Advantage of tacrolimus/mycophenolate mofetil regimen for cytotoxic T cell-mediated defence and its inhibition by additive steroid administration in high-risk liver transplant recipients

Our previous work revealed that the recipients with the highest pre-existing numbers of CD8(+) effector T cells (T-E) [hyperparathyroidism (HPT)(E) recipients] occupied approximately 30% of adult transplant recipients performed in our hospital. HPTE recipients demonstrated very poor clinical outcome compared with the remaining 70% of recipients with the lowest pre-existing T-E (LPTE recipient). This study aimed to clarify the best combined immunosuppressive regimen related to function of cytotoxic T lymphocytes (CTLs) for HPTE recipients. Eighty-one HPTE recipients were classified into three types, according to the immunosuppressive regimens: type 1, tacrolimus (Tac)/glucocorticoid (GC); type 2, Tac/mycophenolate mofetil (MMF)/GC; and type 3, Tac/MMF. Frequencies of severe infection, rejection and hospital death were the highest in types 1 and 2, whereas the lowest occurred in type 3. The survival rate in type 3 was the highest (100%) during follow-up until post-operative day 2000. Regarding the immunological mechanism, in type 1 T-E perforin and interferon (IFN)- were generated through the self-renewal of CD8(+) central memory T cells (T-CM), but decreased in the early post-transplant period due to marked down-regulation of interleukin (IL)-12 receptor beta-1 of T-CM. In type 2, the self-renewal T-CM did not develop, and the effector function could not be increased. In type 3, in contrast, the effectors and cytotoxicity were correlated inversely with IL-12R1(+) T-CM levels, and increased at the highest level around the pre-transplant levels of IL-12R1(+) T-CM. However, the immunological advantage of Tac/MMF therapy was inhibited strongly by additive steroid administration.