*Purpose: Blood transfusion remains important in the treatment of patients with sickle cell disease (SCD). However, alloimmunization after multiple blood transfusions is associated with patient morbidity and mortality. Triple-knockout (TKO) pigs may be an alternative source of RBCs for these patients because many humans have no pre-formed antibodies to TKO pig RBCs (pRBCs). The aims of this study were (i) to measure IgM/IgG binding and complement-dependent cytotoxicity (CDC) from plasma of alloimmunized or non-alloimmunized SCD patients to TKO pRBCs in vitro, and (ii) to determine survival of (a) TKO pRBCs (xenotransfusion) and (b) monkey RBCs (allotransfusion) in capuchin monkeys.

*Methods: In vitro study: Plasma from alloimmunized (n=12) or non-alloimmunized (n=12) SCD patients were used to determine IgM/IgG binding to, and CDC of, TKO pRBCs. In vivo study: After an estimated 25% of blood volume was withdrawn from each of two capuchin monkeys, CFSE-labeled TKO pRBCs were transfused. Loss of TKO pRBCs was monitored, and seven weeks later, 25% of blood was withdrawn, and CFSE-labeled monkey RBCs were transfused.

*Results: In vitro study: Demonstrated that plasma from neither alloimmunized nor non-alloimmunized SCD patients bound IgM/IgG to, or induced CDC of, TKO pRBCs (Figure 1). In vivo study: Survival of TKO pRBCs in the two capuchin monkeys was of 5 and 7 days, respectively, whereas after allotransfusion survival was >28 days (Figure 2).

*Conclusions: (i) Alloimmunized SCD patients have no antibodies that cross-react with TKO pRBCs. (ii) TKO pigs could be an alternate blood source in an emergency if no human RBCs are available. Further genetic engineering of the source pig may extend RBC survival after xenotransfusion.

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