1a) the prevalence of TA-MC in two additional clinical populations in which its occurrence is plausible, burn and orthopedic surgery patients, relative to trauma patients; 1b) the recognizable health problems associated with long-term TA-MC; 2) the kinetics and immunologic mechanisms of TA-MC; and 3) the extent of donor hematopoietic stem cell engraftment and donor lymphocyte clonality in transfusion recipients with long-term high level TA-MC. The epidemiologic aims 1a and 1b will be addressed through a retrospective cohort study (n=600), and the immunologic mechanisms of TA-MC will be investigated in detail in a prospective study of transfused trauma patients (n=360). These studies will identify selected subjects with high-level long-term TA-MC for investigation of engraftment and clonality in aim 3 (n=10). LAY LANGUAGE DESCRIPTION OF THE RESEARCH: From the standpoint of blood use policy, we believe that it is now critical to determine the prevalence of transfusion-associated microchimerism and whether it represents a harmful consequence of transfusion. TA-MC also offers an opportunity to better understand, and potentially exploit, injury-induced tolerance for future therapeutic purposes.