Anti-ICAM-1 mono-maintenance therapy induced long-term liver allograft survival without chronic rejection

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 mono-maintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n=4) received steroid, tacrolimus, and sirolimus by 4 months post-transplantation. The induction MD3 group (IN-MD3, n=5) received short-term MD3 therapy for 3 months with conventional immunosuppression. The maintenance MD3 group (MA-MD3, n=4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T-cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 mono-maintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.