title: A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy.
abstract: Immune thrombocytopenia (ITP) is a bleeding disorder characterized by antibody-opsonized platelets being prematurely destroyed in the spleen, although some patients with ITP may have a cell-mediated form of thrombocytopenia. Although several animal models of ITP have been developed, few mimic primary chronic ITP nor have any shown cell-mediated platelet destruction. To create this type of model, splenocytes from CD61 knockout mice immunized against CD61(+) platelets were transferred into severe combined immunodeficient (SCID) (CD61(+)) mouse recipients, and their platelet counts and phenotypes were observed. As few as 5 x 10(4) splenocytes induced a significant thrombocytopenia and bleeding mortality (80%) in recipients within 3 weeks after transfer. Depletion of lymphocyte subsets before transfer showed that the splenocyte's ability to induce thrombocytopenia and bleeding completely depended on CD4(+) T helper cells and that both CD19(+) B cell (antibody)- and CD8(+) T cell (cell)-mediated effector mechanisms were responsible. Treatment of the SCID mouse recipients with intravenous gamma-globulins raised platelet counts and completely prevented bleeding mortality induced by antibody-mediated effector mechanisms but did not affect cell-mediated disease. This novel model not only shows both antibody- and cell-mediated ITP and bleeding but also suggests that these 2 effector mechanisms have a differential response to therapy.
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, Canada.
authors.forename: Leola
authors.initials: L
authors.lastname: Chow
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Aslam
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Speck
authors.forename: Michael
authors.initials: M
authors.lastname: Kim
authors.forename: Norman
authors.initials: N
authors.lastname: Cridland
authors.forename: Michelle Lee
authors.initials: ML
authors.lastname: Webster
authors.forename: Pingguo
authors.initials: P
authors.lastname: Chen
authors.forename: Kim
authors.initials: K
authors.lastname: Sahib
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.forename: Alan H
authors.initials: AH
authors.lastname: Lazarus
authors.forename: M Bernadette
authors.initials: MB
authors.lastname: Garvey
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage*; D039661:Integrin beta3 / Q000276:immunology; D008212:Lymphocyte Depletion; D008533:Megakaryocytes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013154:Spleen / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology
chemical_list: D018941:Antigens, CD19; D016756:Immunoglobulins, Intravenous; D039661:Integrin beta3