Mechanisms and clinical effects of microchimerism in transfused trauma patients

描述（由申请人提供）：微嵌合体（MC），即来自一个个体的细胞或组织在另一个个体中的稳定持久存在，已被描述为与妊娠、孪生、移植以及最近的常规输血相关。长期MC最近被牵连在各种慢性自身免疫性疾病的发展。我们已经报道并证实了一个令人惊讶的发现，即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接受者体内持续至少三年，其水平随时间上升至接受者总循环白细胞的3-4%。在我们的初步研究中，这种输血相关MC（TA-MC）长期影响10%的输血创伤患者，即使所有输注的血液制品都是白细胞减少（LR）的，发生率也相似。TA-MC中似乎涉及多种白细胞谱系，包括B-和T-淋巴细胞以及骨髓单核细胞。这项拟议研究背后的广泛假设是，TA-MC是严重组织损伤患者输血的常见并发症，具有不良和治疗意义。为了研究这一假说，我们提出了一组密切相关的特定目标，以确定：1a）TA-MC在两个额外的临床人群中的患病率，其中TA-MC的发生是合理的，相对于创伤患者，烧伤和骨科手术患者; 1b）与长期TA-MC相关的可识别的健康问题; 2）TA-MC的动力学和免疫学机制;（3）长期高水平TA-MC输血受者的供者造血干细胞植入程度和供者淋巴细胞克隆性。流行病学目标1a和1b将通过回顾性队列研究（n=600）进行讨论，TA-MC的免疫学机制将在输血创伤患者（n=360）的前瞻性研究中进行详细研究。这些研究将确定选定的高水平长期TA-MC受试者，以研究目标3中的植入和克隆性（n=10）。从血液使用政策的角度来看，我们认为现在关键是要确定输血相关微嵌合体的患病率，以及它是否代表输血的有害后果。TA-MC还提供了一个机会，以更好地了解，并可能利用，损伤诱导的耐受性，为未来的治疗目的。

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.