What Have We Learned From In Vitro Studies About Pig-to-primate Organ Transplantation?

Area of Science:

• Immunology
• Xenotransplantation
• Transplantation immunology

Background:

• Natural antibodies against pig antigens are a primary barrier to successful pig xenograft transplantation in nonhuman primates (NHPs).
• In vivo studies are time-intensive, necessitating efficient in vitro methods for evaluating xenograft compatibility.

Purpose of the Study:

• To summarize findings from in vitro assays investigating antibody responses to pig cells in humans and NHPs.
• To identify optimal pig models and assess factors influencing xenograft rejection.

Main Methods:

• Utilized in vitro antibody binding and complement-dependent cytotoxicity assays.
• Analyzed antibody responses in humans and NHPs to wild-type and genetically modified pig cells (e.g., triple-knockout [TKO]).

Main Results:

• Humans develop minimal antibodies to TKO pig cells, suggesting suitability for xenotransplantation, especially with human protective proteins.
• Old World NHPs develop antibodies to TKO pig cells, making galactosyltransferase gene-knockout/β4GalNT2KO pigs a preferred alternative.
• Immunoglobulin M (IgM) binding correlates with complement-mediated injury, while the roles of IgE and IgA require further investigation.

Conclusions:

• In vitro assays effectively predict xenograft rejection outcomes, guiding the selection of appropriate pig models.
• Genetically engineered pigs (TKO, β4GalNT2KO) demonstrate reduced immunogenicity, enhancing the potential for successful xenotransplantation.
• Understanding antibody profiles in potential recipients is crucial for mitigating xenograft rejection.