IMMUNE MECHANISMS IN ORGAN ALLOGRAFT REJECTION

Abstract

The cellular requirements for renal allograft rejection were assessed by adoptive transfer studies in a rat model. Sublethally irradiated (780 rad) LEW (RTI1) recipients of WF (RT1u) renal allografts were selectively reconstituted with spleen cells from specifically sensitized donors. In some experiments the reconstituting inocula were depleted of SIg+ [surface Ig+] cells by passage over anti-Ig columns or subjected to additional depletion of cytotoxic T cells (Tc) and their precursors reactive with monoclonal antibody OX8. WF renal allografts underwent acute rejection in the unmodified LEW recipient with day 7 serum creatinines of 6.8 .+-. 0.9 mg/dl (mean .+-. SD; n = 7), graft histology characterized by marked mononuclear cell infiltration and evidence of a brisk humoral response (complement-dependent cytotoxicity (CDC) titer > 26) and generation of Tc demonstrable by in vitro monitoring. Sublethally irradiated recipients mounted no detectable immune response, and day 7 serum creatinine and graft histological findings were not significantly different from those obtained in isograft controls. Renal allografts were rejected in sublethally irradiated recipients reconstituted with unfractionated immune spleen cells, as evidenced by functional and histologic criteria (day 7 serum creatinine of 5.5 .+-. 1.2 mg/dl; histology characterized by extensive interstitial hemorrhage, fibrinoid necrosis of blood vessels and polymorphic infiltration). Neither antibody nor Tc appear, in this model, to be required to effect rejection, because recipients reconstituted with inocula depleted of SIg+ cells (day 7 CDC titer < 21) or subjected to additional depletion of Tc and their precursors (day 7 lymphocyte-mediated cytotoxicity assay: % specific Cr release at 100/1 E/T [effector/target cell] ratios < 5%) underwent acute rejection with a day 7 serum creatinine of 5.0 .+-. 1 and 4.3 .+-. 1.5 mg/dl, respectively, and histological findings were characterized by marked mononuclear cell infiltration and a paucity of hemorrhage.