Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia.
Experiments were conducted to investigate the effects of intravenous immunoglobulin (IVIG) in a rat model of immune thrombocytopenia (ITP). Rats were pretreated with 0 to 2 g/kg IVIG and then challenged with an antiplatelet antibody (7E3, 8 mg/kg). IVIG effects on 7E3-induced thrombocytopenia and on 7E3 pharmacokinetics were determined. IVIG pretreatment led to significant changes in the degree and time-course of 7E3-induced thrombocytopenia (P =.031). Nadir percent platelet counts were 121% to 279% greater in animals treated with IVIG (0.4-2 g/kg) than in animals receiving 7E3 alone. IVIG treatment also led to dose-dependent increases in 7E3 clearance (P <.001), with more than 2-fold increases in 7E3 clearance seen following the highest dose of IVIG. In vitro experiments showed that IVIG effects on platelet count are not likely due to anti-idiotypic inhibition of 7E3-platelet binding and that IVIG did not directly bind to 7E3. Consequently, IVIG-7E3 binding cannot explain the increase of 7E3 clearance following IVIG treatment. We propose that the observed increase in 7E3 clearance with IVIG therapy is due to saturation of the FcRn salvage receptor for IgG. The importance of the effect of IVIG on 7E3 clearance to the prevention of thrombocytopenia in these animals is unclear at present; nonetheless, these data provide experimental support for a new mechanism of IVIG action in ITP (ie, IVIG-mediated increases in antiplatelet antibody elimination). This model of ITP will be useful for further investigations of IVIG mechanism of action and for development of new therapies for ITP.
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
Ryan J
RJ
Hansen
Joseph P
JP
Balthasar
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000187:drug effects* / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D008954:Models, Biological; D010975:Platelet Aggregation Inhibitors / Q000276:immunology*; D010976:Platelet Count; D051381:Rats; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000188:drug therapy* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D010975:Platelet Aggregation Inhibitors