Drug-induced thrombocytopenia: development of a novel NOD/SCID mouse model to evaluate clearance of circulating platelets by drug-dependent antibodies and the efficacy of IVIG.
Drug-induced immune thrombocytopenia (DITP) is an adverse drug effect mediated by drug-dependent antibodies. Intravenous immunoglobulin (IVIG) is frequently used to treat DITP and primary immune thrombocytopenia (ITP). Despite IVIG's proven beneficial effects in ITP, its efficacy in DITP is unclear. We have established a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of DITP in which human platelets survive for more than 24 hours, allowing platelet clearance by DITP/ITP antibodies to be studied. Rapid human platelet clearance was uniformly observed with all quinine-induced thrombocytopenia (QITP) patient sera studied (mean platelet lifespans: QITP 1.5 ± 0.3 hours vs controls 16.5 ± 4.3 hours), consistent with the clinical presentation of DITP. In contrast, clearance rates with ITP antibodies were more variable. IVIG treatment partially prevented platelet clearance by DITP and ITP antibodies. Our results suggest that the NOD/SCID mouse model is useful for investigating the efficacy of current and future DITP therapies, an area in which there is little experimental evidence to guide treatment.
Liang
Simon X
SX
St George Clinical School, University of New South Wales, Sydney, Australia.
Pinkevych
Mykola
M
Khachigian
Levon M
LM
Parish
Christopher R
CR
Davenport
Miles P
MP
Chong
Beng H
BH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000918:Antibody Specificity / Q000276:immunology; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D011803:Quinine / Q000008:administration & dosage / Q000009:adverse effects; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D000906:Antibodies; D016756:Immunoglobulins, Intravenous; D011803:Quinine