Procedures to diagnose renal allograft rejection depend upon detection of graft dysfunction and the presence of a mononuclear leukocytic infiltrate; however, the presence of a modest cellular infiltrate is often not conclusive and can be detected in non-rejecting grafts. We have pursued a molecular approach utilizing reverse transcription (

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There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process.

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in gthe NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n=47) and validated on independent test-set (n=198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

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Abstract. Recent evidence suggests that a population of professional regulatory cells, which limit immune responsiveness, exist in rodents and healthy human subjects. However, their role in disease states remains unclear. A proportion of renal transplant recipients do not demonstrate in vitro reactivity toward their mismatched donor-derived HLA-DR antigens; it was therefore hypothesized that this may be due to such regulatory cells. A cohort of 23 renal transplant recipients was studied at a single institution. In patients with no history of acute rejection, 6 (40%) of 15 demonstrated regulation toward the mismatched HLA-DR allopeptides by CD25 ϩ cells. By contrast, only one (12.5%) in eight of those with a history of acute rejection demonstrated regulation. Interestingly, if the patient assays were stratified according to initial in vitro immune responsiveness toward the mismatched allopeptides, 8 (47.1%) of 17 of patient assays with low allopeptide responsiveness (alloreactive T cell frequencies less than 60/million) demonstrated regulation of indirect pathway alloresponses by CD25 ϩ cells, whereas 0 of 8 with higher responses (frequencies greater than 60/million) demonstrated no such regulation (P Ͻ 0.05 by 2 test). The regulatory cells are present in the circulation as early as 3 mo after transplantation and persist for a number of years, despite conventional immunosuppression.