DELAYED-TYPE HYPERSENSITIVITY-LIKE MECHANISMS DOMINATE LATE ACUTE REJECTION EPISODES IN RENAL-ALLOGRAFT RECIPIENTS

Episodes of acute rejection (aRx) may occur in functional renal allogr afts even at a very late stage post-Tx, Histopathology in early and la te aRx looks quite similar-however, there is a slower deterioration of graft function in late aRx, suggesting that pathogenetic immune mecha nisms are different. In order to investigate this phenomenon we studie d the gene expression pattern (IL-1 beta, 2, 4, 8, 10, IFN gamma, TNF alpha, GrnA, IL-2R p55/p75) in PBMC and core biopsies from long-term r enal allograft recipients with histologically proven late aRx and comp ared it with transplant and nontransplant controls using a semiquantit ative RT-PCR technique, PBMC and graft-infiltrating cells of patients with late aRx showed an upregulation, especially of IFN-gamma, IL-4, I L-10, and TNF alpha transcripts. While IL-2 mRNA was only detected in PBMC of two patients with late aRx who were not on cyclosporine, upreg ulation of intragraft IL-2 mRNA allowed the best discrimination betwee n aRx and the other groups (sensitivity: 83%, specificity: 93%). In co ntrast to several reports on early Rx we did not notice an elevation o f granzyme A transcripts in comparison with the controls, suggesting t hat cell-mediated inflammatory processes (CD 4+ T cell-mediated DTH) d ominate the late aRx, while early aRx is characterized by the addition al involvement of cytotoxic T cell response, This may explain the dist inct clinical course. Additionally, in a pilot study we successfully t reated late aRx in 10/12 patients with the anti-CD 4 mAb, 16H5, Our en couraging therapeutic results underline the pathogenetic role of CD 4 T cells and support our hypothesis on DTH-like mechanisms in late aRx .