-Author name in bold denotes the presenting author
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1258 Atomic-Level Dissection of the Polyclonal Immune Response to the Human Platelet Alloantigen, HPA-1a (PlA1)

Program: Oral and Poster Abstracts
Session: 401. Basic Science and Clinical Practice in Blood Transfusion: Poster I
Hematology Disease Topics & Pathways:
Clinically relevant
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Huiying Zhi, PhD1, Maria Therese Ahlen, PhD2*, Aye Myat Myat Thinn, PhD1, Hartmut Weiler, PhD1, Brian R. Curtis, PhD1, Bjorn Skogen, MD2*, Jieqing Zhu, PhD1 and Peter Newman, PhD3

1Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI
2University Hospital of North Norway, Department of Immunology and Transfusion Medicine, Tromsø, Norway
3Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI

Alloantibodies to platelet-specific antigens are responsible for two clinically-important bleeding disorders: Post-transfusion purpura and fetal/neonatal alloimmune thrombocytopenia (FNAIT). The HPA-1a/1b (also known as PlA1/A2) alloantigen system of human platelet membrane glycoprotein (GP)IIIa is controlled by a Leu33Pro polymorphism, and is responsible for ~80% of the cases of FNAIT. Local residues surrounding polymorphic residue 33 are suspected to have a profound effect on alloantibody binding and subsequent downstream effector events. To define the molecular requirements for HPA-1a alloantibody binding, we generated transgenic mice that expressed murine GPIIIa isoforms harboring select humanized residues within the PSI and EGF1 domain, and examined their ability to support the binding of a series of monoclonal and polyclonal HPA-1a-specific antibodies. Humanizing the PSI domain of murine GPIIIa was sufficient to recreate the HPA-1a epitope recognized by some HPA-1a-specific antibodies, however humanizing distinct amino acids within the linearly distant, but conformationally close, EGF1 domain was required to enable binding of others. Using a series of transgenic mice and recombinant constructs, we reveal previously unsuspected, complex heterogeneity of the polyclonal alloimmune response to this clinically important human platelet alloantigen system. High-resolution mapping of this alloimmune response may improve diagnosis of FNAIT by providing cells that distinguish specific alloantibody subpopulations, and should facilitate the rational design and selection of contemplated prophylactic and therapeutic anti-HPA-1a reagents.

Disclosures: Curtis: Ionis Pharmaceuticals: Consultancy.

*signifies non-member of ASH