A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy

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

“…9,25 Perhaps related to the latter points, human IgG was used in the mouse model, which may have introduced extraneous xenogenic effects such as cross-reactivity with murine red blood cells). However, other studies have successfully used human IVIg in different animal models of ITP with no apparent xenogeneic effects, [10][11][12]24,25 and, in our hands, human IVIg at least does not bind with murine red blood cells (J.W.S., unpublished data, December 1999). Thus, taken together, our data suggest that IVIg therapy is efficacious for antibodymediated thrombocytopenia but not the CD8 ϩ T cell-mediated form of the disease.…”

“…[9][10][11][12]47 The excessive bleeding in our model suggests that additional immune factors are involved. For example, the IgG anti-CD61 antibody response in immune CD61 KO mice was extremely strong (titers Ͼ 1:12 000) and contains antibodies with multiple CD61 epitope specificities 24,25 that not only induce FcR-mediated phagocytosis but also significantly inhibit platelet function. 48 Thus, SCID mouse recipients that contain these antiplatelet antibodies are virtually devoid of platelet function, and this may be an important reason why they bleed excessively.…”

“…Fetal death because of bleeding occurred, and in successful pregnancies the neonatal pups were thrombocytopenic and exhibited a bleeding diathesis. 24 In this report, we have created a novel murine model of severe chronic ITP that shows both antibody-mediated and cell-mediated platelet and megakaryocyte destruction and show that, although antibodymediated thrombocytopenia is responsive to IVIg treatment, cellmediated disease is not. This model may be applicable for understanding the immune nature of severe ITP, and the lack of response of cell-mediated thrombocytopenia and bleeding to IVIg therapy may suggest that other therapeutic strategies may be needed to treat this form of ITP.…”

“…[9][10][11][12] Although these models have been instrumental in understanding the pathophysiology of secondary ITP and the mechanisms of action of treatments such as IVIg, they are not ideal for chronic ITP pathophysiology where both T-cell and B-cell autoimmune attacks are focused on platelet-specific antigens. Recently, however, a platelet-specific immune model of neonatal alloimmune thrombocytopenia was developed with the use of immune CD61 knockout (KO) mice 24 that were pregnant with wild-type (WT) CD61 ϩ fetuses. Fetal death because of bleeding occurred, and in successful pregnancies the neonatal pups were thrombocytopenic and exhibited a bleeding diathesis.…”

“…Sera from these immune KO mice have been previously shown to induce a profound thrombocytopenia when injected into naive mice. 24,25 To produce third-party immune control animals, BALB/c mice were transfused as above with platelets from major histocompatibility complex allogeneic C57BL/6 mice. Immunization was monitored by measuring IgG antiplatelet antibody production in the sera by flow cytometry.…”