Immunoprophylaxis to Kell RBC Alloimmunization During Pregnancy

怀孕期间凯尔红细胞同种免疫的免疫预防

• 批准号: 8866087
• 负责人: JEANNE E HENDRICKSON
• 金额: $ 17.28万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866087
• 关键词: Immunoprophylaxis; Kell; RBC; Alloimmunization; During

DESCRIPTION (provided by applicant): RBC alloimmunization may occur through exposure to non- self RBC antigens during transfusion therapy or during fetal/maternal bleeds in pregnancy or delivery. These antibodies can be dangerous from the perspective that alloimmunized patients are at increased risk of having hemolytic transfusion reactions following subsequent transfusions. They may also be dangerous; however, to fetuses whose RBCs express cognate antigens. Hemolytic disease of the fetus and newborn (HDFN) occurs in more than 1/600 pregnancies and may be deadly. Although naturally occurring antibodies against A or B antigens may cause mild HDFN, severe HDFN is caused predominantly by antibodies directed against antigens such as D or Kell. The only therapy that exists to prevent alloimmunization during pregnancy is polyclonal anti-D, and its mechanism(s) of action are unclear. There are currently no therapies to prevent immunization to non-D antigens, nor are there targeted therapies to minimize the dangers of existing maternal alloantibodies. This therapeutic gap exists in part due to technical and ethical limitations of human studies, most of which have been limited to observation/correlation studies between antibody specificity, titer, and fetal outcome. Herein, we present a novel murine model of pregnancy (and transfusion) induced anti-KEL RBC alloimmunization, in which anti-KEL crosses the placenta, binds to KEL positive fetal RBCs, and appears detrimental to pups. Progressively smaller litters are produced by immunized mothers in successive pregnancies compared to virgin non-immunized control females. Central Hypothesis: Maternal KEL alloantibodies are detrimental to KEL positive pups through 1) binding and subsequent clearance of fetal RBCs and/or 2) suppression of fetal erythropoiesis. Maternal de novo generation of anti-KEL will be prevented by IM administration of polyclonal (but not monoclonal) "KEL"Gam through removal of KEL positive fetal RBCs and/or through masking/loss of the KEL antigen on these RBCs. Specific Aim 1: Functional Characterization of Anti-KEL Generated Through Transfusion Versus That Generated Through Pregnancy Specific Aim 2: Assessment of the Abilities of Polyclonal "KEL"Gam and Monoclonal Anti-KEL on Fetal RBCs and on the Prevention of Maternal RBC Alloimmunization during Pregnancy Public Health Significance/Long Term Goals: This proposal is relevant to public health in that it describes the first animal model of RBC alloimmunization induced by pregnancy which results in fetal demise, capitalizing on the strengths of an animal model to explore questions that have not (and cannot) be answered through observational human studies. The ultimate long term goal of this work is to diminish the morbidity/mortality of maternal RBC alloimmunization in fetuses and newborns alike.

描述（由申请方提供）：在输血治疗期间或妊娠或分娩期间胎儿/母体出血期间，通过暴露于非自身RBC抗原，可能发生RBC同种免疫。从同种免疫患者在随后的输血后发生溶血性输血反应的风险增加的角度来看，这些抗体可能是危险的。它们也可能是危险的;然而，对于RBC表达同源抗原的胎儿。胎儿和新生儿溶血病（HDFN）发生在超过1/600的妊娠中，可能是致命的。尽管天然存在的抗A或B抗原的抗体可能引起轻度HDFN，但严重HDFN主要由抗抗原（如D或Kell）的抗体引起。预防妊娠期同种异体免疫的唯一疗法是多克隆抗D，其作用机制尚不清楚。目前没有预防非D抗原免疫的疗法，也没有靶向疗法来最小化现有母体同种抗体的危险。这种治疗差距的存在部分是由于人类研究的技术和伦理限制，其中大多数仅限于抗体特异性，滴度和胎儿结局之间的观察/相关性研究。在此，我们提出了一种新的小鼠模型妊娠（和输血）诱导的抗KEL RBC同种免疫，其中抗KEL穿过胎盘，结合KEL阳性胎儿RBC，并出现有害的幼崽。与未免疫的对照组处女母鼠相比，免疫母鼠在连续妊娠中产生的窝仔逐渐变小。中心假设：母体KEL同种抗体通过1）结合和随后清除胎儿RBC和/或2）抑制胎儿红细胞生成对KEL阳性幼仔有害。通过IM给予多克隆（而非单克隆）“KEL“Gam，通过去除KEL阳性胎仔RBC和/或通过掩蔽/丢失这些RBC上的KEL抗原，可预防母体新生抗KEL抗体。具体目标1：通过输血产生的抗-KEL与通过妊娠产生的抗-KEL的功能表征特定目标2：多克隆“KEL“Gam和单克隆抗-KEL对胎儿RBC和对妊娠期间母体RBC同种免疫的预防的能力评估公共卫生意义/长期目标：该提议与公共卫生有关，因为它描述了由妊娠诱导的RBC同种异体免疫的第一个动物模型，其导致胎儿死亡，利用动物模型的优势来探索尚未（也不能）通过观察性人类研究回答的问题。这项工作的最终长期目标是减少胎儿和新生儿中母体RBC同种异体免疫的发病率/死亡率。