Allogeneic Platelet MHC Class I Antigens Prevent CD61 Specific Cytotoxic T Cell (CTL)-Mediated Immune Thrombocytopenia (ITP).

Abstract 3686

In the International Consensus Report (Rodeghiero et al. Blood 2009;113:2386-2393), platelet transfusions are only recommended in patients with auto-immune thrombocytopenia (ITP) as an adjunctive therapy for life-threatening bleeding. However, the clinical evidence of post-transfusion increments in ITP suggests that in some cases of ITP, platelet transfusions may be a useful prophylactic therapy. To understand the importance of platelet transfusion in this setting, we utilized our murine model of ITP that demonstrates both antibody- and CTL-mediated thrombocytopenia. BALB/c CD61 knockout (KO) mice were immunized by transfusions of three different platelet populations that were either single antigen positive (e.g. CD61+ or MHC class I+) or double antigen positive (CD61+/MHC class I+). Splenocytes from the immune KO mice were either not depleted (ND) or depleted of CD19+ B cells and then transferred into SCID mice and the development of thrombocytopenia and bleeding diathesis was monitored. When ND splenocytes from MHC class I+ immune KO mice were transferred, no thrombocytopenia or bleeding was observed. In contrast, transfer of ND splenocytes from CD61+ immune mice induced a significant thrombocytopenia with a bleeding mortality of 40% within 3 weeks post-transfer; depletion of B cells was used to analyze CD8+ T cell- mediated thrombocytopenia and these depleted splenocytes also induced thrombocytopenia and bleeding. In addition, compared with healthy mice, the bone marrow of the transferred mice showed elevated numbers of megakaryocytes with some of them appearing to be apoptotic. On the other hand, when splenocytes from the double immunized (CD61+/MHC class I+) mice were transferred, the CD8+ T cell- mediated thrombocytopenia and bleeding mortality was not observed. In addition to preventing the thrombocytopenia and bleeding, histological analysis of the bone marrow showed normal numbers of megakaryocytes. These results suggest that both antibody- and CD8+ T cell-mediated immune thrombocytopenia exist and that when anti-CD61 specific CD8+ T cells interacted with allogeneic MHC antigens on platelets they were prevented from inducing CD8+ T cell-mediated thrombocytopenia. Thus, allogeneic MHC platelet transfusions may be responsible for inhibiting CD8+ T cell-mediated thrombocytopenia and may be a therapeutic option for those patients who suffer from cell-mediated ITP.