Common Immunosuppressants Impair Recipient Immunity but Do Not Safeguard Donor Tissue-resident Immunity in Kidney Transplantation

Background. Immunosuppressive drugs have been used in transplantation for decades; however, their impact on donor and recipient leukocyte dynamics after transplantation have not been well defined. Methods. Murine mismatched kidney transplants were exposed to tacrolimus, mycophenolate, methylprednisolone, abatacept, and T-cell depletion therapy. Drug dosing was determined by pharmacokinetic analysis to mimic therapeutic levels of human kidney recipients. Donor and recipient leukocytes of 19 subsets, isolated from the graft and periphery after kidney transplantation in the presence of monotherapy or combination immunosuppression, were examined. Results. Immunosuppression significantly reduced recipient leukocyte infiltration into the graft. Additionally, methylprednisolone reduced peripheral leukocyte counts, while mycophenolate had a moderate effect. Tacrolimus was most immunosuppressive, reducing day 7 graft histological rejection scores, inducing changes in graft donor and recipient macrophage phenotypes, reducing T-cell co-inhibitory receptor and granzyme B expression, and peripheral leukocyte counts. Combination therapy with tacrolimus, mycophenolate, and methylprednisolone displayed an additive immunosuppressive effect. Despite these significant changes to recipient leukocyte immunity, the impact of conventional immunosuppressive agents on donor leukocyte retention was modest. Conclusions. These data confirm the critical importance of tacrolimus in preventing acute graft rejection. We demonstrate that conventional immunosuppressive strategies do not contribute to substantial donor leukocyte maintenance in grafted kidneys despite impairing recipient immunity, highlighting the need for alternative approaches to preserve beneficial donor immunity after kidney transplantation.