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.
Maternal RBC alloantibodies may be dangerous to developing fetuses/neonates, affecting 1 in 600 births and leading to short and long term morbidity/mortality due to suppression of erythropoiesis and/or hemolysis. Currently, very few treatment options exist to minimize the dangers of maternal alloantibodies to fetuses, and not a single prophylactic therapy exists to prevent maternal alloimmunization to any RBC antigen besides D. Using what we believe is the first animal model of hemolytic disease of the newborn (HDFN) involving a clinically significant human RBC antigen (KEL), we propose reductionist studies to better understand maternal antibody development and prevention thereof;long term goals of these studies include developing translational therapies to minimize the fetal/neonatal morbidity and mortality currently associated with maternal alloimmunization and HDFN.
|Santhanakrishnan, M; Tormey, C A; Natarajan, P et al. (2016) Clinically significant anti-KEL RBC alloantibodies are transferred by breast milk in a murine model. Vox Sang 111:79-87|
|Stowell, Sean R; Arthur, C Maridith; Girard-Pierce, Kathryn R et al. (2015) Anti-KEL sera prevents alloimmunization to transfused KEL RBCs in a murine model. Haematologica 100:e394-7|