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In this report of our 3-yr protocol biopsy program, we describe the evolution of acute rejection (AR) and chronic renal allograft nephropathy (CAN) in a cohort of 21 children treated with antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. The aims of this study were to compare the pathogenicity of clinical acute rejection (CAR) and subclinical acute rejection (SAR), and to determine whether functional studies accurately represent acute and chronic renal allograft pathology in pediatric recipients with disproportionately large grafts. Using concurrent biopsies, we evaluated: (i) the utility of changes in the baseline sCr (DeltasCr) to predict both the onset of AR and the response to immunosuppressive therapy; and (ii) the relationship of the calculated creatinine clearance and the presence of pathologic proteinuria to the severity of CAN. We performed 112 biopsies: 11 donor, 73 protocol, 16 acute graft dysfunction and 12 1-month follow-up AR therapy. CAR and SAR were similar in incidence, timing and histologic severity. Progression of CAN was associated with the first episode of CAR (p < 0.02) and the cumulative number of episodes of CAR (p < 0.01), SAR (p < 0.05), CAR plus SAR (p < 0.002) and borderline SAR (B-SAR) (p < 0.006). One-month post-treatment DeltasCrs could not distinguish 1-month follow-up biopsies with histologically confirmed worsened or unchanged AR from those with improved histology (35.2 +/- 74.8% vs. 23.8 +/- 24.9%, p = NS). These findings led to the addition of anti-lymphocyte antibody therapy in five of 10 (50%) cases. Despite 100% 3-yr actuarial graft survival and excellent function (GFR = 111 +/- 36 mL/min/1.73 m(2)), 18 of 21 (86%) patients had grade I CAN or greater chronic histology at a mean +/- sd follow-up period of 18.2 +/- 13.1 months. Thirteen of 21 (62%) patients progressed to grade I CAN at 5.2 +/- 3.6 months and five (38%) of these patients progressed to grade II CAN at 17.8 +/- 11.3 months. Schwartz GFR did not differ between patients with or without CAN (108 +/- 38 mL/min/1.73 m(2) vs. 127 +/- 8 mL/min/1.73 m(2), p = NS). In biopsies with CAN and no associated AR, neither the Banff chronic tubulointerstitial (Banff ci) score nor the Banff chronic grade correlated with the GFR. Proteinuria was not associated with CAN. Clinical AR and SAR are similar histologic lesions with a capacity for CAN progression. In pediatric renal transplant recipients, longitudinal protocol biopsies are superior to functional studies for the diagnosis and post-therapeutic monitoring of AR and for the surveillance of CAN.

Gammadelta T cells have been implicated in the pathogenesis of acute graft-versus-host disease (GVHD). We therefore performed experiments to determine whether mortality from GVHD is reduced in C57BL/6 x DBA/2 F1-hybrid (BDF1-hybrid) mice when parental strain, T-cell receptor-delta (TCRdelta) knockout (KO) donors are used. We compared mortality, weight loss, interferon-gamma (IFN-gamma) production and cytotoxic activity in recipients of either wild-type or TCRdelta KO grafts. In both groups there was significant weight loss and an identical level of mortality. Elevated IFN-gamma levels were present in both groups, but recipients of TCRdelta KO grafts produced twice as much as recipients of wild-type grafts. Elevated natural killer (NK) and NK-like activity was also seen in both. These results demonstrate that TCRdelta KO grafts can induce GVHD as severe as that seen in recipients of wild-type grafts, a finding that is at odds with studies demonstrating reduced mortality when gammadelta T cells are purged from donor mice. We suggest that the inconsistency may lie in the higher levels of IFN-gamma seen with TCRdelta KO grafts and that the protection afforded by the absence of gammadelta T cells in the graft is overwhelmed by the higher levels of IFN-gamma.

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