Pig-to-human kidney xenotransplants using genetically modified minipigs

Area of Science:

• Transplantation immunology
• Xenotransplantation research
• Gene editing in xenografts

Background:

• Kidney xenotransplantation offers a potential solution to organ shortages.
• Genetic modification of donor organs is crucial for reducing immune rejection.
• Understanding immune responses in human recipients is vital for xenograft survival.

Purpose of the Study:

• To develop an observational model for assessing kidney function recovery in human xenotransplantation.
• To evaluate xenogeneic immune responses, including T-cell and antibody-mediated rejection.
• To investigate the impact of gene editing and immunosuppression strategies in a human xenograft model.

Main Methods:

• Two brain-dead patients received kidney xenotransplants from genetically modified minipigs (triple-gene knockouts with human gene transfers).
• Immunosuppression protocols were administered, with and without CD40-CD154 pathway blockade.
• Sequential xenograft biopsies were analyzed to assess cellular infiltration and pathology; viral testing was performed.

Main Results:

• Initial restoration of renal xenograft function was observed.
• Acute rejection occurred by day 12 in the absence of CD40-CD154 pathway blockade, involving T-cell and antibody-mediated rejection (AMR).
• Porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) reactivation was detected, contributing to immunopathological changes.

Conclusions:

• Effective immunosuppression, including specific pathway blockade, is critical for preventing acute rejection in kidney xenotransplantation.
• Viral reactivation in xenografts poses a significant challenge and can exacerbate immune responses.
• Extended clinical observation in deceased human models is essential for advancing xenograft success and safety.