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A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy

Chow, Leola; Aslam, Rukhsana; Speck, Edwin R; Kim, Michael; Cridland, Norman; Webster, Michelle Lee; Chen, Pingguo; Sahib, Kim; Ni, Heyu and Lazarus, Alan H, et al. (2010) In Blood 115(6). p.53-1247
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... (More)

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.

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@misc{547c6648-1392-46c5-bf8f-f35af195cd99,
  abstract     = {<p>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.</p>},
  author       = {Chow, Leola and Aslam, Rukhsana and Speck, Edwin R and Kim, Michael and Cridland, Norman and Webster, Michelle Lee and Chen, Pingguo and Sahib, Kim and Ni, Heyu and Lazarus, Alan H and Garvey, M Bernadette and Freedman, John and Semple, John W},
  issn         = {1528-0020},
  keyword      = {Animals,Antigens, CD19,Blood Platelets,CD8-Positive T-Lymphocytes,Disease Models, Animal,Female,Flow Cytometry,Immunoglobulins, Intravenous,Integrin beta3,Lymphocyte Depletion,Megakaryocytes,Mice,Mice, Inbred BALB C,Mice, Inbred C57BL,Mice, Knockout,Mice, SCID,Platelet Count,Purpura, Thrombocytopenic, Idiopathic,Spleen,T-Lymphocytes, Helper-Inducer,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {02},
  number       = {6},
  pages        = {53--1247},
  publisher    = {ARRAY(0x9f4eee0)},
  series       = {Blood},
  title        = {A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy},
  url          = {http://dx.doi.org/10.1182/blood-2009-09-244772},
  volume       = {115},
  year         = {2010},
}