Antibody- and Cell-Mediated Immune Thrombocytopenia Are Differentially Sensitive to Intravenous Gammaglobulin Therapy

Abstract

Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by IgG autoantibody-opsonized platelets prematurely being destroyed in the spleen although recent evidence suggests that thrombocytopenia in perhaps as many as 40% of patients with ITP can be mediated by CD8+ T cells. Although several animal models of immune thrombocytopenia have been developed, few are induced by platelet-specific autoimmune mechanisms nor have any demonstrated cell-mediated platelet destruction. We developed a murine model of ITP by first immunizaing GPIIIa (CD61) knockout (KO) mice against wildtype (WT) CD61+ platelet transfusions and subsequently transferring their splenocytes (5×104 cells/transfer) intraperitonealy into irradiated SCID mouse recipients. The SCID mice developed significant bleeding mortality and thrombocytopenia within 2 weeks post-transfer. Lower doses (<104) of immune splenocytes transferred induced thrombocytopenia in the SCID mouse recipients with no mortality. Depletion of lymphocyte subsets in the splenocytes before transfer showed that both CD19+ B cell (antibody)- and CD8+ T cell (cell)-mediated thrombocytopenia existed and that bleeding mortality was particularly associated with antibody-mediated thrombocytopenia. Treatment of the SCID mouse recipients bi-weekly with 2g/kg intravenous gammaglobulins (IVIg) demonstrated that IVIg was beneficial in eliminating bleeding mortality and thrombocytopenia only in the recipients displaying the antibody-mediated form of ITP. Cell-mediated bleeding mortality and thombocytopenia was completely resistant to IVIg therapy. This model suggests a potential reason why some patients with ITP fail IVIg therapy and may aid in the development of new therapeutics for individuals inflicted with cell mediated thrombocytopenia.