A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy.
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.
Chow
Leola
L
Toronto Platelet Immunobiology Group, Toronto, Canada.
Aslam
Rukhsana
R
Speck
Edwin R
ER
Kim
Michael
M
Cridland
Norman
N
Webster
Michelle Lee
ML
Chen
Pingguo
P
Sahib
Kim
K
Ni
Heyu
H
Lazarus
Alan H
AH
Garvey
M Bernadette
MB
Freedman
John
J
Semple
John W
JW
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
D018941:Antigens, CD19; D016756:Immunoglobulins, Intravenous; D039661:Integrin beta3