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 antibodyopsonized 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 ؋ 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 ␥-globulins raised platelet counts and completely prevented bleeding mortality induced by antibodymediated 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. (Blood. 2010;115:1247-1253) IntroductionImmune thrombocytopenia (ITP), one of the most common hematologic autoimmune bleeding disorders, is characterized by premature platelet clearance by Fc␥ receptor (Fc␥R)-mediated phagocytosis in the reticuloendothelial system. 1-8 ITP was distinguished by 2 forms, termed acute and chronic, but an international group of recognized experts has significantly revised the definitions of and recommendations for the clinical diagnosis of ITP. 8 Primary ITP is now defined as an autoimmune disorder characterized by isolated thrombocytopenia (peripheral blood platelet count Ͻ 100 ϫ 10 9 /L) in the absence of other causes or disorders that may be associated with thrombocytopenia. 8 The various phases of ITP are defined by the time since diagnosis; newly diagnosed ITP occurs within 3 months from diagnosis, whereas persistent ITP is between 3 and 12 months from diagnosis, and chronic ITP is now defined as thrombocytopenia lasting for more than 12 months. 8 The classification of severe ITP is now reserved for those patients in whom there is the presence of bleeding symptoms at presentation or the occurrence of new bleeding symptoms requiring therapeutic intervention. 8 First-line treatments for patients with chronic ITP include steroids and intravenous ␥-globulins (IVIgs), and previous studies have shown that IVIg can also protect against passive ITP in mice. [9][10][11][12] At least 70% of patients with chronic ITP have identifiable serum autoantibodies that are composed primarily of IgG1 and IgG3 isotypes and generally target platelet glycoproteins (GPs) IIb/IIIa and/or GPIbIX. ...

Thrombocytopenia as a Preoperative Risk Assessment Tool in Patients With Rheumatic Heart Disease Undergoing Valve Replacement Surgery

“…There are some conditions, like tumors, viral infections, or immunological diseases, that could induce immune‐mediated thrombocytopenia. In rheumatic disease, the immune system might produce abundant platelet antibodies; they specifically bind receptors of the blood platelet surface membrane, resulting in the increment of platelet destruction and thrombocytopenia 26, 27, 28…”

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

“…9 A new murine model of severe ITP induced by both antibody and CD8 ϩ T cells has further confirmed the T cellmediated immune disorder in ITP. 10 Li et al 49 discovered that activated CD8 ϩ T cells in bone marrow of patients with chronic ITP might suppress megakaryocyte apoptosis and lead to impaired platelet production in vitro. sFas, derived from activated CD8 ϩ T cells, might act as a paracrine regulator of the megakaryocytic apoptosis.…”

“…[1][2][3][4] Although autoantibodies produced by autoreactive B cells against self-antigens, specifically immunoglobulin G (IgG) antibodies against glycoprotein IIb (GPIIb)/IIIa and/or GPIb/IX, are considered to play a crucial role, T-cell-mediated immune abnormalities, such as Th1 bias, 5,6 the decreased number or defective function of regulatory T cells, 7,8 and the platelet destruction by cytotoxic T cells 9,10 have been considered equally important in the pathogenesis of ITP. As a result of the accelerated destruction, platelet production is thought to compensatorily increase.…”

Immune thrombocytopenia in children and adults: what's the same, what's different?

“…This has recently been shown in an elegant mouse model of ITP. 6 In contrast, the influence of anti-platelet antibodies on thrombopoiesis by inhibiting megakaryocyte maturation in the bone marrow or platelet release across the endothelial barrier is still poorly characterized. It has long been known that antibodies present in the serum of ITP patients can bind to megakaryocytes 7 that share most of their surface receptors with platelets.…”