PREDOMINANT TH1 CELL INFILTRATION IN ACUTE REJECTION EPISODES OF HUMAN KIDNEY GRAFTS

T-cells and their cytokines are thought to play a major role in the ge nesis of cellular infiltration and rejection in human kidney allograft s. Production of Th1 (IFN-gamma) and Th2-type (IL-4 and IL-5) cytokine s was assessed in a large series of T-cell clones, derived from core b iopsies of kidney grafts in 10 patients with acute interstitial grade VII rejection (AIR), 6 patients with a histology of ''borderline rejec tion'' (BLR) and 3 with cyclosporine A (CsA) toxicity, all receiving s tandard maintenance immunosuppression. Biopsies were pre-cultured in I L-2 in order to preferentially expand T-cells activated in vitro, and T-cell blasts were cloned with phytohemaglutinin (PHA) and IL-2 using a highly efficient (23 to 98%) cloning technique. A total of 483 T-cel l clones obtained from AIR episodes were compared with 346 and 132 clo nes derived from patients with BLR episodes and CsA toxicity, respecti vely. In two series of 22 AIR and 77 BLR T-cell clones, alloreactivity against donor cells was shown by 25 and 14% of CD8(+) and 21 and 4% o f CD4(+) clones, respectively. When stimulated by donor-derived EBV B- cells, all these alloreactive clones produced IFN-gamma, but not IL-4 or IL-5 (Th1 clones). Upon stimulation with PHA, the principal qualita tive and quantitative differences between AIR- and BLR-derived T-cell clones were that cells derived from AIR patients: (i) showed significa ntly higher proportions (80 +/- 15 vs. 55 +/- 13%) of Th1 clones in th eir progeny; (ii) included smaller proportions (3 +/- 4 vs. 20 +/- 17% ) of clones incapable of producing IFN-gamma, IL-4 or IL-5 ('null' clo nes); and (iii) produced significantly higher quantities of IFN-gamma (100 +/- 50 vs. 36 +/- 7 U/10(6) cells/ml), these quantities also bein g significantly correlated (r = 0.83) with the degree of interstitial graft infiltration (item 'i' in the Banff histological grading). The c lones derived from CsA toxicity biopsies exhibited a pattern very simi lar to that found in BLR cases. These data lead us to conclude that th e powerful inflammatory response elicited in acute rejection of a kidn ey graft recruits and activates both allospecific and non-specific Th1 effector cells, which are primed to high IFN-gamma production. Our re sults also suggest that IFN-gamma could contribute, at least in part, to the degree of graft infiltration and to the severity of the rejecti on episode.