Alloimmunization to human platelet antigens (HPAs) can lead to neonatal alloimmune thrombocytopenia (NAIT), post transfusion purpura (PTP), and platelet refractoriness. We are studying the immune response to HPA-1a (or PlA1) in mice and are testing the efficacy of CTLA4-Ig, an immunosuppressive agent that interferes with an essential costimulatory response required for T-cell activation. The HPA-1 alloantigen system is due to a conformational epitope(s) created by substitution of leucine (HPA-1a) for proline (HPA-1b) at position 33 of human glycoprotein IIIa (GPIIIa). We have completed the sequencing of the amino terminal region of the murine GPIIIa gene that is homologous to the region of the HPA-1 alloepitope; the predicted protein is 94% homologous and 82% identical to the human protein within this region (a.a. 1-66). In 9 genetically divergent strains of mice, none carry the HPA-1a or b sequence. We inoculated two strains of mice with a glutathione S-transferase (GST) fusion protein containing the first 66 amino acids of the human GPIIIa protein and the HPA-1a sequence (PlA1 Barron-Casella et al., Blood 84:1157, 1994). Five of 5 mice of one strain produced anticonformational antibodies against HPA-1a that did not appear to recognize the HPA-1b form of human GPIIIa. When CTLA4-Ig was administered simultaneously, only 1 of 5 mice made detectable antibody against the HPA-1 antigen. These preliminary results demonstrate that the murine response against the conformational epitope(s) contained in the PlA1 fusion protein can be blocked by paired injection of antigen and immunosuppressant. Our studies suggest that mouse models may be useful in modeling the human alloimmune response to HPA-1a, and that immunosupressive agents such as CTLA4-Ig could be potential therapeutic agents for alloimmune disorders.