Future prospects for the clinical transfusion of pig red blood cells

Chornenkyy, Yevgen; Yamamoto, Takayuki; Hara, Hidetaka; Stowell, Sean R.; Ghiran, Ionita; Robson, Simon C.; Cooper, D. K. C.

doi:10.1016/j.blre.2023.101113

Cited by 3 publications

(5 citation statements)

References 98 publications

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“…These results suggest that hCD55 expression partially protects pRBCs from serum-mediated hemolysis. To our knowledge, this is the first evidence that the product of an inserted human gene is functional in pRBCs ( 6 , 35 ). Because TKO/hCD55.hCD39KI pigs have been developed for solid organ xenotransplantation, hCD39 on pRBCs, which metabolizes ADP and limits platelet activation and aggregation, was not evaluated in this study ( 6 ).…”

Section: Discussionmentioning

confidence: 81%

“…It is possible that different types of phagocytes in the human body can phagocytose pRBCs in a more facilitated manner than we revealed using THP-1 cells. More importantly, antibodies react to pRBCs in vivo , causing antibody-mediated complement activation and phagocytosis and leading to the quick removal of transfused pRBCs ( 35 ). Our hypothesis was supported by the hemolysis results obtained using previously sensitized monkey sera containing anti-pig cell antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…Our data highlight the improved protection of QKO pRBCs and hCD55 expression on pRBCs with sensitized monkey sera, indicating that there is room for further improving pRBCs for transfusion through the appropriate design of genetic modifications. It is expected that gene modifications, including the insertion of human complement regulatory genes CD55 and CD59, as well as the anti-phagocytosis gene CD47, in TKO or QKO pigs may further improve the survival of pRBCs in the circulation of human and nonhuman primates ( 35 ). However, further research is required to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

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Initial investigation on the feasibility of porcine red blood cells from genetically modified pigs as an alternative to human red blood cells for transfusion

Park,

Lee,

Park

et al. 2023

Front. Immunol.

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The decline in blood donation rates and the ongoing shortage of blood products pose significant challenges to medical societies. One potential solution is to use porcine red blood cells (pRBCs) from genetically modified pigs as an alternative to human red blood cells (hRBCs). However, adverse immunological reactions remain a significant obstacle to their use. This study aimed to evaluate the compatibility of diverse genetically modified pRBCs with human serum. We acquired human complement-competent serum, complement 7 (C7)-deficient serum, and hRBCs from all ABO blood types. Additionally, we used leftover clinical samples from health checkups for further evaluation. pRBCs were collected from wild-type (WT) and genetically modified pigs: triple knockout (TKO), quadruple KO (QKO), and TKO/hCD55.hCD39 knockin (hCD55.hCD39KI). The extent of C3 deposition on RBCs was measured using flow cytometry after incubation in C7-deficient serum diluted in Ca++-enriched or Ca++-depleted and Mg++-enriched buffers. The binding of immunoglobulin (Ig) M/IgG antibody to RBCs after incubation in ABO-type human serum was evaluated using flow cytometry. Naïve human serum- or sensitized monkey serum-mediated hemolysis was also evaluated. Phagocytosis was assessed by incubating labeled RBCs with the human monocytic cell line THP-1 and measurement by flow cytometry. All three genetic modifications significantly improved the compatibility of pRBCs with human serum relative to that of WT pRBCs. The extent of IgM/IgG binding to genetically modified pRBCs was lower than that of WT pRBCs and similar to that of O-type hRBCs. Total and alternative pathway complement activation in all three genetically modified pRBCs was significantly weaker than that in WT pRBCs and did not differ from that in O-type hRBCs. The extent of serum-mediated hemolysis and phagocytosis of these genetically modified pRBCs was low and similar to that of O-type hRBCs. Sensitized monkey serum-mediated hemolysis in QKO and TKO/hCD55.hCD39KI pRBCs was higher than in O-type hRBCs but lower than in TKO pRBCs. The elimination of porcine carbohydrate antigens in genetically modified pigs significantly enhanced pRBC compatibility with naïve human sera, which was comparable to that of O-type hRBCs. These findings provide valuable insights into the development of pRBCs as potential alternatives to hRBCs.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Initial investigation on the feasibility of porcine red blood cells from genetically modified pigs as an alternative to human red blood cells for transfusion

Park,

Lee,

Park

et al. 2023

Front. Immunol.

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“…To address this issue, studies are being conducted to develop alternatives to traditional blood transfusions, including blood substitutes and animal blood ( 2 ). Historically, xenogeneic blood transfusions were practiced but abandoned due to the higher risks compared to allogeneic transfusions ( 3 ). There is also a lack of modern scientific evaluation of their safety and efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…To prevent the potential risk of blood shortage, researchers are developing alternative products or technologies to replace human blood for transfusion ( 2 ). Porcine red blood cells (pRBCs) are a potential alternative to human RBCs (hRBCs) for transfusion ( 3 ). Transfusion of animal blood is not a new concept; it was attempted in the past, and its potential value was recognized in emergencies with acute hemorrhage until the 19 th century ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the efficacy and safety of wild- type and triple-gene knockout pig RBC transfusions in nonhuman primates

Roh,

Hwang,

Park

et al. 2024

Front. Immunol.

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IntroductionDecreasing rates of blood donation and close margins between blood supply and demand pose challenges in healthcare. Genetically engineered pig red blood cells (pRBCs) have been explored as alternatives to human RBCs for transfusion, and triple-gene knockout (TKO) modification improves the compatibility of pRBCs with human blood in vitro. In this study, we assessed the efficacy and risks of transfusing wild-type (WT)- and TKO-pRBCs into nonhuman primates (NHPs).MethodsBlood from O-type WT and TKO pigs was processed to produce pRBCs for transfusion, which were transfused or not into NHPs (n=4 per group: WT, TKO, and control) after 25% total blood volume withdrawal: their biological responses were compared. Hematological, biochemical, and immunological parameters were measured before, immediately after, and at intervals following transfusion. Two months later, a second transfusion was performed in three NHPs of the transfusion group.ResultsTransfusion of both WT- and TKO-pRBCs significantly improved RBC counts, hematocrit, and hemoglobin levels up to the first day post-transfusion, compared to the controls. The transfusion groups showed instant complement activation and rapid elicitation of anti-pig antibodies, as well as elevated liver enzyme and bilirubin levels post-transfusion. Despite the higher agglutination titers with WT-pRBCs in the pre-transfusion crossmatch, the differences between the WT and TKO groups were not remarkable except for less impairment of liver function in the TKO group. After the second transfusion, more pronounced adverse responses without any hematological gain were observed.ConclusionsWT- and TKO-pRBC transfusions effectively increased hematologic parameters on the first day, with rapid clearance from circulation thereafter. However, pRBC transfusion triggers strong antibody responses, limiting the benefits of the pRBC transfusion and increasing the risk of adverse reactions.

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ABO blood groups and galectins: Implications in transfusion medicine and innate immunity

Arthur,

Hollenhorst,

et al. 2024

Seminars in Immunology

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Future prospects for the clinical transfusion of pig red blood cells

Cited by 3 publications

References 98 publications

Initial investigation on the feasibility of porcine red blood cells from genetically modified pigs as an alternative to human red blood cells for transfusion

Initial investigation on the feasibility of porcine red blood cells from genetically modified pigs as an alternative to human red blood cells for transfusion

Investigation of the efficacy and safety of wild- type and triple-gene knockout pig RBC transfusions in nonhuman primates

ABO blood groups and galectins: Implications in transfusion medicine and innate immunity

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