Delayed Donor Bone Marrow Infusion Induces Liver Transplant Tolerance

Area of Science:

• Immunology
• Transplantation Biology
• Regenerative Medicine

Background:

• Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) for tolerance induction in liver transplantation (LT) lacks robust testing and may pose safety risks.
• The study investigates the efficacy and safety of T cell-depleted BMI when administered after LT to establish tolerance.

Purpose of the Study:

• To evaluate the effectiveness of delayed T cell-depleted bone marrow infusion (BMI) in inducing donor-specific tolerance after liver transplantation (LT).
• To assess the safety and potential clinical applicability of this delayed BMI strategy in LT recipients.

Main Methods:

• Allogeneic rat LT models were established, with control groups and experimental groups receiving tacrolimus (TAC) for 3-4 weeks.
• Experimental groups underwent either TAC withdrawal alone, nonmyeloablative conditioning (anti-αβTCR mAb + TBI) followed by TAC withdrawal, or nonmyeloablative conditioning plus T cell-depleted donor BMI before TAC withdrawal.

Main Results:

• TAC withdrawal alone led to chronic rejection.
• Nonmyeloablative conditioning alone resulted in long-term survival but impaired liver function and high donor-specific antibody (DSA) levels.
• The combination of conditioning and delayed BMI achieved long-term, drug-free survival with preserved liver function, high mixed chimerism, regulatory T cells, and low DSA titers, without graft-versus-host disease.

Conclusions:

• Delayed T cell-depleted BMI following LT can successfully induce donor-specific tolerance.
• This tolerance is associated with increased mixed chimerism, generation of regulatory T cells, and a decrease in DSA.
• The findings support the potential for safer clinical application of delayed BMI in liver transplantation.