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: 8531342
• 负责人: JEANNE E HENDRICKSON
• 金额: $ 1.29万
• 依托单位: EMORY 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 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531342
• 关键词: Alloimmunization; Animal Model; Animals; Antibodies; Antibody Specificity; Antigens; Binding; Biomedical Research; Blood group antibody D; Correlation Studies; Disease; Erythropoiesis; Ethics; Evaluation; Event; Excision; Exploratory/Developmental Grant; Exposure to; Female; Fetus; Funding; Future; Generations; Glycoproteins; Goals; Harvest; Hemorrhage; Hospitals; Human; Immunization; Immunologics; Immunosuppression; Infant; Injection of therapeutic agent; Isoantibodies; Knowledge; Lead; Masks; Maternal Mortality; Maternal antibody; Mediating; Methodology; Modeling; Morbidity - disease rate; Mothers; Mus; Newborn Infant; Oryctolagus cuniculus; Outcome; Patients; Placenta; Pregnancy; Preparation; Prevention; Preventive; Process; Public Health; Reaction; Research; Risk; Services; System; Testing; Therapeutic; Transfusion; Transgenic Mice; Translating; Work; clinically significant; fetal; immunoprophylaxis; innovation; novel; polyclonal antibody; prevent; pup; response; tool; volunteer

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（由申请人提供）：红细胞异体免疫可通过输血治疗或妊娠或分娩中胎儿/母亲出血期间暴露于非自身红细胞抗原而发生。这些抗体可能是危险的，因为接受同种异体免疫的患者在随后输血后发生溶血性输血反应的风险增加。它们也可能是危险的；然而，红细胞表达同源抗原的胎儿。胎儿和新生儿溶血性疾病（hddn）发生在超过1/600的妊娠中，可能是致命的。虽然自然产生的针对A或B抗原的抗体可能引起轻度HDFN，但严重的HDFN主要是由针对D或Kell等抗原的抗体引起的。妊娠期预防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。目前还没有预防非d抗原免疫的治疗方法，也没有靶向治疗方法来最大限度地减少现有母体同种异体抗体的危险。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，其中大多数研究仅限于抗体特异性、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妊娠（和输血）诱导抗KEL红细胞异体免疫模型，其中抗KEL穿过胎盘，与KEL阳性的胎儿红细胞结合，并对幼崽有害。与未接种疫苗的母鼠相比，接种疫苗的母鼠连续怀孕产生的胎仔越来越小。中心假设：母体KEL同种抗体通过1)结合并随后清除胎儿红细胞和/或2)抑制胎儿红细胞生成对KEL阳性幼崽有害。通过去除KEL阳性的胎儿红细胞和/或通过掩盖/丢失这些红细胞上的KEL抗原，IM给药多克隆（但不是单克隆）“KEL”Gam可以阻止母体从头产生抗KEL。特异性目标1：通过输血产生的抗KEL与通过妊娠产生的抗KEL的功能特征特异性目标2：评估多克隆“KEL”Gam和单克隆抗KEL对胎儿红细胞的能力以及对妊娠期间母体红细胞同种异体免疫的预防。该建议与公共卫生相关，因为它描述了第一个由妊娠引起的红细胞异体免疫导致胎儿死亡的动物模型，利用动物模型的优势来探索通过观察性人体研究无法（也无法）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母体红细胞同种异体免疫的发病率/死亡率。