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Pig-to-monkey islet xenotransplantation using multi-transgenic pigs
R Bottino1, M Wijkstrom, D J van der Windt
1Division of Immunogenetics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA.
Summary
Genetically engineered pig islets showed reduced early destruction in xenotransplantation models. However, long-term graft function remained inconsistent, highlighting challenges in achieving sustained success for diabetes treatment.
Area of Science:
- Xenotransplantation research
- Genetic engineering in preclinical models
- Immunology and transplant science
Background:
- Xenotransplantation, using animal organs or cells in humans, faces significant immunological barriers.
- Genetic modification of donor animals is crucial for overcoming xenograft rejection.
- Pig islets are a promising source for islet transplantation to treat diabetes.
Purpose of the Study:
- To assess the efficacy of multi-genetically modified pig islets in a non-human primate model.
- To evaluate the impact of specific genetic modifications on early islet survival and long-term function.
- To compare outcomes with historical control groups receiving islets with fewer genetic modifications.
Main Methods:
- Generation of pigs with multiple genetic modifications including human CD46, TFPI, CD39, and CTLA4-Ig.
- Intraportal transplantation of isolated pig islets into streptozotocin-diabetic, immunosuppressed cynomolgus monkeys.
- Immunosuppression regimen involving anti-CD154 mAb costimulation blockade.
- Monitoring of islet destruction, glycemic control, insulin requirements, and histopathology.
Main Results:
- Transplantation of multi-transgenic pig islets demonstrated reduced early islet destruction compared to controls.
- Early graft survival showed improvement in the first hours post-transplantation.
- Long-term graft function was inconsistent, with only 2 out of 5 recipients showing function beyond 5 months.
Conclusions:
- Multi-genetic modification of pig islets can mitigate early xenograft destruction.
- Significant challenges remain in achieving consistent long-term graft function for xenotransplantation.
- Further research is needed to optimize genetic modifications and immunosuppression for successful xenotransplantation.
