Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function

Area of Science:

• Immunology
• Transplantation Biology
• Endocrinology

Background:

• Xenoislet transplantation faces challenges due to xenospecific immunity, hindering preclinical trial success.
• The galactose-α1,3-galactose (Gal) epitope is a known target in solid organ xenotransplantation, but its role in islet xenotransplantation is less clear.
• Understanding Gal-specific immunity is crucial for advancing xenoislet transplantation.

Purpose of the Study:

• To directly compare the immunogenicity, survival, and function of neonatal porcine islets (NPIs) from wild-type (WT) and Gal-deficient (GTKO) donors.
• To evaluate the impact of Gal epitopes on xenoislet transplant outcomes in a pig-to-primate model.

Main Methods:

• Neonatal porcine islets from WT and GTKO donors were transplanted into diabetic rhesus macaques.
• Recipient monitoring included blood glucose, transaminase levels, and serum xenoantibody levels.
• In vitro assays assessed antibody and complement binding to WT and GTKO NPIs.

Main Results:

• Four of five GTKO recipients achieved insulin-independent normoglycemia, compared to one of five WT recipients.
• WT islet transplantation led to significantly higher transaminase levels, indicating greater liver injury.
• WT NPIs showed increased susceptibility to antibody and complement-mediated destruction in vitro.

Conclusions:

• Gal epitopes are a significant factor influencing xenoislet transplant outcomes.
• Gal-deficient porcine islets demonstrate improved survival and function, leading to better glycemic control.
• Utilizing GTKO donors represents a critical advancement for more consistent and interpretable xenoislet transplantation studies.