Transient-mixed Chimerism With Nonmyeloablative Conditioning Does Not Induce Liver Allograft Tolerance in Nonhuman...

Area of Science:

• Transplantation immunology
• Immunosuppression and tolerance induction

Background:

• Liver transplant survival is limited by immunosuppression complications.
• Achieving rapid tolerance post-transplant could improve outcomes.
• Transient donor chimerism induces tolerance in kidney, but not other organs.

Purpose of the Study:

• To test if a transient donor chimerism protocol used for kidney transplants could induce liver tolerance.
• To investigate the feasibility of inducing liver tolerance using established protocols for renal transplants.

Main Methods:

• Seven cynomolgus macaques underwent immune conditioning and simultaneous donor bone marrow and liver transplantation.
• Immunosuppression was withdrawn on postoperative day 28.
• Chimerism, immune reconstitution, liver function, and graft survival were monitored.

Main Results:

• Liver transplant recipients showed chimerism levels comparable to kidney transplant models.
• The liver was rejected shortly after immunosuppression withdrawal.
• Rejection involved increased CD8 T effector cells, elevated IL-6 and IL-2, and anti-donor antibodies, without increased regulatory T cells.

Conclusions:

• The transient chimerism protocol failed to induce liver tolerance.
• Greater CD8 T cell responses compared to kidney models likely explain the lack of tolerance.
• Enhanced control or deletion of CD8 T cells may be necessary for successful liver tolerance induction.