title: A GPIIb/IIIa bioreactor for specific treatment of immune thrombocytopenic purpura, an autoimmune disease. Preparation, in vitro characterization, and preliminary proof-of-concept animal studies.
abstract: Immune thrombocytopenic purpura (ITP) is an autoimmune disease that affects thousands of Americans each year. The resulting thrombocytopenia, which develops from destruction of platelets (PLT) by anti-PLT autoantibodies (APAb), is often associated with hemorrhagic complications. Existing therapies are not effective and are associated with significant morbidity. Recently, a new treatment modality using plasmapheresis with a Protein-A column has shown some clinical promise. Yet, although this method would remove the pathogenic APAb, it would also deplete protective antibodies, thereby weakening the body's self-defense system. Because about 80% of patients with ITP develop APAb against the GPIIb/IIIa antigens on PLT, a novel approach of attaching a GPIIb/IIIa-linked bioreactor with an extracorporeal circuit is suggested herein to achieve highly effective/specific APAb removal and overcome shortcomings of plasmapheresis in treating ITP. A hollow fiber-based bioreactor device was fabricated, and GPIIb/IIIa antigens were immobilized onto the inner lumens of the hollow fibers by using the epichlorohydrin activation method. An optimized bioreactor containing a loading of 1.63 mg GPIIb/IIIa/g fibers and adsorption capacity of 1.9 mg 7E3/g fibers was developed. Preliminary proof-of-concept investigation using a 7E3-induced thrombocytopenic rat model (which mimicked clinical ITP) was carried out. A complete (100%) return of PLT counts to their initial levels was observed in rats within 6 h after the GPIIb/IIIa bioreactor treatment. In addition, a rapid restoration of WBC counts in the treated rats was also found. These preliminary findings shed light of promise of using the GPIIb/IIIa bioreactor approach in achieving highly improved ITP therapy.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.
authors.forename: Emel
authors.initials: E
authors.lastname: Emregul
authors.forename: Allan
authors.initials: A
authors.lastname: David
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balthasar
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
mesh_terms: D000818:Animals; D019149:Bioreactors; D005260:Female; D006863:Hydrogen-Ion Concentration; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism* / Q000627:therapeutic use; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex