EVIDENCE THAT IMPROVED LATE RENAL-TRANSPLANT OUTCOME CORRELATES WITH THE DEVELOPMENT OF INVITRO DONOR ANTIGEN-SPECIFIC HYPOREACTIVITY

Previous studies suggest stable renal transplant recipients can have e ither prednisone (P) or cyclosporine withdrawn; however, 30% of these patients undergo rejection requiring reinstitution of P or CsA. Some p atients return to baseline creatinine levels, while others either stab ilize at a higher creatinine level or lose their graft. It would be id eal to establish immunologically based criteria for selecting patients who can be successfully withdrawn or tapered from immunosuppression. We have investigated the development of donor antigen-specific hyporea ctivity by using donor cells and/or homozygous typing cells defining t he HLA-Dw specificities of the donor cells as stimulator cells in the mixed lymphocyte culture (MLC) and comparing the pre- and posttranspla nt responses of peripheral blood mononuclear cells from 199 kidney tra nsplant recipients. Of these, 27% of the haploidentical living-related donor and 25% of the cadaver recipients developed in vitro donor anti gen-specific hyporeactivity. The LRD recipients who did so have lower mean creatinine levels at 6, 12, and 24 months posttransplant (1.3, 1. 3, and 1.2, respectively) than those who remained responsive to the do nor antigens (1.6, 1.7, and 1.8) (P<0.05). However, no differences in the mean creatinine levels were observed between CAD recipients who de veloped donor antigen-specific hyporeactivity and those who remained r esponsive. Rejection episodes were common in all groups in the first 3 months posttransplant; however, recipients who developed donor antige n-specific hyporeactivity tended to experience fewer rejection episode s after 3 months posttransplant. The percentage of recipients who rema ined rejection-free after 3 months posttransplant was 95% for CAD reci pients who developed donor antigen-specific hyporeactivity vs. 83% for those who remained responsive. Only 1 hyporesponsive recipient (0/15 LRD; 1/20 CAD) developed chronic rejection vs. 12 (5/41, LRD; 7/60, CA D) recipients who remained responsive. For those with graft function a t 3 months (when hyporesponsiveness was first determined), the actuari al 36-month graft survival was higher in the hyporesponsive (92%, LRD; 94%, CAD) than in responsive groups (LRD, 76%; CAD, 91%). No differen ces in the degree of HLA-DR mismatching (MM) were observed for the LRD hyporesponsive (1.20 DR MM) vs. reactive (0.98 DR MM) groups or for t he CAD hyporesponsive (1.35 DR MM) vs. reactive (1.30 DR MM) groups. D onor antigen-specific hyporeactivity could not be determined (UND) for 30 of the LRD recipients and 33 of the CAD recipients due to lack of mismatching for DR antigens (0.03 DR MM and 0.25 DR MM, respectively). Although these groups of recipients were well matched for HLA-DR anti gens, the number of late rejection episodes, incidence of chronic reje ction, mean creatinine values, and graft survival were comparable to t hose who remained reactive to the donor disparate antigens. We conclud e that immune regulation-as evidenced by the development of donor anti gen-specific hyporeactivity-correlates with improved graft outcome and may permit lower immunosuppression.