Project Grant R01HL169144

INTERROGATING CLINICALLY RELEVANT ATTRIBUTES OF MATERNAL ALLOIMMUNITY IN FETAL/NEONATAL ALLOIMMUNE THROMBOCYTOPENIA - ABSTRACT IMMUNE RESPONSES TO PLATELET ALLOANTIGENS CAUSE PATHOLOGY IN THE SETTINGS OF TRANSFUSION AND PREGNANCY, THE LATTER RESULTING IN THE RELATIVELY COMMON AND MORE SERIOUS NON-MALIGNANT HEMATOLOGIC BLEEDING DISORDER, FETAL/ NEONATAL ALLOIMMUNE THROMBOCYTOPENIA (FNAIT). FNAIT OCCURS WHEN MATERNAL ANTIBODIES, SPECIFIC FOR PATERNAL PLATELET ALLOANTIGENS INHERITED BY THE FETUS, CROSS THE PLACENTA AND CLEAR PLATELETS FROM THE FETAL AND/OR NEONATAL CIRCULATION, RESULTING IN THROMBOCYTOPENIA AND BLEEDING THAT ARE OFTEN SERIOUS ENOUGH TO REQUIRE TRANSFUSION IN THE NEONATAL PERIOD. FNAIT ARISES IN SOME BUT NOT ALL AT-RISK PREGNANCIES. IN AN UNPREDICTABLE SUBSET OF SEVERELY THROMBOCYTOPENIC CASES, MAJOR ORGAN BLEEDS SUCH AS INTRACRANIAL HEMORRHAGE OCCUR IN THE FETAL PERIOD, PLACING SUCH INFANTS AT RISK FOR IRREVERSIBLE BRAIN DAMAGE, LIFELONG DISABILITY AND DEATH. OFF-LABEL THERAPIES ARE USED TO MANAGE THROMBOCYTOPENIA IN SUBSEQUENT PREGNANCIES OF A MOTHER WHO HAS DELIVERED AN AFFECTED INFANT. IT IS CURRENTLY NOT POSSIBLE TO IDENTIFY PREGNANCIES AT HIGH RISK FOR SEVERE BLEEDING SO THAT THEY CAN BE SPECIFICALLY TARGETED FOR THERAPY OR TO PREVENT DEVELOPMENT OF FNAIT. RESEARCH NEEDED TO DEVELOP DIAGNOSTIC TESTS FOR SEVERE FORMS OF FNAIT, TO BETTER UNDERSTAND DISEASE ETIOLOGY, AND TO TEST STRATEGIES FOR DISEASE PREVENTION ARE DIFFICULT, IF NOT IMPOSSIBLE, TO PERFORM IN THE PREGNANT WOMEN AND NEONATES WHO CONSTITUTE THE FNAIT POPULATION. THERE IS A COMPELLING NEED FOR TRANSFORMATIVE ANIMAL MODELS THAT CAN NARROW THE EXISTING INFORMATION GAP AND IMPROVE DIAGNOSIS, TREATMENT, AND PREVENTION OF THIS NOTABLE CAUSE OF MORBIDITY AND MORTALITY IN HUMAN NEONATES. WE HAVE DEVELOPED A UNIQUE, ALLOANTIGEN-SPECIFIC, PRECLINICAL MOUSE MODEL OF FNAIT THAT RECAPITULATES CLINICALLY IMPORTANT ASPECTS OF HUMAN DISEASE. HEREIN, WE APPLY EXTENSIVE IMMUNOLOGICAL EXPERTISE TO THIS MODEL TO 1) DETERMINE WHETHER THE SEVERE BLEEDING AND OTHER PREGNANCY COMPLICATIONS THAT ACCOMPANY FNAIT ARE CAUSED BY SUBPOPULATIONS OF ALLOANTIGEN-SPECIFIC ANTIBODIES THAT BIND TO AND IMPAIR THE FUNCTIONS OF FETAL PLATELETS, SYNCYTIOTROPHOBLASTS AND ENDOTHELIAL CELLS AND 2) IDENTIFY EVENTS CAPABLE OF CAUSING DEVELOPMENT OF FNAIT DURING PREGNANCY AND PROPHYLACTIC STRATEGIES NEEDED TO PREVENT IT. OUR STUDIES ARE MADE FEASIBLE BY ESTABLISHED IMMUNIZATION SCHEMES, BREEDING PROTOCOLS, ANTIBODY INFUSION STRATEGIES, AND METHODS FOR CLASSIFYING PREGNANCY OUTCOMES AND ALLOANTIBODY EPITOPE SPECIFICITIES AND FUNCTION BLOCKING ACTIVITIES. OUR STUDIES WILL HAVE DIAGNOSTIC AND THERAPEUTIC SIGNIFICANCE IN THAT THEY WILL LAY THE GROUNDWORK FOR DEVELOPMENT OF DIAGNOSTIC TESTS THAT CAN SAFELY DISCRIMINATE BETWEEN PREGNANCIES AT RISK FOR MILD VS. SEVERE FNAIT, THEREBY PROVIDING A MECHANISTIC BASIS FOR RATIONAL THERAPEUTIC INTERVENTION, AND WILL IDENTIFY POTENTIAL CAUSES OF FNAIT THAT CAN BE VALIDATED IN HUMAN STUDIES AND INFORM EFFORTS TO PREVENT DEVELOPMENT OF FNAIT DURING PREGNANCY. THIS CUTTING-EDGE WORK AT THE INTERFACE OF MOLECULAR BIOLOGY, IMMUNOLOGY, AND HEMATOLOGY WILL PROVIDE NOVEL AND INFORMATIVE INSIGHTS TO TRANS- FORM OUR UNDERSTANDING OF ANTI-PLATELET ALLOIMMUNE RESPONSES TO BENEFIT THE FIELD OF NON-MALIGNANT HEMATOLOGY.