Complement Activation and Hemolysis in Non-human Primates Following Transfusion of Genetically Modified Pig Red Blood Cells
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Background: Pig red blood cells (RBCs) are rapidly eliminated when transfused into non- human primates (NHPs) because of immune reactions involving antibody binding and complement activation. We assessed the relationship between post-transfusion hemolysis and complement activation. Methods: RBCs for transfusion were prepared from wild-type (WT) and genetically modi- fied pigs and NHPs. After the withdrawal of 25% of the blood volume, NHPs received trans- fusions of WT (N=4), triple knockout (TKO, N=8), and TKO pig RBCs expressing human CD55 and CD39 (TKO/hCD55.hCD39, N=4). Additional groups received repeated xeno- transfusions (ReXTf, N=3), NHP RBC transfusions (N=3), or a saline infusion (N=4). Blood samples were collected at multiple time points to measure Hb and complement fragment (C3a, C4a, and factor Bb) levels and agglutination titers. Results: Hb levels were restored by transfusions but not by saline infusion. The degree of complement activation varied with the type of transfused RBCs, with significant increases in C3a and factor Bb levels immediately after xenotransfusions but not allotransfusions. These increases were particularly notable in ReXTf and negatively correlated with Hb levels on post-transfusion day 1 (ρ =–0.547 and –0.556; P =0.0187 and 0.0165, respectively). In TKO/hCD55.hCD39 pig RBC transfusions, C3a and factor Bb peak levels were delayed until post-transfusion day 3, unlike in TKO pig RBC transfusions. Conclusions: Post-transfusion complement activation varies depending on prior sensitiza- tion and genetic modifications in pig RBCs. Monitoring complement activation can provide insight into the survival and compatibility of transfused RBCs in NHPs.
Abstract
Background: Pig red blood cells (RBCs) are rapidly eliminated when transfused into non- human primates (NHPs) because of immune reactions involving antibody binding and complement activation. We assessed the relationship between post-transfusion hemolysis and complement activation. Methods: RBCs for transfusion were prepared from wild-type (WT) and genetically modi- fied pigs and NHPs. After the withdrawal of 25% of the blood volume, NHPs received trans- fusions of WT (N=4), triple knockout (TKO, N=8), and TKO pig RBCs expressing human CD55 and CD39 (TKO/hCD55.hCD39, N=4). Additional groups received repeated xeno- transfusions (ReXTf, N=3), NHP RBC transfusions (N=3), or a saline infusion (N=4). Blood samples were collected at multiple time points to measure Hb and complement fragment (C3a, C4a, and factor Bb) levels and agglutination titers. Results: Hb levels were restored by transfusions but not by saline infusion. The degree of complement activation varied with the type of transfused RBCs, with significant increases in C3a and factor Bb levels immediately after xenotransfusions but not allotransfusions. These increases were particularly notable in ReXTf and negatively correlated with Hb levels on post-transfusion day 1 (ρ =–0.547 and –0.556; P =0.0187 and 0.0165, respectively). In TKO/hCD55.hCD39 pig RBC transfusions, C3a and factor Bb peak levels were delayed until post-transfusion day 3, unlike in TKO pig RBC transfusions. Conclusions: Post-transfusion complement activation varies depending on prior sensitiza- tion and genetic modifications in pig RBCs. Monitoring complement activation can provide insight into the survival and compatibility of transfused RBCs in NHPs.