Protecting Fetuses and Newborns from Maternal RBC Alloantibodies

描述(申请人提供)：母体红细胞异体免疫，由先前怀孕/分娩或先前输血引起，使发育中的胎儿/新生儿面临贫血和胎儿和新生儿溶血性疾病(HDFN)的风险。每600名婴儿中就有1名有患HDFN的风险，没有针对性的治疗方法可供同种免疫的孕妇使用，也没有针对非D抗原的预防性治疗方法。靶向治疗的缺乏在一定程度上是因为不愿在孕妇或她们的胎儿身上测试创新疗法，这是可以理解的。为了绕过这个问题，我们开发了我们认为是第一个HDFN动物模型，在该模型中，怀孕/分娩能够刺激母体同种异体免疫，并且这些母体抗体导致HDFN。事实上，这个模型涉及一种与HDFN(KEL)高度相关的人类抗原的RBC特异性表达，这进一步增加了它的创新。作为我们R21模型的扩展，我们现在建议利用该模型以损害控制的方式保护发育中的胎儿免受现有母体同种抗体的影响，并以预防性的方式防止原发抗KEL的形成。中心假设：现有或发展中的母体抗红细胞同种异体抗体对胎儿和新生儿的危险可以通过主动或被动的母体免疫调节治疗来预防。具体目标1：研究将现有的母体抗KEL同种异体抗体对发育中的胎儿和新生儿的危险降至最低的策略。具体目标2：研究在妊娠/分娩期间预防初级抗-KEL红细胞同种免疫的策略。具体目的3：研究其他(非KEL)RBC同种异体抗体对发育中胎儿和新生儿的影响。公共卫生意义/长期目标：通过减少胎儿和新生儿HDFN的发病率和死亡率，开发有针对性的治疗方法，最大限度地减少现有RBC同种抗体的危险，或防止携带表达同种RBC抗原的胎儿的初次同种免疫，将具有重大的公共卫生意义。该项目的长期目标包括将成功的小鼠创新疗法转化为人类，最初是在输血环境中，最终是在怀孕环境中，使用长凳到床边和背部的方法。

DESCRIPTION (provided by applicant): Maternal RBC alloimmunization, induced by prior pregnancy/delivery or prior transfusion, puts the developing fetus/neonate at risk for anemia and hemolytic disease of the fetus and newborn (HDFN). 1 in 600 infants is at risk for HDFN, with no targeted therapies available to offer alloimmunized pregnant women, and no prophylactic therapies available for non-D antigens. This paucity of targeted therapies is due in part to an understandable reluctance to test innovative therapies on pregnant women or their fetuses. To circumvent this issue, we have developed what we believe is the first animal model of HDFN in which pregnancy/delivery is capable of stimulating maternal alloimmunization and in which these maternal antibodies result in HDFN. The fact that this model involves RBC specific expression of a human antigen highly implicated in HDFN (KEL) adds further to its innovation. As an extension of our R21 to develop and characterize this model, we now propose to utilize this model to protect developing fetuses from existing maternal alloantibodies in a damage control manner, and to prevent primary anti-KEL formation in a prophylactic manner. Central Hypothesis: The dangers of existing or developing maternal anti-RBC alloantibodies to fetuses and newborns can be prevented through active or passive maternal immunomodulatory therapies. Specific Aim 1: Investigate strategies to minimize the dangers of existing maternal anti-KEL alloantibodies to developing fetuses and newborns. Specific Aim 2: Investigate strategies to prevent primary anti-KEL RBC alloimmunization during pregnancy/delivery. Specific Aim 3: Investigate the impact of other (non-KEL) RBC alloantibodies on developing fetuses and newborn. Public Health Significance/Long Term Goals: The development of targeted therapies to minimize the dangers of existing RBC alloantibodies or to prevent primary alloimmunization in women carrying fetuses expressing the cognate RBC antigen would have significant public health significance, through a decrease in fetal and neonatal HDFN morbidity and mortality. Long term goals of this project include translating successful murine innovative therapies to humans, initially in a transfusion setting and ultimately in a pregnancy setting, usin a bench to bedside and back approach.