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Does expression of a human complement-regulatory protein on xenograft cells protect them from systemic complement
Abhijit Jagdale1, Huy Nguyen1, Juan Li2
1Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
International Journal of Surgery (London, England)
|September 28, 2020
Summary
Human CD46 expression on pig cells significantly reduced complement-mediated damage, offering protection against xenograft rejection. This study demonstrates the efficacy of genetic modification in preventing xenograft injury from systemic complement activation.
Area of Science:
- Xenotransplantation research
- Immunology
- Genetic engineering
Background:
- Systemic complement activation poses a significant risk to pig xenografts.
- Human complement-regulatory proteins (hCRPs) like hCD46 offer partial protection.
- The protective effect of hCD46 against systemic complement activation in xenografts remains unclear.
Purpose of the Study:
- To evaluate the protective effect of hCD46 expression on pig aortic endothelial cells (pAECs) against systemic complement activation.
- To determine if hCD46-expressing pAECs are protected from complement-mediated injury.
- To assess the impact of complement activation on wild-type (WT), gene-knockout (GTKO), and GTKO/hCD46 pAECs.
Main Methods:
- Pig aortic endothelial cells (pAECs) from WT, GTKO, and GTKO/hCD46 pigs were incubated with human serum.
- Cells were labeled with CFSE and incubated with rabbit complement.
- Complement-dependent cytotoxicity was quantified using flow cytometry.
Main Results:
- GTKO/hCD46 pAECs showed significantly reduced lysis (6%) compared to WT (91%) and GTKO (32%) pAECs when exposed to human serum.
- Co-incubation with WT pAECs increased lysis of GTKO pAECs but did not affect GTKO/hCD46 pAECs.
- These findings indicate that hCD46 effectively protects pAECs from complement-mediated damage.
Conclusions:
- Transgenic expression of human CD46 confers significant protection to pig aortic endothelial cells against systemic complement activation.
- hCD46 is a promising therapeutic target for mitigating hyperacute rejection in pig-to-human xenotransplantation.
- Further research is warranted to explore the full potential of hCD46 in enhancing xenograft survival.
