Mechanisms and clinical effects of microchimerism in transfused trauma patients

描述(申请人提供)：微嵌合体(MC)，来自一个个体的细胞或组织稳定地存在于另一个个体内，已被描述为与怀孕、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生有关。我们已经报告并证实了这一令人惊讶的发现，在创伤的临床环境中，来自单个献血者的白细胞可以在受血者体内持续至少三年，随着时间的推移，水平上升到受血者循环中白细胞总数的3%-4%。在我们的初步研究中，这种与输血相关的MC(TA-MC)长期影响10%的输血创伤患者，即使在所有输血产品都是白细胞减少(LR)的情况下，其发生率也是相似的。TA-MC涉及多种类型的白细胞，包括B淋巴细胞、T淋巴细胞以及粒单核细胞。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，我们提出了一套密切相关的具体目标，以确定：1a)相对于创伤患者，TA-MC在另外两个临床人群中的患病率，即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；以及3)长期高水平TA-MC输血受者的供者造血干细胞植入和供者淋巴细胞克隆的程度。流行病学目标1a和1b将通过回溯性队列研究来解决(n=600)，TA-MC的免疫学机制将在输血创伤患者的前瞻性研究中详细研究(n=360)。这些研究将确定具有高水平长期TA-MC的受试者，以调查目标3(n=10)的植入和克隆性。这项研究的语言描述：从血液使用政策的角度来看，我们认为现在至关重要的是确定与输血相关的微嵌合体的流行率以及它是否代表着输血的有害后果。TA-MC还提供了一个更好地理解和潜在地利用伤害诱导的耐受用于未来治疗目的的机会。

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.