MOLECULAR EXECUTORS OF CELL-DEATH DIFFERENTIAL INTRARENAL EXPRESSION OF FAS LIGAND, FAS, GRANZYME-B, AND PERFORIN DURING ACUTE AND OR CHRONIC REJECTION OF HUMAN RENAL-ALLOGRAFTS/

Two distinct cytolytic pathways have been characterized: one in which the interaction between the Fas antigen and its ligand results in apop tosis, and another in which the pore forming protein perforin and the serine protease granzyme B contribute to DNA fragmentation and cell de ath. We investigated intrarenal expression of these molecular executor s of cell death in light of the potential participation of cytolytical ly active cellular elements in the antiallograft repertory. Reverse tr anscriptase-polymerase chain reaction was used to identify intrarenal expression of Fas antigen, Fas ligand, granzyme B and perforin in eigh ty human renal allograft biopsies; mRNA display was correlated with th e Banff histological diagnosis of renal allografts. Our studies demons trate that: (1) intrarenal expression of Fas ligand mRNA and of granzy me B mRNA are correlates of acute but not chronic rejection ; (2) Fas ligand mRNA is not detectable in allografts in the absence of rejectio n; (3) intrarenal coexpression of members of each lytic pathway (Fas l igand and Fas, granzyme B, and perforin) and that both pathways (e.g., Fas ligand and granzyme B) are correlates of acute rejection; and (4) a direct correlation exists between the histological severity of acut e rejection and intrarenal coexpression of mRNA encoding Fas ligand, F as, granzyme B, and perforin. Our studies identify, for the first time , the differential expression of the two major lytic pathways in acute and chronic allograft rejection and suggest that specific therapy dir ected at the cytotoxic attack molecules might be efficacious in the pr evention and/or treatment of acute rejection.