Pathobiology of Incompatible transfusion

不相容输血的病理学

• 批准号: 9058138
• 负责人: JAMES C. ZIMRING
• 金额: $ 46.75万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058138
• 关键词: Acute; Animal Model; Antibodies; Antigens; Autoantibodies; Autoimmune hemolytic anemia; Benign; Binding; Biochemical; Biochemical Genetics; Biological; Biology; Blood; Blood Circulation; Blood Group Antigens; Blood donor; Blood typing procedure; Bone Marrow Diseases; Cessation of life; Chronic; Complement Activation; Coombs' Test; Data; Disease; Erythrocyte Transfusion; Erythrocytes; Fetus; Frequencies; GYPA gene; Generations; Glycoproteins; Grant; Health; Hemoglobinopathies; Hemolysis; Human; Human Biology; IgG Receptors; IgG1; IgG4; Immune system; Immunoglobulin G; Injury; Isoantibodies; Life; Ligation; Mediating; Medical; Membrane; Modeling; Molecular; Mus; Nature; Newborn Infant; Outcome; Pathology; Pathway interactions; Patients; Phenotype; Plasma Cells; Play; Population; Process; Proteins; Reaction; Reagent; Resistance; Risk; Role; Symptoms; System; Testing; Tissues; Transfusion; Transgenic Mice; Transgenic Organisms; Trauma; adaptive immunity; autoreactive B cell; blood group; central tolerance; genetic approach; humanized antibody; in utero; killings; microbial; mouse model; novel; pathogen; prevent

DESCRIPTION (provided by applicant): Transfusion of red blood cells (RBCs) is a life saving maneuver in acute trauma, a life sustaining treatment for diseases of the bone marrow and hemoglobinopathies, and an important component of medical support for a variety of different pathologies. Generation of alloantibodies against donor RBCs can be a major impediment to transfusion therapy, especially in patients who require chronic transfusion. Although incompatible transfusion is strictly avoided, because of the risks of hemolysis, hemolysis is not the inevitable outcome of incompatible transfusion. On the contrary, many incompatible transfusion are given with no signs or symptoms of hemolysis. Likewise, up to 1/1000 healthy blood donors have anti-RBC autoantibodies. Thus, it appears that there are biological mechanisms in place by which host tissues can avoid destruction from their own antibodies or alloantibodies. It is only poorly understood why some transfusions do not result in hemolysis, despite antibody coating of donor RBCs. We have developed several murine models of incompatible RBC transfusion, using authentic human blood group antigens, in which incompatible transfusions do not hemolyze. In some cases, the offending antigen is lost form the RBC without damaging the RBC, which then circulates normally. This phenomenon (called antigen-loss) has been well described in humans for a number of blood group antigens, but only very little mechanistic understanding has been generated. To the best of our knowledge, we have described the only model of antigen loss from RBCs. We have likewise described a second model in which an incompatible transfusion leads to the clearance of most RBCs; however, the RBCs that survive appear to represent a distinct population that is resistant to normal hemolytic mechanisms. This same biology can be observed in humans who have persistent DAT positive donor RBCs in circulation after a hemolytic transfusion reaction. As above, to the best of our knowledge, we have described the only animal model of this process. In this grant, we propose a hypothesis driven elucidation of the mechanisms of both antigen-loss and hemolysis resistance. These findings have potential relevance not only to the biology of antibody binding RBCs, but more broadly to any process in which an antibody is bound directly to a tissue. RBCs give a unique advantage in that they neither synthesize new protein nor undergo division, providing a stable substrate upon which to analyze protein and cellular changes during the process of antibody binding and subsequent biologies (e.g. complement activation, Fc gamma receptor ligation, etc.) We propose specific efforts to maintain the tractable nature of murine systems while progressively humanizing the models, including human RBC antigens, human Fc gamma receptors, and humanized antibodies. We propose 3 specific aims. Specific Aim 1: Molecular and Cellular Mechanisms of Non-Hemolytic Antigen-Loss. Specific Aim 2: Molecular and Cellular Mechanisms of Hemolysis Resistance. Specific Aim 3: Effects of Murine and Human IgG Subtype on Antigen-Loss and Hemolysis Resistance.

描述（由申请人提供）：红细胞的输血（RBC）是急性创伤中的救生动作，对骨髓和血红蛋白病疾病的维持生命治疗，也是多种不同病理学的医疗支持的重要组成部分。针对供体RBC的同种异体生成可能是输血疗法的主要障碍，尤其是在需要慢性输血的患者中。尽管严格避免了不兼容的输血，但由于溶血的风险，溶血并不是不兼容输血的必然结果。相反，给出许多不兼容的输血，没有溶血的迹象或症状。同样，多达1/1000个健康的献血者具有抗RBC自身抗体。因此，似乎存在着存在的生物学机制，宿主组织可以避免自己的抗体或同种抗体破坏。只有很糟糕的是，尽管供体RBC的抗体涂层，为什么某些输血不会导致溶血。我们使用正宗的人类血管抗原开发了几种不兼容的RBC输血的鼠模型，其中不兼容的输血不会溶解。在某些情况下，违规抗原丢失了RBC，而不会损坏RBC，然后损坏RBC，然后循环正常。这种现象（称为抗原损伤）在人类中已在许多血型抗原中得到很好的描述，但仅产生了很少的机械理解。据我们所知，我们已经描述了RBC的唯一抗原损失模型。我们同样描述了第二个模型，其中不兼容的输血会导致大多数RBC的清除。但是，存活的RBC似乎代表了对正常溶血机制具有抗性的独特种群。在溶血输血反应后具有持久的DAT阳性供体RBC的人类可以观察到这种生物学。如上所述，据我们所知，我们描述了这一过程的唯一动物模型。在这项赠款中，我们提出了假设驱动抗原损伤和抗溶血的机理的驱动驱动的。这些发现不仅与抗体结合RBC的生物学具有潜在的相关性，而且更广泛地与抗体直接与组织结合的任何过程。 RBC给出了独特的优势，因为它们既不合成新的蛋白质，也没有进行分裂，从而在抗体结合过程和随后的生物学过程中分析蛋白质和细胞变化的稳定底物（例如，补体激活，FC Gamma受体连接等），我们提出的特定的努力在逐渐逐渐逐渐逐渐逐渐变化。伽马受体和人源化抗体。我们提出了3个具体目标。特定目标1：非溶血性抗原损伤的分子和细胞机制。特定目的2：抗溶血的分子和细胞机制。特定的目标3：鼠和人IgG亚型对抗原损伤和溶血耐药性的影响。