Outcomes of alpha 1,3-GT-knockout porcine heart transplants into a preclinical nonhuman primate model

Transplant Proc. 2013 Oct;45(8):3085-91. doi: 10.1016/j.transproceed.2013.08.049.

Abstract

Background: Solid organ xenotransplantation is a potential solution to current organ shortages in allotransplantation. We performed four heart transplantations from alpha1, 3-galactosyltransferase gene-knockout (GT-KO) pigs to cynomolgus monkeys and monitored immunological parameters before and after transplantation.

Methods: After blood typing of the cynomolgus monkeys, we assessed the binding activity of immunoglobulin G (IgG) and IgM of monkey serum and serum toxicity toward porcine peripheral blood mononuclear cells (PBMCs) using flow cytometry. Immunosuppressive protocols consisted of anti-thymocyte globulin (25 mg/kg), rituximab (20 mg/kg), anti-CD154mAb (20 mg/kg), cobra venom factor (0.05 mg/kg), tacrolimus, and steroid. Cynomolgus monkeys with A or AB blood type with the lowest antibody binding and serum toxicity activity on porcine PBMCs were selected as recipients.

Results: Absolute numbers of CD3(+) T cells, CD20(+) B cells, and CD3(+)CD95(+) memory T cells in the peripheral blood were suppressed upto 24 days after transplantation. Interferon gamma production of T cells in response to porcine antigens were also significantly suppressed. Heart xenografts from GT-KO pigs survived for upto 24 days without pathologic evidence of rejection.

Conclusion: We successfully performed 4 heart xenotransplantations using GT-KO pigs. We overcame hyperacute rejection by using GT-KO pigs, and all of the heart xenografts from the GT-KO pigs survived between 11 and 24 days without pathologic evidence of rejection, disseminated intravascular coagulation, or consumptive coagulopathy; however, we need to optimize protocols for immune modulation and postoperative care to attain long-term survival of solid organ xenografts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Galactosyltransferases / genetics*
  • Gene Knockdown Techniques
  • Graft Survival
  • Heart Transplantation*
  • Immunosuppressive Agents / administration & dosage
  • Macaca fascicularis
  • Swine

Substances

  • Immunosuppressive Agents
  • Galactosyltransferases